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Sample records for piperidines

  1. PIPERIDINE OLIGOMERS AND COMBINATORIAL LIBRARIES THEREOF

    DEFF Research Database (Denmark)

    1999-01-01

    The present invention relates to piperidine oligomers, methods for the preparation of piperidine oligomers and compound libraries thereof, and the use of piperidine oligomers as drug substances. The present invention also relates to the use of combinatorial libraries of piperidine oligomers...... in libraries (arrays) of compounds especially suitable for screening purposes....

  2. Piperidine alkaloids: human and food animal teratogens.

    Science.gov (United States)

    Green, Benedict T; Lee, Stephen T; Panter, Kip E; Brown, David R

    2012-06-01

    Piperidine alkaloids are acutely toxic to adult livestock species and produce musculoskeletal deformities in neonatal animals. These teratogenic effects include multiple congenital contracture (MCC) deformities and cleft palate in cattle, pigs, sheep, and goats. Poisonous plants containing teratogenic piperidine alkaloids include poison hemlock (Conium maculatum), lupine (Lupinus spp.), and tobacco (Nicotiana tabacum) [including wild tree tobacco (Nicotiana glauca)]. There is abundant epidemiological evidence in humans that link maternal tobacco use with a high incidence of oral clefting in newborns; this association may be partly attributable to the presence of piperidine alkaloids in tobacco products. In this review, we summarize the evidence for piperidine alkaloids that act as teratogens in livestock, piperidine alkaloid structure-activity relationships and their potential implications for human health.

  3. (Anthracen-9-yl(piperidin-1-ylmethanone

    Directory of Open Access Journals (Sweden)

    Hua-You Hu

    2008-11-01

    Full Text Available The title compound, C20H19NO, is a substructure of CP-640186, a potent inhibitor of mammalian acetyl-coenzyme A carboxylases. In the crystal structure, the amide group forms a dihedral angle of 87.0 (1° with the plane of the anthracene unit and the piperidine ring adopts a chair conformation. Molecules are arranged into layers parallel to (100 and adjacent anthracene units within layers form dihedral angles of 13.2 (1°. C—H...O interactions from the piperidine rings to the C=O group of the amide are observed between layers.

  4. Combinatorial Chemistry of Piperidine Based Carbohydrate Mimics

    DEFF Research Database (Denmark)

    Byrgesen, Elisabeth Vang; Nielsen, John; Willart, Marianne

    1997-01-01

    Piperidine carboxylic acids and 4-hydroxypiperidine-3-carboxylic acid, the latter obtained from bakers yeast reduction of the corresponding piperidone, were coupled in solid-phase synthesis to form simplified oligosaccharide analogues. A split-and-mix synthesis approach was used to create small c...

  5. Combinatorial Chemistry of Piperidine Based Carbohydrate Mimics

    DEFF Research Database (Denmark)

    Byrgesen, Elisabeth Vang; Nielsen, John; Willart, Marianne

    1997-01-01

    Piperidine carboxylic acids and 4-hydroxypiperidine-3-carboxylic acid, the latter obtained from bakers yeast reduction of the corresponding piperidone, were coupled in solid-phase synthesis to form simplified oligosaccharide analogues. A split-and-mix synthesis approach was used to create small c...

  6. [2-(Piperidin-1-ylethylamine]dithiocyanatozinc(II

    Directory of Open Access Journals (Sweden)

    Chen-Yi Wang

    2010-04-01

    Full Text Available In the mononuclear title compound, [Zn(NCS2(C7H16N2], the ZnII atom is four-coordinated by two N atoms of the chelating 2-(piperidin-1-ylethylamine ligand and two N atoms from two thiocyanate ligands in a distorted tetrahedral geometry. In the crystal structure, molecules are linked through intermolecular N—H...S hydrogen bonds, forming chains along the b axis.

  7. Piperidine Promoted Regioselective Synthesis of α, β-unsaturated Aldehydes

    Directory of Open Access Journals (Sweden)

    *A. H. Banday

    2013-03-01

    Full Text Available An efficient, facile and regioselective synthesis of α,β-unsaturated aldehydes from β-hydroxynitriles is reported. The reaction is carried out using DIBAL-H and promoted by piperidine under dry conditions at a temperature of -78 oC and can be described as a concomitant reduction-elimination reaction. The same reaction if carried out in the absence of piperidine gives mainly the uneliminated reduction product. The products formed are of immense importance as synthons in a large number of chemical reactions and biological processes.

  8. Potent pyrrolidine- and piperidine-based BACE-1 inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Iserloh, U.; Wu, Y.; Cumming, J.N.; Pan, J.; Wang, L.Y.; Stamford, A.W.; Kennedy, M.E.; Kuvelkar, R.; Chen, X.; Parker, E.M.; Strickland, C.; Voigt, J. (Schering-Plough)

    2008-08-18

    Based on lead compound 1 identified from the patent literature, we developed novel patentable BACE-1 inhibitors by introducing a cyclic amine scaffold. Extensive SAR studies on both pyrrolidines and piperidines ultimately led to inhibitor 2f, one of the most potent inhibitors synthesized to date. The discovery and development of novel BACE-1 inhibitors incorporating a cyclic amine scaffold is described.

  9. Synthesis of Substituted α-Trifluoromethyl Piperidinic Derivatives

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    Sarah Rioton

    2017-03-01

    Full Text Available A comprehensive survey of pathways leading to the generation of α-trifluoromethyl monocyclic piperidinic derivatives is provided (65 references. These compounds have been synthesized either from 6-membered rings e.g., pipecolic acid or lactam derivatives by introduction a trifluoromethyl group, from pyridine or pyridinone derivatives by reduction, and from 5-membered rings e.g., prolinol derivatives by ring expansion, from linear amines by cyclization or from dienes/dienophiles by [4 + 2]-cycloaddition.

  10. Halogenated naphthyl methoxy piperidines for mapping serotonin transporter sites

    Science.gov (United States)

    Goodman, M.M.; Faraj, B.

    1999-07-06

    Halogenated naphthyl methoxy piperidines having a strong affinity for the serotonin transporter are disclosed. Those compounds can be labeled with positron-emitting and/or gamma emitting halogen isotopes by a late step synthesis that maximizes the useable lifeterm of the label. The labeled compounds are useful for localizing serotonin transporter sites by positron emission tomography and/or single photon emission computed tomography.

  11. Synthesis and cytotoxic activity of some derivatives of alkyl piperidine.

    Science.gov (United States)

    Jahan, Sarwat; Akhtar, Shamim; Saify, Zafar Saied; Mushtaq, Nousheen; Sial, Ali Akbar; Kamil, Arfa; Arif, Muhammed

    2013-05-01

    Synthesis of novel phenacyl derivatives of alkyl piperidine as cytotoxic agents via simple and single step reaction procedure is going to be reported here. Twelve new compounds were successfully synthesized in moderate yield and in solid form. Their synthesis was confirmed by TLC, melting point, CHN analysis and through different spectral studies such as UV, IR, Mass and proton NMR. The advantages of this synthetic route are simple operation, mild reaction conditions and good yields. These newly synthesized derivatives were extensively explored for their cytotoxicity by brine shrimp lethality assay.

  12. Piperidine-based glycodendrons as protein N-glycan prosthetics.

    Science.gov (United States)

    Hudak, Jason E; Belardi, Brian; Appel, Mason J; Solania, Angelo; Robinson, Peter V; Bertozzi, Carolyn R

    2016-10-15

    The generation of homogeneously glycosylated proteins is essential for defining glycoform-specific activity and improving protein-based therapeutics. We present a novel glycodendron prosthetic which can be site-selectively appended to recombinant proteins to create 'N-glycosylated' glycoprotein mimics. Using computational modeling, we designed the dendrimer scaffold and protein attachment point to resemble the native N-glycan architecture. Three piperidine-melamine glycodendrimers were synthesized via a chemoenzymatic route and attached to human growth hormone and the Fc region of human IgG. These products represent a new class of engineered biosimilars bearing novel glycodendrimer structures.

  13. Synthesis, antioxidant and antimicrobial activity of novel vanillin derived piperidin-4-one oxime esters: preponderant role of the phenyl ester substituents on the piperidin-4-one oxime core.

    Science.gov (United States)

    Harini, Salakatte Thammaiah; Kumar, Honnaiah Vijay; Rangaswamy, Javarappa; Naik, Nagaraja

    2012-12-15

    The study has been achieved the efficient synthesis of vanillin derived piperidin-4-one oxime esters (5a-m) via four step reaction involved Mannich reaction of vanillin, acetone and ammonium acetate to obtain 2,6-bis(4-hydroxy-3-methoxyphenyl)-piperidin-4-one 2 followed by N-methylation and oximation. Further, to enhance the biological activity of vanillin derived piperidin-4-one oxime core, esterification of 4 with substituted benzoyl chlorides in the presence of strong organic base t-BuOK accomplished a series of vanillin derived piperidin-4-one oxime esters (5a-m). The synthesized analogues are screened for their antioxidant and antimicrobial studies and the preponderant effect of the phenyl ester substituents on the biological activity of piperidin-4-one oxime core was demonstrated. Among the tested compounds, 5i and 5j are emerged as outperformed antioxidants than standard Butylated hydroxy anisole (BHA) whereas, compounds 5b and 5d manifested potent antibacterial and antifungal activity than standard streptomycin and fluconazole respectively.

  14. 4-[(2-Hydroxy-1-naphthyl(piperidin-1-ylmethyl]benzonitrile

    Directory of Open Access Journals (Sweden)

    Yuan Zhang

    2009-09-01

    Full Text Available In the title compound, C23H22N2O, obtained from the condensation reaction of 4-formylbenzonitrile, 2-naphthol and piperidine, the dihedral angle between the naphthalene ring system and the benzene ring is 75.31 (4°. The piperidine ring adopts a chair conformation. The crystal structure is stabilized by intermolecular C—H...N hydrogen bonds, which link the molecules into centrosymmetric dimers. An intramolecular O—H...N hydrogen bond is also present.

  15. Trapping of carbolithiation-derived tertiary benzylic α-lithio piperidines with carbon electrophiles: Controlling the formation of α-amino quaternary and vicinal stereocenters.

    Science.gov (United States)

    Beng, Timothy K; Fox, Nathan; Bassler, Daniel P; Alwali, Amir; Sincavage, Kayla; Silaire, Ann Wens V

    2015-08-28

    The interception of carbolithiation-derived tertiary benzylic α-lithio piperidines with carbon electrophiles, under HMPA-mediated conditions, has led to the diastereoselective synthesis of vicinally functionalized piperidines bearing α-amino quaternary stereocenters.

  16. The metabolism of roxatidine acetate hydrochloride. Liberation of deuterium from the piperidine ring during hydroxylation.

    Science.gov (United States)

    Honma, S; Iwamura, S; Kobayashi, R; Kawabe, Y; Shibata, K

    1987-01-01

    The metabolism of roxatidine acetate hydrochloride (RA), a new histamine-2 receptor antagonist, was studied by GC/MS in rats and dogs in vivo. The co-administration of 14C-RA and RA-d10 labeled with deuterium in the piperidine ring expedited the isolation and identification of 15 urinary metabolites. The major metabolites in both animals were M-1, M-8, M-10, and M-11; M-4 could be found only in the rat. The aromatic and piperidine ring-hydroxylated metabolites were found in small amounts in both species. Following the administration of RA-d10 to rats and dogs, oxygenated metabolites on the piperidine ring, such as M-3 and M-4, were isolated and their analysis indicated the unexpected loss of three or four deuterium atoms from the ring. Also, first and second isotope effects were observed on the conversion rate in vivo and retention time in HPLC, respectively.

  17. Metabolism of roxatidine acetate hydrochloride. Liberation of deuterium from the piperidine ring during hydroxylation

    Energy Technology Data Exchange (ETDEWEB)

    Honma, S.; Iwamura, S.; Kobayashi, R.; Kawabe, Y.; Shibata, K.

    1987-07-01

    The metabolism of roxatidine acetate hydrochloride (RA), a new histamine-2 receptor antagonist, was studied by GC/MS in rats and dogs in vivo. The co-administration of /sup 14/C-RA and RA-d10 labeled with deuterium in the piperidine ring expedited the isolation and identification of 15 urinary metabolites. The major metabolites in both animals were M-1, M-8, M-10, and M-11; M-4 could be found only in the rat. The aromatic and piperidine ring-hydroxylated metabolites were found in small amounts in both species. Following the administration of RA-d10 to rats and dogs, oxygenated metabolites on the piperidine ring, such as M-3 and M-4, were isolated and their analysis indicated the unexpected loss of three or four deuterium atoms from the ring. Also, first and second isotope effects were observed on the conversion rate in vivo and retention time in HPLC, respectively.

  18. (3E,5E)-3,5-Bis(4-methyl­benzyl­idene)-1-[3-(piperidin-1-yl)propano­yl]piperidin-4-one

    Science.gov (United States)

    Kia, Yalda; Osman, Hasnah; Murugaiyah, Vikneswaran; Arshad, Suhana; Razak, Ibrahim Abdul

    2012-01-01

    In the title compound, C29H34N2O2, the central piperidine ring adopts a half-chair conformation, whereas the terminal one adopts a chair conformation. The mean plane of the central piperidine ring [maximum deviation = 0.384 (2) Å] makes dihedral angles of 64.82 (13) and 17.55 (13)° with the benzene rings. In the crystal, mol­ecules are linked into a tape along the b axis via C—H⋯O inter­actions, generating R 2 2(20) and R 2 1(6) graph-set motifs. C—H⋯π inter­actions are observed between the tapes. PMID:22904935

  19. Oxygenase-Catalyzed Desymmetrization of N,N-Dialkyl-piperidine-4-carboxylic Acids**

    Science.gov (United States)

    Rydzik, Anna M; Leung, Ivanhoe K H; Kochan, Grazyna T; McDonough, Michael A; Claridge, Timothy D W; Schofield, Christopher J

    2014-01-01

    γ-Butyrobetaine hydroxylase (BBOX) is a 2-oxoglutarate dependent oxygenase that catalyzes the final hydroxylation step in the biosynthesis of carnitine. BBOX was shown to catalyze the oxidative desymmetrization of achiral N,N-dialkyl piperidine-4-carboxylates to give products with two or three stereogenic centers. PMID:25164544

  20. Solid-phase polyamine synthesis using piperazine and piperidine building blocks

    DEFF Research Database (Denmark)

    Olsen, Christian A; Witt, Matthias; Jaroszewski, Jerzy W;

    2003-01-01

    [reaction: see text]. Polyamines containing piperidine and piperazine moieties have been synthesized on solid support using SN2 alkylation of resin-bound secondary amines with 2-nitrobenzenesulfonates (nosylates). The effect of solvent on this alkylation was investigated. The methodology was empl...

  1. Conformation of hindered piperidines: Spectroscopic evidence for contribution of boat conformations

    Indian Academy of Sciences (India)

    A Thangamani; J Jayabharathi; A Manimekalai

    2010-07-01

    High resolution 1H and 13C NMR resonance assignments and conformational assignments were carried out for four (3)-benzyl-(2),(6)-bis(aryl)piperidin-4-ones 1-4 and their four -nitroso-(3)-benzyl-(2),(6)-bis(aryl)piperidin-4-ones 5-8. In addition to conventional 1D NMR methods, 2D shiftcorrelated NMR techniques (1H-1H COSY and 1H-13C COSY) were used for signal assignments. At room temperature the (3)-benzyl-(2),(6)-bis(aryl)piperidin-4-ones 1-4 exist in only one isomeric form whereas their -nitroso derivatives 5-8 exist in two isomeric forms. The preferred conformations of both the isomeric forms of nitrosamines were determined by comparison of the spectral data with those of the corresponding parent amines 1-4 and with the aid of substituent parameters. The results indicate the presence of an equilibrium mixture of boat forms B1 and B2 for Z isomers of 5-8. For the E isomers of 5-8, boat form B1 is predicted to be the major conformer. The piperidin-4-ones 1-4 exist in normal chair conformations with equatorial orientations of all the substituents.

  2. 3-(Piperidin-1-yl-6-(1H-pyrazol-1-ylpyridazine

    Directory of Open Access Journals (Sweden)

    Abdul Qayyum Ather

    2010-06-01

    Full Text Available In the title compound, C12H15N5, the piperidine ring adopts a chair conformation with the substituent C atom in an equatorial site and the dihedral angle between the pyridazine and pyrazole ring planes is 10.36 (2°.

  3. Conformation-induced regioselective and divergent opening of epoxides by fluoride: facile access to hydroxylated fluoro-piperidines.

    Science.gov (United States)

    Yan, Nan; Fang, Zheng; Liu, Qing-Quan; Guo, Xiao-Hong; Hu, Xiang-Guo

    2016-04-01

    Utilizing molecular conformation as a controlling factor, epoxide-containing 2-aryl-piperidines can be ring-opened with the reagent combination of tetrabutylammonium fluoride (TBAF) and potassium bifluoride (KHF2) in a regioselective and divergent fashion. Four different types of hydroxylated fluoro-piperidines, valuable building blocks in drug development, were readily synthesized using this method. The basic nature of the reagent combination allowed a one-pot deprotection/ring opening process, which increased the efficacy of this transformation.

  4. Conformation equilibrium of 3-(hydroxymethyl)piperidine in solvents with different polarity

    Science.gov (United States)

    Korneichuk, A. Ya.; Senyavin, V. M.; Kuramshina, G. M.

    2017-02-01

    Quantum-chemical calculations of the 3-(hydroxymethyl)piperidine molecule conformers were performed at the B3LYP/6-31+G** level of theory, and four most stable conformations with different relative orientation of CH2OH and N-H groups were determined. The optimized structures, vibration frequencies, and band intensities in the spectra of the conformers were obtained. The conformational equilibria of the most stable rotational isomers in solvents of different polarity was studied within the polarizable continuum model. According to the results of calculations, the conformational equilibrium in solution is substantially changed on varying the solvent polarity. This conclusion was confirmed by comparison with IR absorption spectra of 3-(hydroxymethyl)piperidine solutions in carbon tetrachloride in the region of OH-stretchings.

  5. Exploring the 3-piperidin-4-yl-1H-indole scaffold as a novel antimalarial chemotype.

    Science.gov (United States)

    Santos, Sofia A; Lukens, Amanda K; Coelho, Lis; Nogueira, Fátima; Wirth, Dyann F; Mazitschek, Ralph; Moreira, Rui; Paulo, Alexandra

    2015-09-18

    A series of 3-piperidin-4-yl-1H-indoles with building block diversity was synthesized based on a hit derived from an HTS whole-cell screen against Plasmodium falciparum. Thirty-eight compounds were obtained following a three-step synthetic approach and evaluated for anti-parasitic activity. The SAR shows that 3-piperidin-4-yl-1H-indole is intolerant to most N-piperidinyl modifications. Nevertheless, we were able to identify a new compound (10d) with lead-like properties (MW = 305; cLogP = 2.42), showing antimalarial activity against drug-resistant and sensitive strains (EC50 values ∼ 3 μM), selectivity for malaria parasite and no cross-resistance with chloroquine, thus representing a potential new chemotype for further optimization towards novel and affordable antimalarial drugs.

  6. Quinolizidine and piperidine alkaloid teratogens from poisonous plants and their mechanism of action in animals.

    Science.gov (United States)

    Panter, K E; Keeler, R F

    1993-03-01

    Quinolizidine and piperidine alkaloid teratogens from Lupinus, Conium, and Nicotiana genera have been identified as causes of birth defects in livestock induced by poisonous plants. Many defects now known to be related to poisonous plant ingestion were once thought to have a genetic origin. This supposition delayed diagnosis, reporting, and understanding of such birth defects, because breeders and producers feared the news would make it difficult to sell breeding stock. Defects caused by quinolizidine and piperidine teratogens include cleft palate and contracture-type skeletal defects such as arthrogryposis, scoliosis, torticollis, and kyphosis. Teratogens have been identified, differences in susceptibility to teratogenic compounds among livestock species have been elucidated, periods of gestation when specific types of birth defects occur have been determined, and information about mechanism of action has been developed.

  7. Experimental and ab initio studies of the novel piperidine-containing acetylene glycols

    CERN Document Server

    Mirsakiyeva, Amina; Elgammal, Karim; Ten, Assel; Hugosson, Håkan W; Delin, Anna; Yu, Valentina K

    2015-01-01

    Synthesis routes of novel piperidine-containing diacetylene are presented. The new molecules are expected to exhibit plant growth stimulation properties. In particular, the yield in a situation of drought is expected to increase. The synthesis makes use of the Favorskii reaction between cycloketones/piperidone and triple-bond containing glycols. The geometries of the obtained molecules were determined using nuclear magnetic resonance (NMR). The electronic structure and geometries of the molecules were studied theoretically using first-principles calculations based on density functional theory. The calculated geometries agree very well with the experimentally measured ones, and also allow us to determine bond lengths, angles and charge distributions inside the molecules. The stability of the OH-radicals located close to the triple bond and the piperidine/cyclohexane rings was proven by both experimental and theoretical analyses. The HOMO/LUMO analysis was done in order to characterize the electron density of t...

  8. Synthesis of (R-Dihydropyridones as Key Intermediates for an Efficient Access to Piperidine Alkaloids

    Directory of Open Access Journals (Sweden)

    Serkos A Haroutounian

    2007-04-01

    Full Text Available The efficient transformation of D-glucal to (2R-hydroxymethyldihydro-pyridinone 5 in seven steps and 35 % overall yield is reported. Dihydropyridone 5 constitutes a versatile chiral building block for the synthesis of various piperidine alkaloids. In this regard, 5 was converted to piperidinol 13 and piperidinone 15, that may be further elaborated for the syntheses of (+-desoxoprosophylline (1 and deoxymannojirimycin (3 or D-mannolactam (4, respectively.

  9. Design, development, drug-likeness, and molecular docking studies of novel piperidin-4-imine derivatives as antitubercular agents.

    Science.gov (United States)

    Revathi, Rajappan; Venkatesha Perumal, Ramachandran; Pai, Karkala Sreedhara Ranganath; Arunkumar, Govindakarnavar; Sriram, Dharmarajan; Kini, Suvarna Ganesh

    2015-01-01

    Tuberculosis remains one of the major grievous diseases worldwide. The emergence of resistance to antituberculosis drugs emphasize the necessity to discover new therapeutic agents for preferential tuberculosis therapy. In this study, various novel 1-(1H-benzimidazol-2-ylmethyl) piperidin-4-imine derivatives were developed and checked for favorable pharmacokinetic parameters based on drug-likeness explained by Lipinski's rule of five. All 20 of the novel chemical entities were found to possess a favorable pharmacokinetic profile since they were not violating Lipinski's rule of five. The title compounds were also synthesized, characterized, and tested for ex vivo antitubercular activity against Mycobacterium tuberculosis H37Rv (ATCC27294). The results revealed that four compounds (2-[1-(1H-benzimidazol-2-ylmethyl)piperidin-4-ylidene] hydrazinecarbothioamide, 2-[1-(1H-benzimidazol-2-ylmethyl)piperidin-4-ylidene]-N-hydroxy-hydrazinecarbo-thioamide, 1-[1-(1H-benzimidazol-2-ylmethyl)piperidin-4-ylidene]guanidine, and 2-[1-(1H-benzimidazol-2-ylmethyl)piperidin-4-ylidene]hydrazinecarboxamide) were the most potent (minimum inhibitory concentration 6.25 µg/mL) antitubercular agents, with less toxicity (selectivity index more than 10). The molecules were also subjected to three-dimensional molecular docking on the crystal structure of enoyl-acyl carrier protein (EACP) reductase enzyme (code 1ZID, Protein Data Bank), which represents a good prediction of the interactions between the molecules and EACP reductase with minimum binding energy.

  10. The Effect of Functional Group Position of the Piperidine Derivatives on the CO{sub 2} Absorption Characteristics in the (H{sub 2}O-Piperidine-CO{sub 2}) System

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Jeong Ho; Yun, Soung Hee; Kim, Yeong Eun; Yoon, Yeo Il; Nam, Sung Chan [Korea Institute of Energy Research, Daejeon (Korea, Republic of)

    2015-02-15

    Absorption characteristics of 2-methylpiperidine (2MPD), 3-methylpiperidine (3MPD) and 4-methylpiperidine (4MPD) absorbents were studied by a vapor-liquid equilibrium (VLE) apparatus and a differential reaction calorimeter (DRC). Using a VLE apparatus, the CO{sub 2} loading capacity of each absorbent was estimated. After reaching the absorption equilibrium, nuclear magnetic resonance spectroscopy (NMR) had been conducted to characterize the species distribution of the (H{sub 2}O-piperidine-CO{sub 2}) system. Using a DRC, the reaction of heat was confirmed in accordance with the absorption capacity. The unique characteristics of 2MPD, 3MPD and 4MPD absorbents appeared by the position of methyl group. The 2MPD possessing the methyl group at the ortho position showed its hindrance effect during the absorption process; however, piperidine derivatives possessing the meta position and para position did not show its characteristics in H{sub 2}O-piperidine-CO{sub 2} system.

  11. Crystal structure of 1-(piperidin-1-yl)butane-1,3-dione.

    Science.gov (United States)

    Schwierz, Markus; Görls, Helmar; Imhof, Wolfgang

    2014-12-01

    In the title compound, C9H15NO2, the piperidine ring exhibits a chair conformation. The butane-dione subunit exhibits a conformation with the ketone C atom in an eclipsed position with respect to the amide carbonyl group. In the crystal, a two-dimensional layered arrangement is formed by hydrogen bonds of the C-H⋯O type between the methyl group and the exocyclic methyl-ene unit as donor sites and the amide carbonyl O atom as the acceptor of a bifurcated hydrogen bond. These layers are oriented parallel to the ab plane.

  12. Crystal structure of 1-(piperidin-1-ylbutane-1,3-dione

    Directory of Open Access Journals (Sweden)

    Markus Schwierz

    2014-12-01

    Full Text Available In the title compound, C9H15NO2, the piperidine ring exhibits a chair conformation. The butanedione subunit exhibits a conformation with the ketone C atom in an eclipsed position with respect to the amide carbonyl group. In the crystal, a two-dimensional layered arrangement is formed by hydrogen bonds of the C—H...O type between the methyl group and the exocyclic methylene unit as donor sites and the amide carbonyl O atom as the acceptor of a bifurcated hydrogen bond. These layers are oriented parallel to the ab plane.

  13. Synthesis of fused bicyclic piperidines: potential bioactive templates for medicinal chemistry.

    Science.gov (United States)

    Zhou, Jinglan; Campbell-Conroy, Erica L; Silina, Alina; Uy, Johnny; Pierre, Fabrice; Hurley, Dennis J; Hilgraf, Nicole; Frieman, Bryan A; DeNinno, Michael P

    2015-01-02

    An array of six pyridyl-substituted fused bicyclic piperidines was prepared as novel cores for medicinal chemistry. For maximum diversity, the size of the fused ring varied from three to six atoms and contained up to two oxygen atoms. The pyridine ring was incorporated to improve physicochemical properties and to challenge the robustness of the chemistry. The presence of the pyridine did interfere with our initial approaches to these molecules, and in several instances, a blocking strategy had to be employed. These new scaffolds possess high sp3 character and may prove useful in multiple medicinal chemistry applications.

  14. Benzoxazole piperidines as selective and potent somatostatin receptor subtype 5 antagonists.

    Science.gov (United States)

    Martin, Rainer E; Mohr, Peter; Maerki, Hans Peter; Guba, Wolfgang; Kuratli, Christoph; Gavelle, Olivier; Binggeli, Alfred; Bendels, Stefanie; Alvarez-Sánchez, Rubén; Alker, André; Polonchuk, Liudmila; Christ, Andreas D

    2009-11-01

    SAR studies of a recently described SST5R selective benzoxazole piperidine lead series are described with particular focus on the substitution pattern on the benzyl and benzoxazole side-chains. Introduction of a second meta substituent at the benzyl unit significantly lowers residual hH1 activity and insertion of substituents onto the benzoxazole periphery entirely removes remaining h5-HT2B activity. Compounds with single digit nM activity, functional antagonism and favorable physicochemical properties endowed with a good pharmacokinetic profile in rats are described which should become valuable tools for exploring the pharmacological role of the SST5 receptor in vivo.

  15. Molecular Modeling Studies of Piperidine Derivatives as New Acetylcholinesterase Inhibitors against Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Elaine F. F. da Cunha

    2013-01-01

    Full Text Available Neurodegenerative disorders are related to the progressive loss of structure or function and, eventually, death of neurons. These processes are responsible for diseases like Parkinson’s, Alzheimer’s, and Huntington’s, and the main molecular target for the drug design against these illnesses today is the enzyme acetylcholinesterase (AChE. Following this line, in the present work, we applied docking techniques to study some piperidine derivative inhibitors of AChE and further propose structures of six new AChE inhibitors as potential new drugs against neurodegenerative disorders. The best inhibitor proposed was submitted to additional molecular dynamics simulations steps.

  16. Piperidine-mediated synthesis of thiazolyl chalcones and their derivatives as potent antimicrobial agents.

    Science.gov (United States)

    Venkatesan, P; Maruthavanan, T

    2012-01-01

    A series of new thiazolyl chalcones, 1-[2-amino-4-methyl-1,3-thiazol-5-yl]-3-aryl-prop-2-en-1-one were prepared by piperidine mediated Claisen-Schmidt condensation of thiazolyl ketone with aromatic aldehyde. These chalcones on cyclisation gave 2-amino-6-(2-amino-4-methyl-1,3-thiazol-5-yl)-4-aryl-4H-pyridine-3-carbonitrile and 2-amino-6-(2-amino-4-methyl-1,3-thiazol-5-yl)-4-aryl-4H-pyran-3-carbonitrile. The result showed that the compounds exhibited marked potency as antimicrobial agents.

  17. 3-Amido-3-aryl-piperidines: A Novel Class of Potent, Selective, and Orally Active GlyT1 Inhibitors.

    Science.gov (United States)

    Pinard, Emmanuel; Alberati, Daniela; Alvarez-Sanchez, Ruben; Brom, Virginie; Burner, Serge; Fischer, Holger; Hauser, Nicole; Kolczewski, Sabine; Lengyel, Judith; Mory, Roland; Saladin, Christian; Schulz-Gasch, Tanja; Stalder, Henri

    2014-04-10

    3-Amido-3-aryl-piperidines were discovered as a novel structural class of GlyT1 inhibitors. The structure-activity relationship, which was developed, led to the identification of highly potent compounds exhibiting excellent selectivity against the GlyT2 isoform, drug-like properties, and in vivo activity after oral administration.

  18. Novel Substituted Heteroaromatic Piperazine and Piperidine Derivatives as Inhibitors of Human Enterovirus 71 and Coxsackievirus A16

    Directory of Open Access Journals (Sweden)

    Xian Zhang

    2013-04-01

    Full Text Available A series of substituted heteroaromatic piperazine and piperidine derivatives were found through virtual screening based on the structure of human enterovirus 71 capsid protein VP1. The preliminary biological evaluation revealed that compounds 8e and 9e have potent activity against EV71 and Coxsackievirus A16 with low cytotoxicity.

  19. Optimization of piperidin-4-yl-urea-containing melanin-concentrating hormone receptor 1 (MCH-R1) antagonists: Reducing hERG-associated liabilities.

    Science.gov (United States)

    Berglund, Susanne; Egner, Bryan J; Gradén, Henrik; Gradén, Joakim; Morgan, David G A; Inghardt, Tord; Giordanetto, Fabrizio

    2009-08-01

    The discovery and optimization of piperidin-4-yl-urea derivatives as MCH-R1 antagonists is herein described. Previous work around the piperidin-4-yl-amides led to the discovery of potent MCH-R1 antagonists. However, high affinity towards the hERG potassium channel proved to be an issue. Different strategies to increase hERG selectivity were implemented and resulted in the identification of piperidin-4-yl-urea compounds as potent MCH-R1 antagonists with minimized hERG inhibition.

  20. Crystal structure of 2,2-dichloro-1-(piperidin-1-ylethanone

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    Markus Schwierz

    2015-01-01

    Full Text Available In the title compound, C7H11Cl2NO, the piperidine ring shows a chair conformation and the bond-angle sum at the N atom is 359.9°. The H atom of the dichloromethyl group is in an eclipsed conformation with respect to the carbonyl group (H—C—C=O = −5°. In the crystal, inversion dimers are linked by pairs of C—H...O hydrogen bonds between the dichloromethyl group and the carbonyl O atom, which generate R22(8 loops. The dimers are linked into a ladder-like structure propagating in the [100] direction by short O...Cl [3.1084 (9 Å] contacts.

  1. Crystal structure of 2,2-dichloro-1-(piperidin-1-ylbutane-1,3-dione

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    Markus Schwierz

    2015-01-01

    Full Text Available In the title compound, C9H13Cl2NO2, the piperidine ring shows a chair conformation and the O—C—C—O torsion angle between the carbonyl groups is 183.6 (4°. In the crystal, molecules are linked into an infinite layer along the ab plane by a bifurcated C—H...O hydrogen bond between the carbonyl O atom adjacent to the methyl group and one of the methylene groups next to nitrogen and an additional hydrogen bond of the C—H...Cl type. These layers are connected into a three-dimensional supramolecular arrangement by O...Cl contacts [2.8979 (12 and 3.1300 (12 Å].

  2. Crystal structure of 2,2-di-chloro-1-(piperidin-1-yl)ethanone.

    Science.gov (United States)

    Schwierz, Markus; Görls, Helmar; Imhof, Wolfgang

    2015-01-01

    In the title compound, C7H11Cl2NO, the piperidine ring shows a chair conformation and the bond-angle sum at the N atom is 359.9°. The H atom of the di-chloro-methyl group is in an eclipsed conformation with respect to the carbonyl group (H-C-C=O = -5°). In the crystal, inversion dimers are linked by pairs of C-H⋯O hydrogen bonds between the di-chloro-methyl group and the carbonyl O atom, which generate R 2 (2)(8) loops. The dimers are linked into a ladder-like structure propagating in the [100] direction by short O⋯Cl [3.1084 (9) Å] contacts.

  3. Dynamics of catalytic resolution of 2-lithio-N-Boc-piperidine by ligand exchange.

    Science.gov (United States)

    Beng, Timothy K; Tyree, William S; Parker, Trent; Su, Chicheung; Williard, Paul G; Gawley, Robert E

    2012-10-10

    The dynamics of the racemization and catalytic and stoichiometric dynamic resolution of 2-lithio-N-Boc-piperidine (7) have been investigated. The kinetic order in tetramethylethylenediamine (TMEDA) for both racemization and resolution of the title compound and the kinetic orders in two resolving ligands have been determined. The catalytic dynamic resolution is second order in TMEDA and 0.5 and 0.265 order in chiral ligands 8 and 10, respectively. The X-ray crystal structure of ligand 10 shows it to be an octamer. Dynamic NMR studies of the resolution process were carried out. Some of the requirements for a successful catalytic dynamic resolution by ligand exchange have been identified.

  4. 4-(Phenylsulfonyl)piperidines: novel, selective, and bioavailable 5-HT(2A) receptor antagonists.

    Science.gov (United States)

    Fletcher, Stephen R; Burkamp, Frank; Blurton, Peter; Cheng, Susan K F; Clarkson, Robert; O'Connor, Desmond; Spinks, Daniel; Tudge, Matthew; van Niel, Monique B; Patel, Smita; Chapman, Kerry; Marwood, Rose; Shepheard, Sara; Bentley, Graham; Cook, Gina P; Bristow, Linda J; Castro, Jose L; Hutson, Peter H; MacLeod, Angus M

    2002-01-17

    On the basis of a spirocyclic ether screening lead, a series of acyclic sulfones have been identified as high-affinity, selective 5-HT(2A) receptor antagonists. Bioavailability lacking in the parent, 1-(2-(2,4-difluorophenyl)ethyl)-4-(phenylsulfonyl)piperidine (12), was introduced by using stability toward rat liver microsomes as a predictor of bioavailability. By this means, the 4-cyano- and 4-carboxamidophenylsulfonyl derivatives 26 and 31 were identified as orally bioavailable, brain-penetrant analogues suitable for evaluation in animal models. Bioavailability was also attainable by N substitution leading to the N-phenacyl derivative 35. IKr activity detected through counterscreening was reduced to insignificant levels in vivo with the latter compound.

  5. Lipoperoxidation and cyclooxygenase enzyme inhibitory piperidine alkaloids from Cassia spectabilis green fruits.

    Science.gov (United States)

    Viegas, Cláudio; Silva, Dulce H S; Pivatto, Marcos; de Rezende, Amanda; Castro-Gambôa, Ian; Bolzani, Vanderlan S; Nair, Muraleedharan G

    2007-12-01

    Phytochemical work in the search for bioactive metabolites from the methanolic extract of Senna spectabilis green fruits led to the isolation of a new piperidine alkaloid, (+)-3- O-feruloylcassine ( 1), in addition to the known (-)-spectaline ( 2) and (-)-3- O-acetylspectaline ( 3). The isolates were submitted to in vitro evaluation of lipoperoxidation (LPO) and cyclooxygenase enzymes (COX-1 and -2) inhibitory properties and showed moderate antioxidant activities (40-70%) at 100 ppm when compared to commercial standards BHT and vitamin E and moderate inhibition of COX-1 (ca . 40%) and marginal inhibition of COX-2 enzymes (<10%) at 100 ppm when compared to nonsteroidal anti-inflammatory drugs (NSAIDs) aspirin, rofecoxib, and celecoxib, respectively.

  6. Prins fluorination cyclisations: Preparation of 4-fluoro-pyran and -piperidine heterocycles

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    Guillaume G. Launay

    2010-04-01

    Full Text Available The Prins reaction was investigated using BF3·OEt2 as a Lewis acid. It has been recently demonstrated, that if BF3·OEt2 is used in stoichiometric amounts then these reactions generate fluorinated products where the BF3·OEt2 contributes fluoride ion to quench the intermediate carbocations. In this study oxa- and aza-Prins reactions for the synthesis of 4-fluoro-pyrans and -piperidines were investigated. The products were obtained in good yields, but only with moderate diastereoselectivity. These Prins fluorination reactions can be accelerated under microwave conditions. The study extends the Prins fluorination methodology for the generation of the C–F bond in heterocycles.

  7. Synthesis and pharmacological evaluation of piperidine (piperazine)-substituted benzoxazole derivatives as multi-target antipsychotics.

    Science.gov (United States)

    Huang, Ling; Zhang, Wenjun; Zhang, Xiaohua; Yin, Lei; Chen, Bangyin; Song, Jinchun

    2015-11-15

    The present study describes the optimization of a series of novel benzoxazole-piperidine (piperazine) derivatives combining high dopamine D2 and serotonin 5-HT1A, 5-HT2A receptor affinities. Of these derivatives, the pharmacological features of compound 29 exhibited high affinities for the DA D2, 5-HT1A and 5-HT2A receptors, but low affinities for the 5-HT2C and histamine H1 receptors and human ether-a-go-go-related gene (hERG) channels. Furthermore, compound 29 reduced apomorphine-induced climbing and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced head twitching without observable catalepsy, even at the highest dose tested. Thus, compound 29 is a promising candidate as a multi-target antipsychotic treatment.

  8. Syntheses and Characterizations of Two New Organic-inorganic Hybrids Based on Heteropolymolybdates and Piperidine Molecules

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Two new organic-inorganic compounds [(CH2)5NH2]3[PMo12O40]·3[(CH2)5NH] 1 and [(CH2)5NH2]6[P2Mo18O62]·5H2O 2 have been synthesized using conventional and hydrothermal methods, respectively, and characterized by elemental analyses, IR, TG and single-crystal X-ray diffraction. X-ray analyses show that in these compounds heteropolymolybdates [PMo12O40]3- and [P2Mo18O62]6- are reserved their Keggin or Dawson structures and linked to piperidine through electrostatic and hydrogen-bonding interactions.

  9. Benzophenone-N-ethyl piperidine ether analogues--synthesis and efficacy as anti-inflammatory agent.

    Science.gov (United States)

    Khanum, Shaukath A; Girish, V; Suparshwa, S S; Khanum, Noor Fatima

    2009-04-01

    A sequence of substituted benzophenone-N-ethyl piperidine ether analogues has been synthesized and evaluated as orally active anti-inflammatory agents with reduced side effects. The anti-inflammatory and ulcerogenic activities of the compounds were compared with naproxen, indomethacin, and phenylbutazone. These analogues showed an interesting anti-inflammatory activity in carrageenan-induced foot pad edema assay. In the air-pouch test, some of the analogues reduced the total number of leukocytes of the exudate, which indicates inhibition of prostaglandin production. Side effects of the compounds were examined on gastric mucosa, in the liver and stomach. None of the compounds illustrated significant side effects compared with standard drugs like indomethacin and naproxen.

  10. Anti-malarial activity of a non-piperidine library of next-generation quinoline methanols

    Directory of Open Access Journals (Sweden)

    Melendez Victor

    2010-02-01

    Full Text Available Abstract Background The clinical utility for mefloquine has been eroded due to its association with adverse neurological effects. Better-tolerated alternatives are required. The objective of the present study was the identification of lead compounds that are as effective as mefloquine, but exhibit physiochemical properties likely to render them less susceptible to passage across the blood-brain barrier. Methods A library of drug-like non-piperidine analogs of mefloquine was synthesized. These compounds are diverse in structure and physiochemical properties. They were screened in appropriate in vitro assays and evaluated in terms of their potential as lead compounds. The correlation of specific structural attributes and physiochemical properties with activity was assessed. Results The most potent analogs were low molecular weight unconjugated secondary amines with no heteroatoms in their side-chains. However, these compounds were more metabolically labile and permeable than mefloquine. In terms of physiochemical properties, lower polar surface area, lower molecular weight, more freely rotatable bonds and fewer H-bond acceptors were associated with greater potency. There was no such relationship between activity and LogP, LogD or the number of hydrogen bond donors (HBDs. The addition of an H-bond donor to the side-chain yielded a series of active diamines, which were as metabolically stable as mefloquine but showed reduced permeability. Conclusions A drug-like library of non-piperidine analogs of mefloquine was synthesized. From amongst this library an active lead series of less permeable, but metabolically stable, diamines was identified.

  11. Synthesis and structure-activity relationships of N-aryl-piperidine derivatives as potent (partial) agonists for human histamine H3 receptor.

    Science.gov (United States)

    Ishikawa, Makoto; Furuuchi, Takeshi; Yamauchi, Miki; Yokoyama, Fumikazu; Kakui, Nobukazu; Sato, Yasuo

    2010-07-15

    4-((1H-imidazol-4-yl)methyl)-1-aryl-piperazine and piperidine derivatives were designed and synthesized as candidate human histamine type 3 agonists. The piperazine derivatives were found to have low (or no) affinity for human histamine H3 receptor, whereas the piperidine derivatives showed moderate to high affinity, and their agonistic activity was greatly influenced by substituents on the aromatic ring. Among the piperidine-containing compounds, 17d and 17h were potent human histamine H3 receptor agonists with high selectivity over the closely related human H4 receptor. Our results indicate that appropriate conformational restriction, that is, by the piperidine spacer moiety, favors specific binding to the human histamine H3 receptor.

  12. Deciphering Piperidine Formation in Polyketide-Derived Indolizidines Reveals a Thioester Reduction, Transamination, and Unusual Imine Reduction Process.

    Science.gov (United States)

    Peng, Haidong; Wei, Erman; Wang, Jiali; Zhang, Yanan; Cheng, Lin; Ma, Hongmin; Deng, Zixin; Qu, Xudong

    2016-12-16

    Piperidine and indolizidine are two basic units of alkaloids that are frequently observed in natural and synthetic compounds. Their biosynthesis in natural products is highly conserved and mostly derived from the incorporation of lysine cyclization products. Through in vitro reconstitution, we herein identified a novel pathway involving a group of polyketide-derived indolizidines, which comprises the processes of tandem two-electron thioester reduction, transamination, and imine reduction to convert acyl carrier protein (ACP)-tethered polyketide chains into the piperidine moieties of their indolizidine scaffolds. The enzymes that catalyze the imine reduction are distinct from previous known imine reductases, which have a fold of acyl-CoA dehydrogenase but do not require flavin for reduction. Our results not only provide a new way for the biosynthesis of the basic units of alkaloids but also show a novel class of imine reductases that may benefit the fields of biocatalysis and biomanufacturing.

  13. Harnessing the Electrophilicity of Keteniminium Ions: A Simple and Straightforward Entry to Tetrahydropyridines and Piperidines from Ynamides

    Science.gov (United States)

    Lecomte, Morgan

    2016-01-01

    Abstract An efficient, modular and straightforward entry to tetrahydropyridines and piperidines is reported. This reaction is based on a formal intramolecular hydroalkylation of readily available, properly substituted ynamides which, upon simple activation under acidic conditions, generate highly reactive activated keteniminium ions whose reactivity can be finely controlled to induce a remarkably efficient [1,5]‐hydride shift from unactivated C−H bonds and trigger a cationic cyclization which is complete within minutes. PMID:26934474

  14. One-pot five-component synthesis of highly functionalized piperidines using oxalic acid dihydrate as a homogenous catalyst

    Institute of Scientific and Technical Information of China (English)

    Seyed Sajad Sajadikhah; Malek Taher Maghsoodlou; Nourallah Hazeri; Sayyed Mostafa Habibi-Khorassani; Anthony C. Willis

    2012-01-01

    An efficient green protocol is described for the preparation of highly functionalized piperidines via a one-pot five-component reaction between aromatic aldehydes,anilines and β-ketoesters in the presence of oxalic acid dihydrate as catalyst in ethanol at ambient temperature.The structure as well as the relative stereochemistry of these compounds was confirmed by single X-ray crystallographic analysis.

  15. Preparation and properties of piperidine salts of 6-hydroxy-4,6-diaryl-5-ethoxycarbonyl-3-cyanopiperidine-2-thiones

    Energy Technology Data Exchange (ETDEWEB)

    Krauze, A.A.; Liepin' sh, E.E.; Pelcher, Yu.E.; Kalme, Z.A.; Dubur, G.Ya.

    1987-07-01

    Alkylation of piperidine salts of 6-hydroxy-4,6-diaryl-5-ethoxycarbonyl-3-cyanopiperidine-2(1H)-thiones yielded 6-hydroxy-2-alkylthio-4,6-diaryl-5-ethoxycarbonyl-1-3-cyano-3,4,5,6-tetrahydropyridines which were dehydrogenated with the formation of 2-methylthio-1,4- and 4,5-dihydropyridines. The oxidation of the compounds prepared has been studied.

  16. Autophagy protects against neural cell death induced by piperidine alkaloids present in Prosopis juliflora (Mesquite

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    VICTOR D.A. SILVA

    Full Text Available ABSTRACT Prosopis juliflora is a shrub that has been used to feed animals and humans. However, a synergistic action of piperidine alkaloids has been suggested to be responsible for neurotoxic damage observed in animals. We investigated the involvement of programmed cell death (PCD and autophagy on the mechanism of cell death induced by a total extract (TAE of alkaloids and fraction (F32 from P. juliflora leaves composed majoritary of juliprosopine in a model of neuron/glial cell co-culture. We saw that TAE (30 µg/mL and F32 (7.5 µg/mL induced reduction in ATP levels and changes in mitochondrial membrane potential at 12 h exposure. Moreover, TAE and F32 induced caspase-9 activation, nuclear condensation and neuronal death at 16 h exposure. After 4 h, they induced autophagy characterized by decreases of P62 protein level, increase of LC3II expression and increase in number of GFP-LC3 cells. Interestingly, we demonstrated that inhibition of autophagy by bafilomycin and vinblastine increased the cell death induced by TAE and autophagy induced by serum deprivation and rapamycin reduced cell death induced by F32 at 24 h. These results indicate that the mechanism neural cell death induced by these alkaloids involves PCD via caspase-9 activation and autophagy, which seems to be an important protective mechanism.

  17. Piperidine-Substituted Perylene Sensitizer for Dye-Sensitized Solar Cells

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    Joe Otsuki

    2011-01-01

    Full Text Available We have prepared a novel piperidine-donor-substituted perylene sensitizer, PK0002, and studied the photovoltaic performance in dye-sensitized solar cells (DSSCs. Physical properties and photovoltaic performance of this new perylene derivative PK0002 are reported and compared with those of unsubstituted perylene sensitizer, PK0003. PK0002, when anchored to nanocrystalline TiO2 films, achieves very efficient sensitization across the whole visible range extending up to 800 nm. The incident photon-to-current conversion efficiency (IPCE spectrum was consistent with the absorption spectrum and resulted in a high short-circuit photocurrent density (Jsc of 8.8 mA cm-2. PK0002 showed higher IPCE values than PK0003 in the 520–800 nm region. Under standard AM 1.5 irradiation (100 mW cm-2 and using an electrolyte consisting of 0.6 M dimethylpropyl-imidazolium iodide, 0.05 M I2, 0.1 M LiI, and 0.5 M tert-butylpyridine in acetonitrile, a solar cell containing sensitizer PK0002 yielded a short-circuit photocurrent density of 7.7 mA cm-2, an open-circuit photovoltage of 0.57 V, and a fill factor of 0.70, corresponding to an overall conversion efficiency of 3.1%.

  18. [Anti-obesity activity of 3-hydroxymethyl N-methyl piperidine 4-chlorophenoxyacetate hydrochloride in mice treated with gold thioglucose].

    Science.gov (United States)

    Massicot, F; Arapis, G; Falcou, R; Apfelbaum, M; Godfroid, J J

    1986-01-01

    The 3-hydroxyméthyl N-méthyl piperidine 4-chlorophenoxyacetate, hydrochloride, A, a potent anorectic, reduces weight gain of gold thioglucose obese mice through a reduced body fat and a decrease in metabolic efficiency. Compound A has much less effect in the lean mice than in the obese models. In contrast with pair-fed obese or lean mice, the decreased food consumption cannot account for all the reduced weight gain of the obese controls. Basal lipolytic activity in parametrial adipose tissue is greater in obese mice treated with A then in controls. It seems that the stimulating effect of A on lipolysis could contribute to the weight reduction.

  19. Crystal structure of chlorido(piperidine-κN(quinoline-2-carboxylato-κ2N,Oplatinum(II

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    Chi Nguyen Thi Thanh

    2014-07-01

    Full Text Available The title compound, [Pt(C10H6NO2Cl(C5H11N], crystallizes with one molecule in the asymmetric unit. The PtII cation has a slightly distorted square-planar coordination environment defined by a chloride anion, the quinoline N atom and a carboxylate O atom of the bidentate quinaldate ligand and a piperidine N atom. An intramolecular C—H...Cl hydrogen bond occurs. In the crystal, molecules are stacked into columns along the c axis by the formation of N—H...Cl and C—H...O hydrogen bonds.

  20. (E-2-[4-(Piperidin-1-ylbenzylidene]-2,3-dihydro-1H-inden-1-one

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    Mohamed Ashraf Ali

    2010-11-01

    Full Text Available In the title compound, C21H21NO, the indene ring system is essentially planar with a maximum deviation of 0.066 (1 Å and makes dihedral angles of 7.93 (6 and 2.43 (6°, respectively, with the benzene plane and the mean plane of the piperidine ring. These latter two planes make a dihedral angle of 7.61 (7°. In the crystal, molecules are linked by C—H...O interactions, forming infinite chains along the b axis.

  1. Synthesis and biological evaluation of piperidine-substituted triazine derivatives as HIV-1 non-nucleoside reverse transcriptase inhibitors.

    Science.gov (United States)

    Chen, Xuwang; Zhan, Peng; Pannecouque, Christophe; Balzarini, Jan; De Clercq, Erik; Liu, Xinyong

    2012-05-01

    A novel series of piperidine-substituted triazine derivatives have been synthesized and evaluated for anti-HIV activities in MT-4 cells. Most compounds displayed extremely promising activity against wild-type HIV-1 with EC(50) values in low nanomolar concentration, better than that of Nevirapine, Delavirdine, Zidovudine and Dideoxycitidine, and higher potency towards the resistant mutant strain K103N/Y181C than that of Nevirapine and Delavirdine. Selected compounds were also assayed against reverse transcriptase with lower IC(50) values than that of Nevirapine. The structure-activity relationship (SAR) of these novel structural congeners was also discussed.

  2. Synthesis and pharmacological evaluation of 1-alkyl-N-[2-ethyl-2-(4-fluorophenyl)butyl]piperidine-4-carboxamide derivatives as novel antihypertensive agents.

    Science.gov (United States)

    Watanuki, Susumu; Matsuura, Keisuke; Tomura, Yuichi; Okada, Minoru; Okazaki, Toshio; Ohta, Mitsuaki; Tsukamoto, Shin-Ichi

    2011-09-15

    We synthesized and evaluated inhibitory activity against T-type Ca(2+) channels for a series of 1-alkyl-N-[2-ethyl-2-(4-fluorophenyl)butyl]piperidine-4-carboxamide derivatives. Structure-activity relationship studies have revealed that dialkyl substituents at the benzylic position play an important role in increasing inhibitory activity. Oral administration of N-[2-ethyl-2-(4-fluorophenyl)butyl]-1-(2-phenylethyl)piperidine-4-carboxamide (20d) lowered blood pressure in spontaneously hypertensive rats without inducing reflex tachycardia, which is often caused by traditional L-type Ca(2+) channel blockers.

  3. Synthesis and ligand binding studies of 4'-iodobenzoyl esters of tropanes and piperidines at the dopamine transporter.

    Science.gov (United States)

    Singh, S; Basmadjian, G P; Avor, K S; Pouw, B; Seale, T W

    1997-08-01

    Four analogs and two homologs of cocaine, designed as potent cocaine antagonists, were synthesized. The SN2 reaction between ecgonine methyl ester (13) or appropriately substituted piperidinol (19, 21) and appropriately substituted 4-iodobenzoyl chloride gave 4-iodobenzoyl esters of tropanes and piperidines (5-8). 2'-Hydroxycocaine (9) was obtained from 2'-acetoxycocaine (12) by selective transesterification with MeOH saturated with dry HCl gas. 2'-Acetoxycocaine (12) was synthesized from acetylsalicyloyl chloride (23) and ecgonine methyl ester (13). The binding affinities of these compounds were determined at the dopamine transporter for the displacement of [3H]WIN-35428. An iodo group substitution at the 4'-position of cocaine decreased dopamine transporter binding potency, while a hydroxy or acetoxy group at the 2'-position exhibited increased binding potency for the dopamine transporter compared to cocaine (10- and 3.58-fold, respectively). 2'-Hydroxylation also enhanced the bidning potency of 4'-iodococaine (5) by 10-fold. Replacement of the tropane ring with piperidine led to poor binding affinities.

  4. STUDY ON THE PHOTOLYSIS MECHANISM OF POLYESTER FROM SUCCINIC ACID AND N-β-HYDROXYETHYL 2,2,6,6-TETRAMETHYL-4-HYDROXY PIPERIDINE (TINUVIN-622)

    Institute of Scientific and Technical Information of China (English)

    PAN Jiangqing; CUI Song

    1988-01-01

    The photolysis mechanism of polyester of succinic acid with N-β-hydroxyethyl 2,2,6,6-tetramethyl-4-hydroxy piperidine (Tinuvin-622) has been studied by instrumental analysis. The results show that Tinuvin-622 can be easily photolysed. Based on the results of IR, NMR, ESR, GPC, GC, MS, the photolysis mechanism of Tinuvin-622 has been proposed.

  5. Design, synthesis and biological estimation of 1-(benzoxazole-2-y1)piperazine and 4-(benzoxazole-2-yl)piperidine derivatives as potential α1-AR antagonists

    Institute of Scientific and Technical Information of China (English)

    Jia Bin Li; Lin Xia; Bin Wu; Tao Wang; Zhen Zhou Jiang

    2008-01-01

    Two series of 1-(benzoxazole-2-yl)piperazine(8a-i)and 4-(benzoxazole-2-yl)piperidine compounds(10a-i)were designed,synthesized and evaluated for their α1-AR antagonistic activities.Biological assay in vitro indicated that 10h showed slightly stronger α1-AR antagonistic activity to that of our lead compound 1.

  6. A pharmacodynamic comparison of piperidine and pyridine alkaloid actions at fetal muscle-type nicotinic acetylcholine receptors (nAChR)

    Science.gov (United States)

    Piperidine and pyridine alkaloids are found in many species of plants including Lobelia spp., Conium spp., Nicotiana spp., and Lupinus spp. Some of these alkaloids cause multiple congenital contracture deformities (MCC) and cleft palates in cattle, pigs, sheep, and goats. The mechanism behind MCC ...

  7. Steric Effect of Alkyl Substituted Piperidin-4-one Oximes for Corrosion Control of Mild Steel in H2SO4 Medium%Steric Effect of Alkyl Substituted Piperidin-4-one Oximes for Corrosion Control of Mild Steel in H2SO4Medium

    Institute of Scientific and Technical Information of China (English)

    SENTHILKUMAR Annamalai; THARINI Kumaravel; SETHURAMAN Mathur Gopalakrishnan

    2012-01-01

    Three synthesized piperidin-4-one oximes,3-ethyl-2,6-diphenyl-piperidin-4-one oxime (A),1-methyl-3-isopropyl-2,6-diphenyl-piperidin-4-one oxime (B),and 3-isopropyl-2,6-diphenyl-piperidin-4-one oxime (C),were tested at different concentrations to determine their ability to inhibit corrosion of mild steel in 1 mol · L-1 H2SO4 and measured by a mass loss method (at various temperatures),polarization and impedance measurements,X-ray diffraction (XRD),scanning electron microscopy (SEM) with energydispersive X-ray spectroscopy (EDS),and a quantum chemical method.The synergistic influence of compounds A,B and C with iodides has also been evaluated.All three compounds show good inhibition efficiency in the following order:A>B>C.Compounds A,B and C were found to physically adsorb on the surface of mild steel while obeying the Temkin isotherm.Polarization measurements indicated that these compounds behave as a mixed mode inhibitor.XRD and SEM with EDS studies revealed the formation of a protective barrier on the mild steel surface by these oximes.The electron donating ability of the studied molecules was tested using semi empirical methods.The studies revealed that the oxime nitrogen,the piperidine moiety,and the phenyl ring assist largely in corrosion control.The studies also showed that the steric crowding by the alkyl group in the piperidine ring affects the inhibitor efficiency.Further,it is interesting to note that all of the studied compounds exhibit synergism with iodide ions.

  8. Discovery of 1-(1,3,5-triazin-2-yl)piperidine-4-carboxamides as inhibitors of soluble epoxide hydrolase.

    Science.gov (United States)

    Thalji, Reema K; McAtee, Jeff J; Belyanskaya, Svetlana; Brandt, Martin; Brown, Gregory D; Costell, Melissa H; Ding, Yun; Dodson, Jason W; Eisennagel, Steve H; Fries, Rusty E; Gross, Jeffrey W; Harpel, Mark R; Holt, Dennis A; Israel, David I; Jolivette, Larry J; Krosky, Daniel; Li, Hu; Lu, Quinn; Mandichak, Tracy; Roethke, Theresa; Schnackenberg, Christine G; Schwartz, Benjamin; Shewchuk, Lisa M; Xie, Wensheng; Behm, David J; Douglas, Stephen A; Shaw, Ami L; Marino, Joseph P

    2013-06-15

    1-(1,3,5-Triazin-yl)piperidine-4-carboxamide inhibitors of soluble epoxide hydrolase were identified from high through-put screening using encoded library technology. The triazine heterocycle proved to be a critical functional group, essential for high potency and P450 selectivity. Phenyl group substitution was important for reducing clearance, and establishing good oral exposure. Based on this lead optimization work, 1-[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]-N-{[[4-bromo-2-(trifluoromethoxy)]-phenyl]methyl}-4-piperidinecarboxamide (27) was identified as a useful tool compound for in vivo investigation. Robust effects on a serum biomarker, 9, 10-epoxyoctadec-12(Z)-enoic acid (the epoxide derived from linoleic acid) were observed, which provided evidence of robust in vivo target engagement and the suitability of 27 as a tool compound for study in various disease models.

  9. Crystal structure of 2,2-di-chloro-1-(piperidin-1-yl)butane-1,3-dione.

    Science.gov (United States)

    Schwierz, Markus; Görls, Helmar; Imhof, Wolfgang

    2015-01-01

    In the title compound, C9H13Cl2NO2, the piperidine ring shows a chair conformation and the O-C-C-O torsion angle between the carbonyl groups is 183.6 (4)°. In the crystal, mol-ecules are linked into an infinite layer along the ab plane by a bifurcated C-H⋯O hydrogen bond between the carbonyl O atom adjacent to the methyl group and one of the methyl-ene groups next to nitro-gen and an additional hydrogen bond of the C-H⋯Cl type. These layers are connected into a three-dimensional supra-molecular arrangement by O⋯Cl contacts [2.8979 (12) and 3.1300 (12) Å].

  10. N-(2-{[5-Bromo-2-(piperidin-1-ylpyrimidin-4-yl]sulfanyl}-4-methoxyphenyl-2,4,6-trimethylbenzenesulfonamide

    Directory of Open Access Journals (Sweden)

    Mohan Kumar

    2012-09-01

    Full Text Available In the title compound, C25H29BrN4O3S2, the benzene rings bridged by the sulfonamide group are tilted relative to each other by 63.9 (1° and the dihedral angle between the sulfur-bridged pyrimidine and benzene rings is 64.9 (1°. The molecular conformation is stabilized by a weak intramolecular π–π stacking interaction between the pyrimidine and the 2,4,6-trimethylbenzene rings [centroid–centroid distance = 3.766 (2 Å]. The piperidine ring adopts a chair conformation. In the crystal, molecules are linked into inversion dimers by pairs of N—H...O hydrogen bonds and these dimers are further linked by C—H...O hydrogen bonds into chains propagating along [010].

  11. Epidihydropinidine, the main piperidine alkaloid compound of Norway spruce (Picea abies) shows promising antibacterial and anti-Candida activity.

    Science.gov (United States)

    Fyhrquist, Pia; Virjamo, Virpi; Hiltunen, Eveliina; Julkunen-Tiitto, Riitta

    2017-03-01

    This study reports for the first time promising antibacterial and antifungal effects of epidihydropinidine, the major piperidine alkaloid in the needles and bark of Norway spruce, Picea abies (L.) Karsten. Epidihydropinidine was growth inhibitory against all bacterial and fungal strains used in our investigation, showing the lowest MIC value of 5.37μg/mL against Pseudomonas aeruginosa, Enterococcus faecalis, Candida glabrata and C. albicans. Epidihydropinidine was nearly three times more active than tetracycline against P. aeruginosa and E. faecalis. Promising antibacterial effects were also recorded against Staphylococcus aureus and Bacillus cereus (MIC 10.75μg/mL) as well as against Salmonella enterica (MIC and MBC 43μg/mL). Our preliminary results suggest that epidihydropinidine as well related alkaloids of Norway spruce could be powerful candidates for new antibiotics and for preventing food spoilage.

  12. Crystal structure of trans-dichlorido(4-nitroaniline-κN1(piperidine-κNplatinum(II

    Directory of Open Access Journals (Sweden)

    Chi Nguyen Thi Thanh

    2015-06-01

    Full Text Available In the title complex, [PtCl2(C5H11N(C6H6N2O2], the PtII metal atom displays a slightly distorted trans-PtN2Cl2 square-planar coordination geometry. The dihedral angle between the mean plane of the benzene and piperidine rings is 89.03 (3°. In the crystal structure, inversion dimers are formed via N—H...Cl hydrogen-bond interactions, resulting in chains parallel to the [001] direction. The benzene rings within the chains show π–π stacking interactions [centroid-to-centroid distances of 3.801 (3 Å] and neighbouring chains interact via N—H...O hydrogen bonds.

  13. HPLC-ESI-MS/MS of brain neurotransmitter modulator lobeline and related piperidine alkaloids in Lobelia inflata L.

    Science.gov (United States)

    Kursinszki, László; Szőke, Éva

    2015-05-01

    There is a renewed interest in lobelia alkaloids because of their activity on the central nervous system. Lobeline, the most active of them, a nicotinic receptor ligand and neurotransmitter transporter inhibitor, is a candidate pharmacotherapy for metamphetamine abuse. In the present work, high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry in positive ion mode was used for investigating the alkaloid profile in Lobelia inflata L. Chromatographic separations were achieved on a Gemini C6-phenyl reversed-phase column providing good peak shape and improved selectivity. Being mostly 2,6-disubstituted piperidines, lobelia alkaloids presented abundant [M + H](+) ions with typical fragmentation. Identification was possible from a few specific ions, especially those resulting from excision of one of the substituents. Based on fragmentation pattern of lobeline as reference compound, 52 alkaloids were identified in the aqueous methanolic extract of L. inflata in contrast to the previously known some 20. Structural variability of these alkaloids identified arises basically from their substituents which can be phenyl-2-ketoethyl- or phenyl-2-hydroxyethyl units as well as their methyl-, ethyl- or propyl- homologues attached in different combinations. Several propyl homologue lobelia alkaloids and five hydroxypiperidine derivatives were found in the plant at the first time. In addition to 8-O-esters of 2-monosubstituted piperidine alkaloids previously reported by us in L. inflata, a 3-hydroxy-3-phenylpropanoic acid ester of hydroxyallosedamine ring-substituted was also identified as a new natural product. High-performance liquid chromatography-electrospray ionization tandem mass spectrometry can be successfully applied to Lobeliacae plant samples in the routine screening for new and known bioactive constituents, quality control of the crude drug, lobelia herba, alkaloid production studies, breeding and chemotaxonomy.

  14. Synthesis and pharmacological evaluation of 1-alkyl-N-[(1R)-1-(4-fluorophenyl)-2-methylpropyl]piperidine-4-carboxamide derivatives as novel antihypertensive agents.

    Science.gov (United States)

    Watanuki, Susumu; Matsuura, Keisuke; Tomura, Yuichi; Okada, Minoru; Okazaki, Toshio; Ohta, Mitsuaki; Tsukamoto, Shin-ichi

    2011-01-01

    We synthesized and evaluated inhibitory activity against T-type Ca(2+) channels for a series of 1-alkyl-N-[(1R)-1-(4-fluorophenyl)-2-methylpropyl]piperidine-4-carboxamide derivatives. Structure-activity relationship studies have revealed that the isopropyl substituent at the benzylic position plays an important role in exerting potent inhibitory activity, and the absolute configuration of the benzylic position was found to be opposite that of mibefradil, which was first launched as a new class of T-type Ca(2+) channel blocker. Oral administration of N-[(1R)-1-(4-fluorophenyl)-2-methylpropyl]-1-[2-(3-methoxyphenyl)ethyl]piperidine-4-carboxamide (17f) lowered blood pressure in spontaneously hypertensive rats without inducing reflex tachycardia, an adverse effect often caused by traditional L-type Ca(2+) channel blockers.

  15. Piperidine-Based Nocaine/Modafinil Hybrid Ligands as Highly Potent Monoamine Transporter Inhibitors: Efficient Drug Discovery by Rational Lead Hybridization

    Science.gov (United States)

    Zhou, Jia; He, Rong; Johnson, Kenneth M.; Ye, Yanping; Kozikowski, Alan P.

    2005-01-01

    Some piperidine-based nocaine/modafinil hybrid ligands have been designed, synthesized, and found to display an improved potency at all three monoamine transporters and particularly for DAT and/or NET. Some highly active and selective monoamine transporter inhibitors with low nanomolar to subnanomolar potency were identified. Ligands of this type may find important applications as positron emission tomography imaging tools and in the treatment of central nervous system disorders such as depression and sleep apnea. PMID:15537337

  16. 4-(Piperidin-1-yl)-4H-benzo[b]tetra­zolo[1,5-d][1,4]diazepin-5(6H)-one

    OpenAIRE

    Christopher Hulme; Kaiser, Christine E.; Zhigang Xu; Nichol, Gary S.

    2010-01-01

    There are two crystallographically unique molecules present in the asymmetric unit of the title compound, C14H16N6O; in both molecules, the seven-membered diazepinone ring adopts a boat-like conformation and the chair conformation piperidine ring is an axial substituent on the diazepinone ring. In the crystal, each molecule forms hydrogen bonds with its respective symmetry equivalents. Hydrogen bonding between molecule A and symmetry equivalents forms two ring motifs, the first formed by inve...

  17. Zn-catalyzed Enantio- and Diastereoselective Formal [4+2] Cycloaddition Involving Two Electron-Deficient Partners: Asymmetric Synthesis of Piperidines from 1-Azadienes and Nitroalkenes

    OpenAIRE

    Chu, John C. K.; Dalton, Derek M.; Rovis, Tomislav

    2015-01-01

    We report a catalytic asymmetric synthesis of piperidines through [4+2] cycloaddition of 1-azadienes and nitroalkenes. The reaction uses earth abundant Zn as catalyst, and is highly diastereo- and regio-selective. A novel BOPA ligand (F-BOPA) confers high reactivity and enantioselectivity in the process. The presence of ortho substitution on the arenes adjacent to the bis(oxazolines) was found to be particularly impactful, due to limiting the undesired coordination of 1-azadiene to the Lewis ...

  18. Inhibition of Sterol Biosynthesis by 2-Isopropyl-4-dimethylamino-5-methylphenyl-1-piperidine Carboxylate Methyl Chloride in Tobacco and Rat Liver Preparations.

    Science.gov (United States)

    Douglas, T J; Paleg, L G

    1972-03-01

    2-Isopropyl-4-dimethylamino-5-methylphenyl-1-piperidine carboxylate methyl chloride, 90%, applied to rootless tobacco (Nicotiana tabacum cv. Samson) seedlings inhibits the incorporation of (14)C-mevalonate into sterols. Concomitantly, the retardant causes the accumulation of squalene-2,3-epoxide, an intermediate in sterol biosynthesis. The results with tobacco are identical to those produced by the retardant in cell-free rat liver preparations.

  19. A kryptoracemic salt: 2-{[2,8-bis(trifluoromethylquinolin-4-yl](hydroxymethyl}piperidin-1-ium (+-3,3,3-trifluoro-2-methoxy-2-phenylpropanoate

    Directory of Open Access Journals (Sweden)

    James L. Wardell

    2016-06-01

    Full Text Available The asymmetric unit of the title salt, C17H17F6N2O+·C10H8F3O3−, comprises two piperidin-1-ium cations and two carboxylate anions. The cations, each having an l-shaped conformation owing to the near orthogonal relationship between the quinolinyl and piperidin-1-ium residues, are pseudo-enantiomeric. The anions have the same absolute configuration but differ in the relative orientations of the carboxylate, methoxy and benzene groups. Arguably, the most prominent difference between the anions occurs about the Cq—Om bond as seen in the Cc—Cq—Om—Cm torsion angles of −176.1 (3 and −67.1 (4°, respectively (q = quaternary, m = methoxy and c = carboxylate. The presence of Oh—H...Oc and Np—H...Oc hydrogen bonds leads to the formation of a supramolecular chain along the a axis (h = hydroxy and p = piperidin-1-ium; weak intramolecular Np—H...Oh hydrogen bonds are also noted. Chains are connected into a three-dimensional architecture by C—H...F interactions. Based on a literature survey, related molecules/cations adopt a uniform conformation in the solid state based on the letter L.

  20. Preparation, characterization, and antitumor activity of new cisplatin analogues with 1-methyl-4-(methylamino)piperidine: crystal structure of [PtII(1-methyl-4-(methylamino) piperidine)(oxalate)].

    Science.gov (United States)

    Mukhopadhyay, Uday; Thurston, John; Whitmire, Kenton H; Siddik, Zahid H; Khokhar, Abdul R

    2003-02-01

    A series of new platinum(II) complexes of the type [Pt(II)(mmap)X] (where mmap, 1-methyl-4-(methylamino)piperidine and X, 1,1-cyclobutanedicarboxylato (CBDCA), oxalato, malonato, methylmalonato, dimethylmalonato, ethylmalonato, diethylmalonato or 2,3-naphthalene dicarboxylato (NDCA)) have been synthesized and characterized by elemental analysis, infrared (IR), and 13C and 195Pt nuclear magnetic resonance (NMR) spectroscopy. The crystal structure of the analogue [Pt(II)(mmap)(oxalate)] was determined using the single crystal X-ray diffraction method. Based upon a total of 4964 collected reflections, we determined that the compound crystallizes in the monoclinic space group P2(1)/c (with a=11.890(2) A, b=9.6695(19) A, c=9.875(2) A, beta=102.03(3) degrees, Z=4, and R=0.0428). In this complex, platinum has a slightly distorted square planar geometry with the two adjacent corners being occupied by two nitrogen atoms of the mmap ligand, whereas the remaining cis positions are occupied by two oxygen atoms of the oxalate molecule. The mmap ligand is in a boat conformation and forms six-membered chelating rings as well as the oxalate molecule forms five-membered chelating rings with platinum. The complexes were evaluated for their cytotoxic potential against the sensitive A2780 tumor model and cisplatin-resistant clone derived in vitro from potential cells.

  1. Leishmanicidal activity of the crude extract, fractions and major piperidine alkaloids from the flowers of Senna spectabilis.

    Science.gov (United States)

    de Albuquerque Melo, Gabriela Muniz; Silva, Marcela Campelo Rodrigues; Guimarães, Thaís Pereira; Pinheiro, Kátia Mantovani; da Matta, Carolina Barbosa Brito; de Queiroz, Aline Cavalcanti; Pivatto, Marcos; Bolzani, Vanderlan da Silva; Alexandre-Moreira, Magna Suzana; Viegas, Claudio

    2014-02-15

    Senna spectabilis (sin. Cassia excelsa, C. spectabilis) is an endemic tree of South America and Africa, very common in Brazil, where it is known as "canafistula-de-besouro" and "cassia-do-nordeste". In folk medicine, this plant is indicated for the treatment of constipation, insomnia, anxiety, epilepsy, malaria, dysentery and headache. Phytopharmacological studies have also confirmed anticonvulsive, sedative, anti-malarial, antimicrobial and cytotoxic properties of many parts of S. spectabilis. In this communication, we present a comparative study of the leishmanicidal activity of the crude ethanolic extract, its fractions and also the two major alkaloidal metabolites (-)-cassine/(-)-spectaline, trying to establish a relationship between the presence of piperidine alkaloidal constituents and leishmanicidal activity. The growth inhibitory effect of promastigote forms of Leishmania major was determined for the crude extract, fractions of the flowers of S. spectabilis and a mixture of (-)-cassine/(-)-spectaline in comparison to pentamidine used as standard drug. The cytotoxic effects were assessed on macrophage strain J774 by lactate dehydrogenase assay. Fractions dichloromethane (FL-DCM) and n-butanol (FL-Bu) and a mixture of (-)-cassine/(-)-spectaline (∼7:3) exhibited significant activity against the parasite Leishmania major (IC50 values of 0.6±0.1 μg/ml, 1.6±0.9 μg/ml and 24.9±1.4 μg/ml, respectively), without toxic effects on murine macrophages. Due to the promising results elicited, further studies in vivo need to be performed to confirm the therapeutic potential of Senna spectabilis.

  2. Nano magnetite (Fe3O4, an efficient and robust catalyst for the one-pot synthesis of 1-(aryl(piperidin-1-ylmethylnaphthalene-2-ol and 1-(α-amido alkyl-2-naphthol under ultrasound irradiation

    Directory of Open Access Journals (Sweden)

    Masoud Mokhtary

    2017-01-01

    Full Text Available The direct three component reaction via condensation of aldehydes, 2-naphthol and piperidine or acetamide to generate 1-(aryl(piperidin-1-ylmethylnaphthalene-2-ol and N-((2-hydroxy naphthalene-1-yl(arylmethylacetamide derivatives has been carried out over Fe3O4 magnetic nanoparticle with high efficiency under ultrasound irradiation. These reactions were studied under different conditions. In terms of reaction time and yield, it was found that optimum results were obtained for the synthesis of 1-(aryl(piperidin-1-ylmethylnaphthalene-2-ol under solvent free condition and for preparation of N-((2-hydroxynaphthalene-1-yl(arylmethylacetamide in acetic acid under ultrasound irradiation at 80 °C. Clean methodologies, easy workup procedure, and high yields are some advantages of this work.

  3. Synthesis and characterization of new thiourea and urea derivatives of 6-fluoro-3-(piperidin-4-yl)benzo[] isoxazole: In vitro Antimicrobial and Antioxidant activity

    Indian Academy of Sciences (India)

    Hasti Sudhamani; S K Thaslim Basha; Nagam Venkateswarlu; Tartte Vijaya; Chamarthi Nagaraju

    2015-10-01

    A new class of antimicrobial and antioxidant agents, based on thiourea and urea derivatives of 6-fluoro-3-(piperidin-4-yl)benzo[] isoxazole were synthesized by adopting a simple and efficient method. Synthesized compounds were characterized by spectral data of IR, 1H, 13C NMR and mass spectra. The compounds were evaluated for their efficacy as antimicrobial and antioxidant agents. A few compounds showed good antibacterial, antifungal and antioxidant activity when compared to standard drugs and thus represent a new class of promising lead compounds.

  4. The effect of solvent on the kinetics of the oxidation of 3-methyl-2,6-diphenyl-piperidin-4-one by quinolinium fluorochromate in aqueous organic media

    Directory of Open Access Journals (Sweden)

    KUPPANAGOUNDER P. ELANGO

    2001-06-01

    Full Text Available The kinetics of the oxidation of 3-methyl-2,6-diphenyl-piperidin-4-one by quinolinium fluorochromate (QFC have been investigated in aqueous solutions of dimethyl sulphoxide, 1,4-dioxane, tert-butanol and acetone. The influence of the added co-solvent on the reactivity were analysed in the light of various simple and multiple regression equations, viz the Laidler-Eyring, Grunwald-Winstein, Swain and Kamlet-Taft equations. The obtained results showed that the solvation phenomenon plays a dominant role on the reactivity.

  5. New synthetic way to prepare 2-aryl-8-(piperidin-4-yl)-5, 7-dimethoxy-4H-chromen-4-one as key intermediate for CDK inhibitor

    Institute of Scientific and Technical Information of China (English)

    Yan Ling Li; Hao Fang; Wen Fang Xu; Bing He Wang

    2008-01-01

    As an important intermediate to study cyclin-dependent kinase (CDK) inhibitors, 2-aryl-8-(piperidin-4-yl)-5,7-dimethoxy-4H-chromen-4-one derivatives were prepared using β-diketone route with low yield. In our study, chalcone route has been investigatedand the result suggested that the benzaldehydes substituted with electron-donating group give much better yield than β-diketoneroute. This new method will be an efficient way to start further research on new anticancer flavonoids.2008 Hao Fang. PuNished by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.

  6. Binding properties of nine 4-diphenyl-acetoxy-N-methyl-piperidine (4-DAMP) analogues to M1, M2, M3 and putative M4 muscarinic receptor subtypes.

    OpenAIRE

    Waelbroeck, M.; Camus, J.; Tastenoy, M.; Christophe, J.

    1992-01-01

    1. We compared the binding properties of 4-diphenyl-acetoxy-N-methyl-piperidine methiodide (4-DAMP) and nine analogues of this compound on muscarinic receptors of human neuroblastoma NB-OK1 cells (M1 subtype), rat heart (M2 subtype), rat pancreas (M3 subtype) and to the putative M4 subtype in striatum. 2. The requirements for high affinity binding were somewhat different for the four receptor subtypes. In general, the requirements of M3 receptors were more stringent than for M1, M2 or putativ...

  7. Determination of low concentrations of pyridine in piperidine by gas chromatography and infrared spectroscopy; Determinacion de bajas concentraciones de piperidina en piridina por cromatografia de gases y espectroscopia infrarroja

    Energy Technology Data Exchange (ETDEWEB)

    Perez Garcia, M. M.; Parellada Bellod, R.

    1979-07-01

    This paper describes the determination of low amounts of piperidine in pyridine in the concentration range of 0-5%. After an exhausting review of the bibliography on the column selection, the chromatographic separation and determination are made on the following column: 27% Pennwalt- 223; 4% KOH on Gas-Chrom R; 80-100 mesh with flame ionization detector. The retention indexes of both compounds and tho Rohrschneider constants of the phase used are calculated. The minimum detection limit achieved for piperidine is 0,25%. (Author) 25 refs.

  8. Synthesis, characterization, computational calculation and biological studies of some 2,6-diaryl-1-(prop-2-yn-1-yl)piperidin-4-one oxime derivatives.

    Science.gov (United States)

    Sundararajan, G; Rajaraman, D; Srinivasan, T; Velmurugan, D; Krishnasamy, K

    2015-03-15

    A new series of 2,6-diaryl-1-(prop-2-yn-1-yl)piperidin-4-one oximes (17-24) were designed and synthesized from 2,6-diarylpiperidin-4-one oximes (9-16) with propargyl bromide. Unambiguous structural elucidation has been carried out by investigating IR, NMR ((1)H, (13)C, (1)H-(1)H COSY and HSQC), mass spectral techniques and theoretical (DFT) calculations. Further, crystal structure of compound 17 was evaluated by single crystal X-ray diffraction analysis. Single crystal X-ray structural analysis of compound 17 evidenced that the configuration about CN double bond is syn to C-5 carbon (E-form). The existence of chair conformation was further confirmed by theoretical DFT calculation. All the synthesized compounds were screened for in vitro antimicrobial activity against a panel of selected bacterial and fungal strains using Ciprofloxacin and Ketoconazole as standards. The minimum inhibition concentration (MIC) results revealed that most of the 2,6-diaryl-1-(prop-2-yn-1-yl)piperidin-4-one oximes (17, 19, 20 and 23) exhibited better activity against the selected bacterial and fungal strains.

  9. Synthesis and Characterization of the Adducts of Morpholinedithioccarbamate Complexes of Oxovanadium (IV, Nickel(II, and Copper(II with Piperidine and Morpholine

    Directory of Open Access Journals (Sweden)

    Mousami Sharma

    2012-01-01

    Full Text Available A series of 1:1 adducts of bis(morpholinedithiocarbamato complex of VO(IV, 1:1 and 1:2 adducts of bis(morpholinedithiocarbamato complexes of Ni(II and Cu(II with piperidine and morpholine have been synthesized and characterized by elemental analysis, molar conductance, magnetic susceptibility, IR, UV-Vis, and TGA/DTA techniques. Analytical data reveals that VO(IV complex forms only 1:1 adducts with the formula [VO(morphdtc2L].H2O while Ni(II and Cu(II complexes form both 1:1 and 1:2 adducts with 1:1 adducts having general formula Ni(morphdtc2.L and Cu(morphdtc2.L and 1:2 adducts having general formula Ni(morphdtc2.L2 and Cu(morphdtc2.L2 (morphdtc = morpholinedithiocarbamate, L = morpholine and piperidine. Antifungal activity of some complexes has been carried out against the fungal strain Fusarium oxysporium. Thermal studies indicate a continuous weight loss. A square pyramidal geometry has been proposed for the 1:1 adducts of Ni(II and Cu(II complexes while an octahedral geometry has been proposed for the 1:1 adducts of VO(IV and for the 1:2 adducts of Ni(II and Cu(II complexes.

  10. Piperine, a piperidine alkaloid from Piper nigrum re-sensitizes P-gp, MRP1 and BCRP dependent multidrug resistant cancer cells.

    Science.gov (United States)

    Li, Sen; Lei, Yu; Jia, Yingjie; Li, Na; Wink, Michael; Ma, Yonggang

    2011-12-15

    Over-expression of P-gp, MRP1 and BCRP in tumor cells is one of the important mechanisms leading to multidrug resistance (MDR), which impairs the efficacy of chemotherapy. P-gp, MRP1 and BCRP are ABC (ATP-Binding Cassette) transporters, which can expel a variety of lipophilic anti-cancer drugs and protect tumor cells. During a screening of MDR reversal agents among alkaloids of various structural types, a piperidine alkaloid, piperine (a main piperidine alkaloid in Piper nigurm) was identified as an inhibitor. Piperine can potentiate the cytotoxicity of anti-cancer drugs in resistant sublines, such as MCF-7/DOX and A-549/DDP, which were derived from MCF-7 and A-549 cell lines. At a concentration of 50 μM piperine could reverse the resistance to doxorubicin 32.16 and 14.14 folds, respectively. It also re-sensitized cells to mitoxantrone 6.98 folds. In addition, long-term treatment of cells by piperine inhibits transcription of the corresponding ABC transporter genes. These results suggest that piperine can reverse MDR by multiple mechanisms and it may be a promising lead compound for future studies.

  11. Crystal structure of [propane-1,3-diylbis(piperidine-4,1-di-yl)]bis-[(pyridin-4-yl)methanone]-isophthalic acid (1/1).

    Science.gov (United States)

    Murray, Nathan H; Biros, Shannon M; LaDuca, Robert L

    2014-11-01

    In the crystal structure of the title co-crystal, C25H32N4O2·C8H6O4, isophthalic acid and [propane-1,3-diylbis(piperidine-4,1-di-yl)]bis-(pyridin-4-yl-methanone) mol-ecules are connected into supra-molecular chains aligned along the c axis by O-H⋯N hydrogen bonding. These aggregate into supra-molecular layers oriented parallel to the ac plane by C-H⋯O inter-actions. These layers then stack in an ABCD pattern along the b-axis direction by additional C-H⋯O inter-actions to give the full three-dimensional crystal structure. The central chain in the di-pyridyl-amide molecule has an anti-gauche conformation.

  12. Zn-catalyzed enantio- and diastereoselective formal [4 + 2] cycloaddition involving two electron-deficient partners: asymmetric synthesis of piperidines from 1-azadienes and nitro-alkenes.

    Science.gov (United States)

    Chu, John C K; Dalton, Derek M; Rovis, Tomislav

    2015-04-08

    We report a catalytic asymmetric synthesis of piperidines through [4 + 2] cycloaddition of 1-azadienes and nitro-alkenes. The reaction uses earth abundant Zn as catalyst and is highly diastereo- and regioselective. A novel BOPA ligand (F-BOPA) confers high reactivity and enantioselectivity in the process. The presence of ortho substitution on the arenes adjacent to the bis(oxazolines) was found to be particularly impactful, due to limiting the undesired coordination of 1-azadiene to the Lewis acid and thus allowing the reaction to be carried out at lower temperature. A series of secondary kinetic isotope effect studies using a range of ligands implicates a stepwise mechanism for the transformation, involving an initial Michael-type addition of the imine to the nitro-alkene followed by a cyclization event. The stepwise mechanism obviates the electronic requirement inherent to a concerted mechanism, explaining the successful cycloaddition between two electron-deficient partners.

  13. Discovery of 5-substituted tetrahydronaphthalen-2yl-methyl with N-phenyl-N-(piperidin-4-yl)propionamide derivatives as potent opioid receptor ligands.

    Science.gov (United States)

    Deekonda, Srinivas; Wugalter, Lauren; Kulkarni, Vinod; Rankin, David; Largent-Milnes, Tally M; Davis, Peg; Bassirirad, Neemah M; Lai, Josephine; Vanderah, Todd W; Porreca, Frank; Hruby, Victor J

    2015-09-15

    A new series of novel opioid ligands have been designed and synthesized based on the 4-anilidopiperidine scaffold containing a 5-substituted tetrahydronaphthalen-2yl)methyl group with different N-phenyl-N-(piperidin-4-yl)propionamide derivatives to study the biological effects of these substituents on μ and δ opioid receptor interactions. Recently our group reported novel 4-anilidopiperidine analogues, in which several aromatic ring-contained amino acids were conjugated with N-phenyl-N-(piperidin-4-yl)propionamide and examined their biological activities at the μ and δ opioid receptors. In continuation of our efforts in these novel 4-anilidopiperidine analogues, we took a peptidomimetic approach in the present design, in which we substituted aromatic amino acids with tetrahydronaphthalen-2yl methyl moiety with amino, amide and hydroxyl substitutions at the 5th position. In in vitro assays these ligands, showed very good binding affinity and highly selective toward the μ opioid receptor. Among these, the lead ligand 20 showed excellent binding affinity (2 nM) and 5000 fold selectivity toward the μ opioid receptor, as well as functional selectivity in GPI assays (55.20 ± 4.30 nM) and weak or no agonist activities in MVD assays. Based on the in vitro bioassay results the lead compound 20 was chosen for in vivo assessment for efficacy in naïve rats after intrathecal administration. Compound 20 was not significantly effective in alleviating acute pain. This discrepancy between high in vitro binding affinity, moderate in vitro activity, and low in vivo activity may reflect differences in pharmacodynamics (i.e., engaging signaling pathways) or pharmacokinetics (i.e., metabolic stability). In sum, our data suggest that further optimization of this compound 20 is required to enhance in vivo activity.

  14. Preparation and analytical characterization of 1-(1-phenylcyclohexyl)piperidine (PCP) and 1-(1-phenylcyclohexyl)pyrrolidine (PCPy) analogues.

    Science.gov (United States)

    Wallach, Jason; De Paoli, Giorgia; Adejare, Adeboye; Brandt, Simon D

    2014-01-01

    Classic examples of psychoactive arylcycloalkylamines include ketamine and 1-(1-phenylcyclohexyl)piperidine (PCP) and many others serve as important structural templates for neuropharmacological research. The recent emergence of PCP analogues that can be obtained from internet retailers requires the implementation of appropriate monitoring strategies for harm reduction purposes. Access to analytical data plays a key part when encountering these substances, especially if reference material is not available. The present study describes the synthesis of three substituted 1-(1-phenylcyclohexyl)piperidines, (3-MeO-, 4-MeO- and 3-Me-PCP) and three substituted 1-(1-phenylcyclohexyl)pyrrolidine analogues (3-MeO-, 4-MeO- and 3-Me-PCPy). Analytical characterizations of all six arylcyclohexylamines and their primary 1-phenylcyclohexanamine intermediates included gas chromatography ion trap electron- and chemical ionization and high resolution mass spectrometry, liquid chromatography electrospray hybrid triple-quadrupole linear ion trap tandem mass spectrometry, infrared, diode array detection and (1) H and (13) C nuclear magnetic resonance (NMR) spectroscopy. Solvent (CDCl3 vs. d6 -DMSO) and protonation effects (free bases vs hydrochloride salts) were studied in order to investigate the impact on shifts and splitting patterns, for example, when attempting to assign separate axial and equatorial proton chemical shifts of NMR spectra. Differentiation between the isomeric 3-MeO-/4-MeO-PCP and PCPy analogues was feasible under mass spectral conditions. Gas chromatography analysis appeared to induce notable degradation of the 4-MeO-substituted analytes, especially when dealing with the HCl salts which led to the detection of the substituted 1-phenylcyclohex-1-ene nucleus. This phenomenon was observed to be less pronounced with the 3-MeO isomers, possibly due to the resonance properties of the para-methoxy group followed by more facile elimination of the amine. Copyright © 2013

  15. 5-Chloro-5′′-[4-(dimethylaminobenzylidene]-4′-[4-(dimethylaminophenyl]-1′,1′′-dimethyldispiro[indoline-3,2′-pyrrolidine-3′,3′′-piperidine]-2,4′′-dione

    Directory of Open Access Journals (Sweden)

    I. S. Ahmed Farag

    2014-01-01

    Full Text Available The title compound, C34H38ClN5O2, has spiro links connecting the pyrrolidine ring and indole residue, as well as the piperidine and pyrrolidine rings. A half-chair conformation is found for the piperidine ring with the C atom connected to the spiro-C atom lying 0.738 (4 Å out of the plane of the remaining five atoms (r.m.s. deviation = 0.0407 Å. The methylene C atom is the flap in the envelope conformation for the pyrrolidine ring. In the crystal, supramolecular chains are sustained by alternating eight-membered {...HNCO}2 and 14-membered {...HC5O}2 synthons. Chains are connected into a three-dimensional network by (pyrrolidine-bound phenyl-methylC—H...π(pyrrolidine-bound phenyl edge-to-face interactions.

  16. Mefloquine derivatives: Crystal structures and anti-tubercular activities of diphenyl[(( R*, S*)-2,8-bis(trifluoromethyl)quinolin-4-yl)-piperidin-2-yl-methanolato- O, N]boron and (±)- erythro-mefloquinium tetraphenylborate solvates

    Science.gov (United States)

    Wardell, James L.; de Souza, Marcus V. N.; Wardell, Solange M. S. V.; Lourenço, Maria C. S.

    2011-03-01

    Thermolysis of ( R*, S*)-(2-{[2,8-bis(trifluoromethyl)quinolin-4-yl](hydroxy)˜methyl}piperidin-1-ium) tetraphenylborate, (±)- erythro-mefloquinium tetraphenylborate, 3, in solution or neat, provides the oxazaborolidine derivative, diphenyl[( R*, S*)-(2,8-bis(trifluoromethyl)quinolin-4-yl)]piperidin-2-yl-methanolato- O, N]boron, 2. Crystal structures of solvates of 2 and 3 are reported. As shown by the 1H NMR spectrum, 2 undergoes a conformation equilibrium in solution. Both 2 and 3 exhibit important anti-tubercular activities as indicated by the minimum inhibitory concentrations (MIC) of 50 and 12.5 μg/ml, respectively, in in vitro assays against M. tuberculosis H37Rv ATTC 27294.

  17. Syntheses and biological evaluation of {sup 18}F-labeled 3-(1-benzyl-piperidin-4-yl)-1-(1-methyl-1H-indol-3-yl)propan-1-ones for in vivo mapping of acetylcholinesterase

    Energy Technology Data Exchange (ETDEWEB)

    Choe, Y.-S. E-mail: yschoe@samsung.co.kr; Oh, S.-J.; Shim, Insop; Naruto, Shunji; Chi, Dae Yoon; Kim, Sang Eun; Lee, Kyung-Han; Choi, Yong; Kim, B.-T

    2000-04-01

    We synthesized novel {sup 18}F-labeled acetylcholinesterase (AChE) inhibitors, 3-[1-(3- and 4-[{sup 18}F]fluoromethylbenzyl)piperidin-4-yl]-1-(1-methyl-1H-indol-3-yl)propan- 1-ones ([{sup 18}F]1 and [{sup 18}F]2) and 3-[1-(4-[{sup 18}F]fluorobenzyl)piperidin-4-yl]-1-(1-methyl-1H-indol-3-yl)propan- 1-one ([{sup 18}F]3) in high yields (decay-corrected, 25%-40%) and with high effective specific activities (>37 GBq/{mu}mol). Tissue distribution studies of the [{sup 18}F]1 and the [{sup 18}F]3 in mice showed the nonspecific bindings in brain regions, with metabolic defluorination of the [{sup 18}F]1. The result suggests that these radioligands may not be suitable agents for in vivo mapping of AChE, despite their potent in vitro anti-AChE activities.

  18. Identification of a new psychoactive substance in seized material: The synthetic opioid N-phenyl-N-[1-(2-phenethyl)piperidin-4-yl]prop-2-enamide (Acrylfentanyl)

    OpenAIRE

    2016-01-01

    Among the new psychoactive substances (NPS), which have recently emerged on the market, many of the new synthetic opioids have shown to be particularly harmful. A new synthetic analogue of fentanyl, N-(1-phenethylpiperidin-4-yl)-N-phenylacrylamide (acrylfentanyl), was identified in a seized capsule found at a forensic psychiatric ward in Denmark. Gas chromatography with mass spectrometry (GC-MS) identified the synthetic precursor N-phenyl-1-(2-phenylethyl)piperidin-4- amine (ANPP). The precur...

  19. A kryptoracemic salt: 2-{[2,8-bis-(tri-fluoro-meth-yl)quinolin-4-yl](hy-droxy)meth-yl}piperidin-1-ium (+)-3,3,3-tri-fluoro-2-meth-oxy-2-phenyl-propanoate.

    Science.gov (United States)

    Wardell, James L; Wardell, Solange M S V; Tiekink, Edward R T

    2016-06-01

    The asymmetric unit of the title salt, C17H17F6N2O(+)·C10H8F3O3 (-), comprises two piperidin-1-ium cations and two carboxyl-ate anions. The cations, each having an l-shaped conformation owing to the near orthogonal relationship between the quinolinyl and piperidin-1-ium residues, are pseudo-enanti-omeric. The anions have the same absolute configuration but differ in the relative orientations of the carboxyl-ate, meth-oxy and benzene groups. Arguably, the most prominent difference between the anions occurs about the Cq-Om bond as seen in the Cc-Cq-Om-Cm torsion angles of -176.1 (3) and -67.1 (4)°, respectively (q = quaternary, m = meth-oxy and c = carboxyl-ate). The presence of Oh-H⋯Oc and Np-H⋯Oc hydrogen bonds leads to the formation of a supra-molecular chain along the a axis (h = hy-droxy and p = piperidin-1-ium); weak intra-molecular Np-H⋯Oh hydrogen bonds are also noted. Chains are connected into a three-dimensional architecture by C-H⋯F inter-actions. Based on a literature survey, related mol-ecules/cations adopt a uniform conformation in the solid state based on the letter L.

  20. Synthesis, spectroscopic (UV-Vis, FT-IR and NMR), single crystal XRD of 3,5-diethyl -2,6-di(thiophen-2-yl)piperidin-4-on-1-ium picrate: A comprehensive experimental and computational study

    Science.gov (United States)

    Arockia doss, M.; Rajarajan, G.; Thanikachalam, V.; Selvanayagam, S.; Sridhar, B.

    2017-01-01

    A piperidin-4-one containing picrate 3,5-diethyl -2,6-di(thiophen-2-yl)piperidin-4-on-1-ium picrate [3,5-DPPP] was synthesized. The molecular structure of 3,5-DPPP was confirmed by FT-IR, NMR, Uv-Vis, single crystal XRD analysis and DFT and HF methods with 6-31G(d,p) basis set. The XRD data confirm the transfer of protons from picric acid (O2) to piperidin-4-one ring (N1). The 3,5-DPPP compound is stabilized by the presence of intermolecular and intramolecular hydrogen bonds (N-H⋯O, C-H⋯S and C-H⋯O). Density functional theory and HF calculations have been used widely for calculating a wide variety of molecular properties such as optimized structure, FT-IR and Uv-Vis spectra, and provided reliable results which are in agreement with experimental data. The charge density data have been used to understand the properties of molecular systems. Furthermore, several quantum chemical insights have been obtained in the form of the total and partial density of states, the HOMO-LUMO energy gap and electrostatic potential map etc. In addition, the polarizability and first hyperpolarizability were calculated to show the potential applications of 3,5-DPPP in nonlinear optics.

  1. Methods for the synthesis of polyhydroxylated piperidines by diastereoselective dihydroxylation: Exploitation in the two-directional synthesis of aza-C-linked disaccharide derivatives

    Directory of Open Access Journals (Sweden)

    Nelson Adam

    2005-08-01

    Full Text Available Abstract Background: Many polyhydroxylated piperidines are inhibitors of the oligosaccharide processing enzymes, glycosidases and glycosyltransferases. Aza-C-linked disaccharide mimetics are compounds in which saturated polyhydroxylated nitrogen and oxygen heterocycles are linked by an all-carbon tether. The saturated oxygen heterocycle has the potential to mimic the departing sugar in a glycosidase-catalysed reaction and aza-C-linked disaccharide mimetics may, therefore, be more potent inhibitors of these enzymes. Results: The scope, limitations and diastereoselectivity of the dihydroxylation of stereoisomeric 2-butyl-1-(toluene-4-sulfonyl-1,2,3,6-tetrahydro-pyridin-3-ols is discussed. In the absence of a 6-substituent on the piperidine ring, the Upjohn (cat. OsO4, NMO, acetone-water and Donohoe (OsO4, TMEDA, CH2Cl2 conditions allow complementary diastereoselective functionalisation of the alkene of the (2R*,3R* diastereoisomer. However, in the presence of a 6-substituent, the reaction is largely controlled by steric effects with both reagents. The most synthetically useful protocols were exploited in the two-directional synthesis of aza-C-linked disaccharide analogues. A two-directional oxidative ring expansion was used to prepare bis-enones such as (2R,6S,2'S-6-methoxy-2-(6-methoxy-3-oxo-3,6-dihydro-2H-pyran-2-ylmethyl-1-(toluene-4-sulfonyl-1,6-dihydro-2H-pyridin-3-one from the corresponding difuran. Selective substitution of its N,O acetal was possible. The stereochemical outcome of a two-directional Luche reduction step was different in the two heterocyclic rings, and depended on the conformation of the ring. Finally, two-directional diastereoselective dihydroxylation yielded seven different aza-C-linked disaccharide analogues. Conclusion: A two-directional approach may be exploited in the synthesis of aza-C-linked disaccharide mimetics. Unlike previous approaches to similar molecules, neither of the heterocyclic rings is directly derived

  2. Piperidine alkaloids from Piperretrofractum Vahl. protect against high-fat diet-induced obesity by regulating lipid metabolism and activating AMP-activated protein kinase

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Kyung Jin [Department of Biomaterials Science and Engineering, Yonsei University, Seoul 120-749 (Korea, Republic of); Lee, Myoung-Su; Jo, Keunae [Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of); Hwang, Jae-Kwan, E-mail: jkhwang@yonsei.ac.kr [Department of Biomaterials Science and Engineering, Yonsei University, Seoul 120-749 (Korea, Republic of); Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of); Translational Research Center for Protein Functional Control, Yonsei University, Seoul 120-749 (Korea, Republic of)

    2011-07-22

    Highlights: {yields} Piperidine alkaloids from Piperretrofractum Vahl. (PRPAs), including piperine, pipernonaline, and dehydropipernonaline, are isolated as the anti-obesity constituents. {yields} PRPA administration significantly reduces body weight gain without altering food intake and fat pad mass. {yields} PRPA reduces high-fat diet-induced triglyceride accumulation in liver. {yields} PRPAs attenuate HFD-induced obesity by activating AMPK and PPAR{delta}, and regulate lipid metabolism, suggesting their potential anti-obesity effects. -- Abstract: The fruits of Piperretrofractum Vahl. have been used for their anti-flatulent, expectorant, antitussive, antifungal, and appetizing properties in traditional medicine, and they are reported to possess gastroprotective and cholesterol-lowering properties. However, their anti-obesity activity remains unexplored. The present study was conducted to isolate the anti-obesity constituents from P. retrofractum Vahl. and evaluate their effects in high-fat diet (HFD)-induced obese mice. Piperidine alkaloids from P. retrofractum Vahl. (PRPAs), including piperine, pipernonaline, and dehydropipernonaline, were isolated as the anti-obesity constituents through a peroxisome proliferator-activated receptor {delta} (PPAR{delta}) transactivation assay. The molecular mechanism was investigated in 3T3-L1 adipocytes and L6 myocytes. PRPA treatment activated AMP-activated protein kinase (AMPK) signaling and PPAR{delta} protein and also regulated the expression of lipid metabolism-related proteins. In the animal model, oral PRPA administration (50, 100, or 300 mg/kg/day for 8 weeks) significantly reduced HFD-induced body weight gain without altering the amount of food intake. Fat pad mass was reduced in the PRPA treatment groups, as evidenced by reduced adipocyte size. In addition, elevated serum levels of total cholesterol, low-density lipoprotein cholesterol, total lipid, leptin, and lipase were suppressed by PRPA treatment. PRPA also

  3. Design, synthesis, and characterization of a novel, 4-[2-(diphenylmethoxy)ethyl]-1-benzyl piperidine-based, dopamine transporter photoaffinity label.

    Science.gov (United States)

    Dutta, A K; Fei, X S; Vaughan, R A; Gaffaney, J D; Wang, N; Lever, J R; Reith, M E

    2001-03-09

    The dopamine transporter (DAT) has been implicated strongly in cocaine's reinforcing effects. Many derivatives of piperidine analogs of GBR 12909 have been developed and were found to be quite potent and selective for the DAT. In this regard, most of these derivatives were found to be much more selective for the DAT than conventional GBR compounds e.g. GBR 12909 when their selectivity was compared with the serotonin transporter (SERT). A brief structure-activity relationship (SAR) study has been carried out in the development of a novel photoaffinity ligand which illustrated the effect of the presence of a sterically bulky iodine atom next to the azido group in activity and selectivity for the DAT. This SAR study also led to the development of the compound 4 which is one of the most potent and selective blockers for the DAT known today. The photoaffinity ligand [125I]AD-96-129 was incorporated into the DAT molecule as was demonstrated by immunoprecipitation with serum 16 which is specific for DAT. This photolabeling was antagonized by DAT-specific blockers and was unaffected by specific SERT and norepinephrine transporter (NET) blockers indicating interaction of this novel ligand with the DAT.

  4. DNA Probe and Cleavage Studies Based on the Interaction between DNA and Yb, Er Complexes of 2-[(Trifluoroaceto)aceto]thinophene-piperidine Ligands

    Institute of Scientific and Technical Information of China (English)

    YIN Caixia; HUO Fangjun; WU Yanbo; LIU Yanlin; YANG Pin

    2009-01-01

    Two kinds of Ln complexes of [Ln(TTA)4]·Hp (Ln=Yb or Er, TrA=2-[(Trifluoroaceto)aceto]thinophene, HP =piperidine) have been synthesized and characterized, and their DNA-binding properties investigated using UV spectra, fluorescent spectra, viscometry and molecular modeling. The results show that they can intercalate into the double helices of DNA. More important thing is that their fluorescence intensity can be enhanced by DNA, thererfore, a sensitive fluorescence method for the determination of DNA may be developed. The cleavage reaction on plasmid DNA has been monitored by agarose gel electrophoresis. Interestingly, the complexes can cleave circular plasmid pBR322 DNA at pH=7.2 and 37 ℃. In addition, BDNPP [bis(2,4-dinitropheny1)-phosphate] was chosen as a model compound to further study their cleavage mechanism of pBR322 DNA. From the first-order kinetics equation, it was proved indirectly that the mechanism may be a hydrolytic cleavage.

  5. Spectrophotometric and thermal studies on the charge--transfer complexes of 4-(aminomethyl) piperidine as donor with σ- and π-electron acceptors.

    Science.gov (United States)

    Mostafa, Adel; El-Ghossein, Nada; Alqaradawi, Siham Y

    2014-01-24

    The spectroscopic characteristics of the solid charge-transfer molecular complexes (CT) formed in the reaction of the electron donor 4-(aminomethyl) piperidine (4AMP) with the σ-acceptor iodine and the π-acceptors 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), 2,4,4,6-tetrabromo-2,5-cyclohexadienone (TBCHD) and 7,7,8,8-tetracyanoquinodimethane (TCNQ) have been studied in chloroform at 25°C. These were investigated through electronic, infrared spectra and thermal analysis as well as elemental analysis. The results show that the formed solid CT-complexes have the formulas [(4AMP)I](+)I3(-), [(4AMP)(DDQ)2] and [(4AMP)(TBCHD)] while in the case of 4AMP-TCNQ reaction, a short-lived CT complex is formed followed by rapid N-substitution by TCNQ forming the final reaction product 7,7,8-tricyano-8-aminomethylpiperidinylquinodimethane [TCAMPQDM] in full agreement with the known reaction stoichiometries in solution as well as the elemental measurements and the thermal analysis confirmed the structure of the obtained compounds. The formation constant kCT, molar extinction coefficient εCT, free energy change ΔG(0) and CT energy ECT have been calculated for the CT-complexes [(4AMP)I](+)I3(-), [(4AMP)(DDQ)2] and [(4AMP)(TBCHD)].

  6. Pharmacokinetics and tissue distribution of the new non-imidazole histamine H3 receptor antagonist 1-[3-(4-tert-butylphenoxy) propyl]piperidine in rats.

    Science.gov (United States)

    Szafarz, Malgorzata; Kryczyk, Agata; Lazewska, Dorota; Kiec-Kononowicz, Katarzyna; Wyska, Elzbieta

    2015-01-01

    1. The aim of this study was to evaluate pharmacokinetics and tissue distribution of novel histamine H3 receptor antagonist 1-[3-(4-tert-butylphenoxy)propyl]piperidine (compound DL76). 2. Following intravenous administration of DL76 at the dose of 3 mg/kg, pharmacokinetic parameters were calculated using non-compartmental analysis. The systemic serum clearance was 10.08 L/h/kg and the estimated blood clearance was 5.64 L/h/kg. The volume of distribution at steady state was 16.1 L/kg which was greater than total body water, terminal half-life and MRT equalled 1.41 h and 1.6 h, respectively. The two-compartment pharmacokinetic model with enterohepatic circulation was also successfully fitted to the experimental data. 3. After systemic administration, DL76 was rapidly distributed into all organs studied (liver, kidney, brain, and lung). The highest AUC of DL76 was observed in lungs followed by brain, where the exposure to the investigated compound expressed as AUC was almost 30 times higher than in serum. 4. Bioavailability, calculated based on the area-under-the-concentration-time curve extrapolated to infinity after intravenous and intragastric administration of the dose 3 mg/kg, equalled 60.9%.

  7. 4-(Piperidin-1-yl)-4H-benzo[b]tetra­zolo[1,5-d][1,4]diazepin-5(6H)-one

    Science.gov (United States)

    Nichol, Gary S.; Xu, Zhigang; Kaiser, Christine E.; Hulme, Christopher

    2011-01-01

    There are two crystallographically unique mol­ecules present in the asymmetric unit of the title compound, C14H16N6O; in both mol­ecules, the seven-membered diazepinone ring adopts a boat-like conformation and the chair conformation piperidine ring is an axial substituent on the diazepinone ring. In the crystal, each mol­ecule forms hydrogen bonds with its respective symmetry equivalents. Hydrogen bonding between mol­ecule A and symmetry equivalents forms two ring motifs, the first formed by inversion-related N—H⋯O inter­actions and the second formed by C—H⋯O and C—H⋯N inter­actions. The combination of both ring motifs results in the formation of an infinite double tape, which propagates in the a-axis direction. Hydrogen bonding between mol­ecule B and symmetry equivalents forms one ring motif by inversion-related N—H⋯O inter­actions and a second ring motif by C—H⋯O inter­actions, which propagate as a single tape parallel with the c axis. PMID:21522729

  8. 4-(Piperidin-1-yl-4H-benzo[b]tetrazolo[1,5-d][1,4]diazepin-5(6H-one

    Directory of Open Access Journals (Sweden)

    Christopher Hulme

    2011-01-01

    Full Text Available There are two crystallographically unique molecules present in the asymmetric unit of the title compound, C14H16N6O; in both molecules, the seven-membered diazepinone ring adopts a boat-like conformation and the chair conformation piperidine ring is an axial substituent on the diazepinone ring. In the crystal, each molecule forms hydrogen bonds with its respective symmetry equivalents. Hydrogen bonding between molecule A and symmetry equivalents forms two ring motifs, the first formed by inversion-related N—H...O interactions and the second formed by C—H...O and C—H...N interactions. The combination of both ring motifs results in the formation of an infinite double tape, which propagates in the a-axis direction. Hydrogen bonding between molecule B and symmetry equivalents forms one ring motif by inversion-related N—H...O interactions and a second ring motif by C—H...O interactions, which propagate as a single tape parallel with the c axis.

  9. 4-(Piperidin-1-yl)-4H-benzo[b]tetra-zolo[1,5-d][1,4]diazepin-5(6H)-one.

    Science.gov (United States)

    Nichol, Gary S; Xu, Zhigang; Kaiser, Christine E; Hulme, Christopher

    2010-12-04

    There are two crystallographically unique mol-ecules present in the asymmetric unit of the title compound, C(14)H(16)N(6)O; in both mol-ecules, the seven-membered diazepinone ring adopts a boat-like conformation and the chair conformation piperidine ring is an axial substituent on the diazepinone ring. In the crystal, each mol-ecule forms hydrogen bonds with its respective symmetry equivalents. Hydrogen bonding between mol-ecule A and symmetry equivalents forms two ring motifs, the first formed by inversion-related N-H⋯O inter-actions and the second formed by C-H⋯O and C-H⋯N inter-actions. The combination of both ring motifs results in the formation of an infinite double tape, which propagates in the a-axis direction. Hydrogen bonding between mol-ecule B and symmetry equivalents forms one ring motif by inversion-related N-H⋯O inter-actions and a second ring motif by C-H⋯O inter-actions, which propagate as a single tape parallel with the c axis.

  10. Diastereomeric complex of ( R/ S)-piperidine-3-carboxylic acid with (2 R,3 R)-tartaric acid: Structural, spectroscopic and computational studies

    Science.gov (United States)

    Bartoszak-Adamska, E.; Dega-Szafran, Z.; Jaskólski, M.; Szafran, M.

    2011-07-01

    2:2 Complex of ( R) and ( S)-piperidine-3-carboxylic acids (P3C) with (2 R,3 R) -tartaric acid (TA), 1, has been characterized by single-crystal X-ray analysis, FTIR and NMR spectroscopies, and by DFT calculations. The crystals of 1 are monoclinic, space group P2 1. The crystal structure is formed by two distinct P3CH +·TA - components, A and B, linked by an O-H⋯O hydrogen bond of 2.603(2) Å. The A and B components differ in the absolute configuration of the C(3) atom of P3CH +; ( S) in A and ( R) in B. The piperidinium-3-carboxylic acid and (2 R,3 R)-semi-tartrate anion moieties of the components A and B are linked by O-H⋯O hydrogen bonds of 2.517(1) and 2.535(1) Å, respectively. In A and B the piperidinium rings adopt the chair conformation with the carboxyl group in the equatorial position. The structures of the monomers of P3CH +·TA -, 3A and 3B, as well as of a dimer 2, have been optimized by the B3LYP/6-31G(d,p) approach. The chemical shift assignments were based on two-dimensional 1H- 1H and 1H- 13C experiments.

  11. Enantioselective σ1 receptor binding and biotransformation of the spirocyclic PET tracer 1'-benzyl-3-(3-fluoropropyl)-3H-spiro[[2]benzofuran-1,4'-piperidine].

    Science.gov (United States)

    Wiese, Christian; Grosse Maestrup, Eva; Schepmann, Dirk; Grimme, Stefan; Humpf, Hans-Ulrich; Brust, Peter; Wünsch, Bernhard

    2011-02-01

    It was shown that racemic (±)-2 [1'-benzyl-3-(3-fluoropropyl)-3H-spiro[[2]benzofuran-1,4'-piperidine], WMS-1813] represents a promising positron emission tomography (PET) tracer for the investigation of centrally located σ(1) receptors. To study the pharmacological activity of the enantiomers of 2, a preparative HPLC separation of (R)-2 and (S)-2 was performed. The absolute configuration of the enantiomers was determined by CD-spectroscopy together with theoretical calculations of the CD-spectrum of a model compound. In receptor binding studies with the radioligand [(3)H]-(+)-pentazocine, (S)-2 was thrice more potent than its (R)-configured enantiomer (R)-2. The metabolic degradation of the more potent (S)-enantiomer was considerably slower than the metabolism of (R)-2. The structures of the main metabolites of both enantiomers were elucidated by determination of the exact mass using an Orbitrap-LC-MS system. These experiments showed a stereoselective biotransformation of the enantiomers of 2. Copyright © 2010 Wiley-Liss, Inc.

  12. catena-Poly[lead(II-[μ-2,4-diamino-6-(piperidin-1-ylpyrimidine N-oxide-κ2O:O]di-μ-iodido

    Directory of Open Access Journals (Sweden)

    Maryam Ranjbar

    2009-07-01

    Full Text Available The N-oxide O atom of the minoxidil unit in the 1/1 adduct with lead(II iodide, [PbI2(C9H15N5O]n, bridges two PbII atoms, as do each of the I atoms. The bridging interactions give rise to a linear chain motif that propagates along the a axis of the orthorhombic unit cell. The coordination sphere around the six-coordinate PbII atom is a distorted ψ-monocapped octahedron in which the stereochemically active lone pair caps one of the faces defined by the O and I atoms forming the longer Pb—O or Pb—I bonds. The PbII atom lies on a mirror plane; the mirror plane is perpendicular to the pyrimidine ring and it bisects the piperidine ring. The aromatic ring is disordered about the mirror plane with respect to the 1-nitrogen and 5-carbon atoms.

  13. Crystal structure and Hirshfeld surface analysis of 2-{[2,8-bis(trifluoromethylquinolin-4-yl](hydroxymethyl}piperidin-1-ium 2-hydroxy-2-phenylacetate hemihydrate

    Directory of Open Access Journals (Sweden)

    James L. Wardell

    2016-11-01

    Full Text Available The asymmetric unit of the title salt, C17H17F6N2O+·C8H7O3−·0.5H2O, comprises a pair of pseudo-enantiomeric (i.e. related by a non-crystallographic centre of symmetry piperidin-1-ium cations, two carboxylate anions and a water molecule of crystallization. The cations have similar conformations approximating to a letter, L: one of them shows disorder of its –CF3 group over two sets of sites in a 0.775 (3:0.225 (3 ratio. Distinctive conformations are found for the anions, one with the carboxylate group lying to one side of the plane through the phenyl ring and the other where the oxygen atoms lie to either side of the plane. In the latter, an intramolecular hydroxy-O—H...O(carboxylate charge-assisted hydrogen bond is found. The packing features extensive O—H...O,N hydrogen bonding, often charge-assisted; C—H...π interactions are also formed. The hydrogen bonding results in the formation of five distinctive supramolecular synthons and assembles molecules in the ac plane. The quinolinyl rings lie to either side of the layer and inter-digitate with layers on either side, are approximately parallel to the b axis and are connected by π–π [inter-centroid separation = 3.6904 (18 Å] as well as C—F...π(quinolinyl interactions to consolidate the three-dimensional crystal. The dominance of the conventional hydrogen bonding in the molecular packing is confirmed by an analysis of the Hirshfeld surface.

  14. 8-{1-[(4′-Fluoro-[1,1′-biphenyl]-4-ylmethyl]piperidin-4-yl}-3,4-dihydroquinolin-2(1H-one chloroform 0.25-solvate

    Directory of Open Access Journals (Sweden)

    Nisar Ullah

    2014-02-01

    Full Text Available In the asymmetric unit of the title compound, C27H27FN2O·0.25CHCl3, there are two independent molecules (A and B together with a partially disordered chloroform molecule situated about an inversion center. The conformation of the two molecules is very similar. The bridging piperidine rings each have a chair conformation while the piperidin-2-one rings of the quinoline moiety have screw-boat conformations. The benzene rings of the biphenyl moiety are inclined to one another by 26.37 (4 and 23.75 (15° in molecules A and B, respectively. The mean plane of the central piperidine ring [r.m.s. deviation = 0.241 (2 Å in both molecules A and B] is inclined to the benzene ring of the quinoline moiety by 80.06 (4 in A and 83.75 (15° in B, while it is inclined to the adjacent benzene ring of the biphenyl group by 73.623 (15 in A and 75.65 (14° in B. In the crystal, individual molecules are linked by pairs of N—H...O hydrogen bonds, forming A–A and B–B inversion dimers with R22(8 ring motifs. The dimers are stabilized by C—H...O hydrogen bonds and linked via C—H...F and C—H...N hydrogen bonds into a three-dimensional network. Several C—H...π interactions are also present.

  15. Exploring the orthosteric binding site of the γ-aminobutyric acid type A receptor using 4-(Piperidin-4-yl)-1-hydroxypyrazoles 3- or 5-imidazolyl substituted: design, synthesis, and pharmacological evaluation.

    Science.gov (United States)

    Krall, Jacob; Jensen, Claus H; Sørensen, Troels E; Nielsen, Birgitte; Jensen, Anders A; Sander, Tommy; Balle, Thomas; Frølund, Bente

    2013-08-22

    A series of 4-(piperidin-4-yl)-1-hydroxypyrazole (4-PHP) 3- or 5-imidazolyl substituted analogues have been designed, synthesized, and characterized pharmacologically. All analogues showed binding affinities in the low micro- to low nanomolar range at native rat GABAA receptors and were found to be antagonists at the human α1β2γ2s receptor. The structure-activity relationship of the compound series demonstrates distinct differences in size and architecture of previously discovered cavities in the vicinity of the 4-PHP scaffold in the orthosteric binding site.

  16. 1-(4-(6-Fluorobenzo [d] isoxazol-3-yl) piperidin-1-yl)-2-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl) ethanone: Synthesis, spectroscopic characterization, Hirshfeld surface analysis, cytotoxic studies and docking studies

    Science.gov (United States)

    Govindhan, M.; Viswanathan, V.; Karthikeyan, S.; Subramanian, K.; Velmurugan, D.

    2017-08-01

    Compound 1-(4-(6-fluorobenzo[d] isoxazol-3-yl) piperidin-1-yl)-2-(4-(hydroxymethyl)-1H-1, 2,3-triazol-1-yl) ethanone was synthesized in good yield by using click chemistry approach with 2-azido-1-(4-(6-flurobenzo[d]isooxazol-3-yl)piperidin-1-yl)ethanone as a starting material. The synthesized compound was characterized using IR, NMR and MS studies. Thermal stability of the compound was analyzed by using TGA and DSC technique. The single crystal XRD analysis was taken part, to confirm the structure of the compound. The intercontacts in the crystal structure are analyzed using Hirshfeld surfaces computational method. Cytotoxicity of the synthesized compound was evaluated and the results were reported. The binding analysis carried out between the newly synthesized molecule with human serum albumin using fluorescence spectroscopy technique to understand the pharmacokinetics nature of the compound for further biological application. The molecular docking studies were evaluated for the compound to elucidate insights of new molecules in carrier protein.

  17. In vivo evaluation in rats of [{sup 18}F]1-(2-fluoroethyl)-4-[(4-cyanophenoxy)methyl]piperidine as a potential radiotracer for PET assessment of CNS sigma-1 receptors

    Energy Technology Data Exchange (ETDEWEB)

    Waterhouse, Rikki N. [Department of Psychiatry, Columbia University, New York, NY 10032 (United States) and Department of Radiology, Columbia University, New York, NY 10032 (United States) and Neurobiology and Imaging Program, Department of Biological Psychiatry, New York State Psychiatric Institute, New York, NY 10032 (United States)]. E-mail: rnw7@columbia.edu; Chang, Raymond C. [Department of Psychiatry, Columbia University, New York, NY 10032 (United States); Neurobiology and Imaging Program, Department of Biological Psychiatry, New York State Psychiatric Institute, New York, NY 10032 (United States); Zhao, Jun [Department of Psychiatry, Columbia University, New York, NY 10032 (United States); Neurobiology and Imaging Program, Department of Biological Psychiatry, New York State Psychiatric Institute, New York, NY 10032 (United States); Carambot, Patty E. [Department of Psychiatry, Columbia University, New York, NY 10032 (United States); Neurobiology and Imaging Program, Department of Biological Psychiatry, New York State Psychiatric Institute, New York, NY 10032 (United States)

    2006-02-15

    Introduction: Sigma-1 receptors are expressed throughout the mammalian central nervous system (CNS) and are implicated in several psychiatric disorders, including schizophrenia and depression. We have recently evaluated the high-affinity (K {sub D}=0.5{+-}0.2 nM, log P=2.9) sigma-1 receptor radiotracer [{sup 18}F]1-(3-fluoropropyl)-4-(4-cyanophenoxymethyl)piperidine, [{sup 18}F]FPS, in humans. In contrast to appropriate kinetics exhibited in baboon brain, in the human CNS, [{sup 18}F]FPS does not reach pseudoequilibrium by 4 h, supporting the development of a lower-affinity tracer [Waterhouse RN, Nobler MS, Chang RC, Zhou Y, Morales O, Kuwabara H, et al. First evaluation of the sigma-1 receptor radioligand [{sup 18}F]1-3-fluoropropyl-4-((4-cyanophenoxy)-methyl)piperidine ([{sup 18}F]FPS) in healthy humans. Neuroreceptor Mapping 2004, July 15-18th, Vancouver, BC Canada 2004]. We describe herein the in vivo evaluation in rats of [{sup 18}F]1-(2-fluoroethyl)-4-[(4-cyanophenoxy)methyl]piperidine ([{sup 18}F]SFE) (K {sub D}=5 nM, log P=2.4), a structurally similar, lower-affinity sigma-1 receptor radioligand. Methods: [{sup 18}F]SFE was synthesized (n=4) as previously described in good yield (54{+-}6% EOB), high specific activity (2.1{+-}0.6 Ci/{mu}mol EOS) and radiochemical purity (98{+-}1%) and evaluated in awake adult male rats. Results: Similar to [{sup 18}F]FPS, regional brain radioactivity concentrations [percentage of injected dose per gram of tissue (%ID/g), 15 min] for [{sup 18}F]SFE were highest in occipital cortex (1.86{+-}0.06 %ID/g) and frontal cortex (1.76{+-}0.38 %ID/g), and lowest in the hippocampus (1.01{+-}0.02%ID/g). Unlike [{sup 18}F]FPS, [{sup 18}F]SFE cleared from the brain with {approx}40% reduction in peak activity over a 90-min period. Metabolite analysis (1 h) revealed that [{sup 18}F]SFE was largely intact in the brain. Blocking studies showed a large degree (>80%) of saturable binding for [{sup 18}F]SFE in discrete brain regions. Conclusions

  18. Discovery and optimization of a novel series of highly CNS penetrant M4 PAMs based on a 5,6-dimethyl-4-(piperidin-1-yl)thieno[2,3-d]pyrimidine core.

    Science.gov (United States)

    Wood, Michael R; Noetzel, Meredith J; Engers, Julie L; Bollinger, Katrina A; Melancon, Bruce J; Tarr, James C; Han, Changho; West, Mary; Gregro, Alison R; Lamsal, Atin; Chang, Sichen; Ajmera, Sonia; Smith, Emery; Chase, Peter; Hodder, Peter S; Bubser, Michael; Jones, Carrie K; Hopkins, Corey R; Emmitte, Kyle A; Niswender, Colleen M; Wood, Michael W; Duggan, Mark E; Conn, P Jeffrey; Bridges, Thomas M; Lindsley, Craig W

    2016-07-01

    This Letter describes the chemical optimization of a novel series of M4 positive allosteric modulators (PAMs) based on a 5,6-dimethyl-4-(piperidin-1-yl)thieno[2,3-d]pyrimidine core, identified from an MLPCN functional high-throughput screen. The HTS hit was potent and selective, but not CNS penetrant. Potency was maintained, while CNS penetration was improved (rat brain:plasma Kp=0.74), within the original core after several rounds of optimization; however, the thieno[2,3-d]pyrimidine core was subject to extensive oxidative metabolism. Ultimately, we identified a 6-fluoroquinazoline core replacement that afforded good M4 PAM potency, muscarinic receptor subtype selectivity and CNS penetration (rat brain:plasma Kp>10). Moreover, this campaign provided fundamentally distinct M4 PAM chemotypes, greatly expanding the available structural diversity for this exciting CNS target.

  19. Synthesis and biological evaluation of 1-(4-[{sup 18}f]fluorobenzyl)-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine for in vivo studies of acetylcholinesterase

    Energy Technology Data Exchange (ETDEWEB)

    Leea, Sang-Yoon; Choe, Yearn Seong E-mail: yschoe@samsung.co.kr; Sugimoto, Hachiro; Kim, Sang Eun; Hwang, Sae Hwan; Lee, Kyung-Han; Choi, Yong; Lee, Jeewoo; Kim, Byung-Tae

    2000-11-01

    We synthesized and evaluated 1-(4-fluorobenzyl)-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine (4-FDP), which is an analog of donepezil. The 4-[{sup 18}F]FDP was prepared by reductive alkylation of debenzylated donepezil with 4-[{sup 18}F]fluorobenzaldehyde in high radiochemical yield (decay-corrected, 40-52%) and with high effective specific activity (30-38 GBq/{mu}mol). Tissue distribution studies in mice demonstrated nonspecific distribution of the 4-[{sup 18}F]FDP in brain regions, suggesting that this radioligand may not be a suitable agent for in vivo studies of acetylcholinesterase (AChE), despite its potent in vitro biological activity.

  20. Novel triple reuptake inhibitors with low risk of CAD associated liabilities: design, synthesis and biological activities of 4-[(1S)-1-(3,4-dichlorophenyl)-2-methoxyethyl]piperidine and related compounds.

    Science.gov (United States)

    Ishichi, Yuji; Kimura, Eiji; Honda, Eiji; Yoshikawa, Masato; Nakahata, Takashi; Terao, Yasuko; Suzuki, Atsuko; Kawai, Takayuki; Arakawa, Yuuichi; Ohta, Hiroyuki; Kanzaki, Naoyuki; Nakagawa, Hideyuki; Terauchi, Jun

    2013-08-01

    A novel triple reuptake inhibitor with low potential of liabilities associated with cationic amphiphilic drug (CAD) was identified following an analysis of existing drugs. Low molecular weight (MW liabilities (CYP2D6 inhibition, hERG inhibition and phospholipidosis). Based on the hypothesis, a series of piperidine compounds was designed with consideration of the common characteristic features of CNS drugs. Optimization of the side chain by adjusting overall lipophilicity suggested that incorporation of a methoxymethyl group could provide compounds with a balance of both potent reuptake inhibition and low liability potential. Compound (S)-3a showed a potent antidepressant-like effect in the mice tail suspension test (MED = 10 mg/kg, p.o.), proportional monoamine transporter occupancies and enhancement of monoamine concentrations in mouse prefrontal cortex.

  1. Synthesis and evaluation of radioiodinated 1-{2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinolin-8-yl}piperidin-4-amine derivatives for platelet-derived growth factor receptor β (PDGFRβ) imaging.

    Science.gov (United States)

    Effendi, Nurmaya; Ogawa, Kazuma; Mishiro, Kenji; Takarada, Takeshi; Yamada, Daisuke; Kitamura, Yoji; Shiba, Kazuhiro; Maeda, Takehiko; Odani, Akira

    2017-08-16

    Platelet-derived growth factor receptor β (PDGFRβ) is a transmembrane tyrosine kinase receptor and it is upregulated in various malignant tumors. Radiolabeled PDGFRβ inhibitors can be a convenient tool for the imaging of tumors overexpressing PDGFRβ. In this study, [(125)I]-1-{5-iodo-2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinoline-8-yl}piperidin-4-amine ([(125)I]IIQP) and [(125)I]-N-3-iodobenzoyl-1-{2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinolin-8-yl}-piperidin-4-amine ([(125)I]IB-IQP) were designed and synthesized, and their potential as PDGFRβ imaging agents was evaluated. In cellular uptake experiments, [(125)I]IIQP and [(125)I]IB-IQP showed higher uptake by PDGFRβ-positive cells than by PDGFRβ-negative cells, and the uptake in PDGFRβ-positive cells was inhibited by co-culture with PDGFRβ ligands. The biodistribution of both radiotracers in normal mice exhibited hepatobiliary excretion as the main route. In mice inoculated with BxPC3-luc (PDGFRβ-positive), the tumor uptake of radioactivity at 1h after the injection of [(125)I]IIQP was significantly higher than that after the injection of [(125)I]IB-IQP. These results indicated that [(125)I]IIQP can be a suitable PDGFRβ imaging agent. However, further modification of its structure will be required to obtain a more appropriate PDGFRβ-targeted imaging agent with a higher signal/noise ratio. Copyright © 2017. Published by Elsevier Ltd.

  2. DuP 734 [1-(cyclopropylmethyl)-4-(2'(4''-fluorophenyl)-2'-oxoethyl)- piperidine HBr], a sigma and 5-hydroxytryptamine2 receptor antagonist: receptor-binding, electrophysiological and neuropharmacological profiles.

    Science.gov (United States)

    Tam, S W; Steinfels, G F; Gilligan, P J; Schmidt, W K; Cook, L

    1992-12-01

    It has been suggested that sigma receptor antagonists may be useful as antipsychotic drugs and that 5-hydroxytryptamine (5-HT2) receptor antagonists produce improvements of the negative symptoms of schizophrenia. [1-(Cyclopropylmethyl)-4-(2'-(4''-fluorophenyl)-2'- oxoethyl)-piperidine HBr] (DuP 734) is a novel compound with high affinity for the sigma (Ki = 10 nM) and 5-HT2 (Ki = 15 nM) receptors, but low affinity for dopamine receptors (Ki > 1000 nM) as well as 33 other receptors, ion channels and second messenger systems in vitro. DuP 734 did not inhibit the synaptosomal uptake of dopamine, 5-HT or norepinephrine. Oral administration of DuP 734 potently blocked 5-hydroxy-L-trytophan (5-HTP)-induced head twitch in the rat (ED50 = 6.5 mumol/kg), indicating 5-HT2 antagonist activity. Extracellular single-unit recording studies demonstrated that DuP 734 antagonized the effect of the selective sigma ligand (+)-3-(3-hydroxyphenyl-N-(1-propyl) piperidine [(+)-3-PPP] on dopamine neuronal activity in the substantia nigra of the rat with an ED90 of 3.6 mumol/kg i.v. The sigma receptor agonists (+)-SKF 10,047 and phencyclidine both elicited rotational behavior in rats with unilateral lesion of the substantia nigra. The rotational behavior induced by either (+)-SKF 10,047 or phencyclidine was dose-dependently antagonized by DuP 734 with oral ED50 of 8.7 and 19.6 mumol/kg, respectively. The 5-HT2 receptor antagonist ICI 169,369, even at high doses (up to 33 mumol/kg, s.c.), did not antagonize the rotational behavior induced by (+)-SKF 10,047.(ABSTRACT TRUNCATED AT 250 WORDS)

  3. CuAAC click chemistry with N-propargyl 1,5-dideoxy-1,5-imino-D-gulitol and N-propargyl 1,6-dideoxy-1,6-imino-D-mannitol provides access to triazole-linked piperidine and azepane pseudo-disaccharide iminosugars displaying glycosidase inhibitory properties.

    Science.gov (United States)

    Zamoner, Luís Otávio B; Aragão-Leoneti, Valquíria; Mantoani, Susimaire P; Rugen, Michael D; Nepogodiev, Sergey A; Field, Robert A; Carvalho, Ivone

    2016-06-24

    Protecting group-free synthesis of 1,2:5,6-di-anhydro-D-mannitol, followed by ring opening with propargylamine and subsequent ring closure produced a separable mix of piperidine N-propargyl 1,5-dideoxy-1,5-imino-D-gulitol and azepane N-propargyl 1,6-dideoxy-1,6-imino-D-mannitol. In O-acetylated form, these two building blocks were subjected to CuAAC click chemistry with a panel of three differently azide-substituted glucose building blocks, producing iminosugar pseudo-disaccharides in good yield. The overall panel of eight compounds, plus 1-deoxynojirimycin (DNJ) as a benchmark, was evaluated as prospective inhibitors of almond β-glucosidase, yeast α-glucosidase and barley β-amylase. The iminosugar pseudo-disaccharides showed no inhibitory activity against almond β-glucosidase, while the parent N-propargyl 1,5-dideoxy-1,5-imino-D-gulitol and N-propargyl 1,6-dideoxy-1,6-imino-D-mannitol likewise proved to be inactive against yeast α-glucosidase. Inhibitory activity could be reinstated in the former series by appropriate substitution on nitrogen. The greater activity of the piperidine could be rationalized based on docking studies. Further, potent inhibition of β-amylase was observed with compounds from both the piperidine and azepane series.

  4. Synthesis, electronic structure investigation of 3-pentyl-2,6-di(furan-2-yl)piperidin-4-one by FT-IR, FT-Raman and UV-Visible spectral studies and ab initio/DFT calculations.

    Science.gov (United States)

    Arockia Doss, M; Savithiri, S; Rajarajan, G; Thanikachalam, V; Anbuselvan, C

    2015-12-05

    FT-IR and FT-Raman spectra of 3-pentyl-2,6-di(furan-2-yl) piperidin-4-one (3-PFPO) were recorded in the solid phase. The structural and spectroscopic analyses of 3-PFPO were made by using B3LYP/HF level with 6-311++G(d, p) basis set. The fundamental vibrations are assigned on the basis of the total energy distribution (TED) of the vibrational modes, calculated with scaled quantum mechanics (SQM) method and PQS program. Comparison of the observed fundamental vibrational frequencies of 3-PFPO with calculated results by HF and DFT methods indicates that B3LYP is superior to HF method for molecular vibrational problems. The electronic properties such as excitation energies, oscillator strength, wavelengths and HOMO-LUMO energies were obtained by time-dependent DFT (TD-DFT) approach. The polarizability and first order hyperpolarizability of the title molecule were calculated and interpreted. The hyperconjugative interaction energy (E((2))) and electron densities of donor (i) and acceptor (j) bonds were calculated using NBO analysis. In addition, MEP and atomic charges of carbon, nitrogen, oxygen and hydrogen were calculated using B3LYP/6-311++G(d, p) level theory. Moreover, thermodynamic properties (heat capacities, entropy and enthalpy) of the title compound at different temperatures were calculated in gas phase. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. Synthesis of 3-Alkylidene-piperidin-4-ones via Intramolecular Nucleophilic Substitution Promoted by TMSCl%TMSCl促进的分子内亲核取代反应合成α-亚烷基-哌啶酮

    Institute of Scientific and Technical Information of China (English)

    钟铮; 密霞; 秦树艳; 冯卫生; 孙德梅

    2016-01-01

    以烯基碘代物为底物,丁基锂为锂代试剂,THF为溶剂,在TMSCl促进下通过分子内亲核取代反应合成了4个α-亚烷基-哌啶酮(2a~2d),其结构经1H NMR,13C NMR和HR-MS(ESI)确证。在最优反应条件(12 mmol, n-BuLi 2.4 mmol, TMSCl 3 mmol, THF 20 mL,于170℃反应1 h)下,2a~2d收率68%~84%。%Four 3-alkylidene-piperidin-4-one analogues (2a~2d) were synthesized by intramolecular nucleophilic substitution promoted by chlorotrimethylsilane , using vinyl iodides as precursors , n-BuLi as lithiating reagent , and THF as solvent .The structures were confirmed by 1 H NMR, 13 C NMR and HR-MS(ESI).The yields of 2a~2d were 68%~84% under the optimized reaction conditions (1 2 mmol, n-BuLi 2.4 mmol, TMSCl 3 mmol, THF 20 mL, reaction at 170 ℃for 1 h).

  6. Synthesis, characterisation, stereochemistry and dynamic NMR studies of N-nitroso and N-formyl-t-3-isopropyl-r-2,c-6-bis(4-methoxyphenyl)piperidin-4-ones

    Science.gov (United States)

    Ponnuswamy, S.; Sethuvasan, S.; Thirunavukarasu, K.

    2015-06-01

    The synthesis, characterisation and stereochemical investigations were made for N-nitroso (2) and N-formyl (3) derivatives of t-3-isopropyl-r-2,c-6-bis(4-methoxyphenyl)piperidin-4-one (1) using IR, mass, 1D and 2D NMR spectral studies. The compound 1 prefers to adopt a chair conformation with equatorial orientations of all substituents. The compounds 2 and 3 showed doubling of all the NMR spectral signals corresponding to syn and anti rotamers at RT and 223 K, respectively. The syn and anti rotamers of 2 exist in an equilibrium between alternate chair (CA) and twist boat (TB1) conformations, respectively. The syn and anti rotamers of 3 exist in TB1 conformation. The stereodynamics of compounds 2 and 3 have been investigated using dynamic 1H NMR spectra and the calculated average energy barriers for N-NO and N-CHO rotations are found to be 77.76 kJ mol-1 and 68.18 kJ mol-1, respectively.

  7. The synthesis and spectroscopic study of stable free radicals related to piperidine-n-oxyl, including a stable bi-radical; Syntheses et etudes spectroscopiques de radicaux libres piperidiniques et d'un biradical stable, du type nitroxyde

    Energy Technology Data Exchange (ETDEWEB)

    Briere, R. [Commissariat a l' Energie Atomique, Grenoble (France). Centre d' Etudes Nucleaires, Laboratoire de chimie organique physique

    1967-06-01

    A new synthesis of di-tert-butyl nitroxide using the reaction between tert-butyl magnesium chloride and nitro-tert-butane is presented in the first section. Synthesis and investigation of stable free piperidine-N-oxyl radicals are described in the second section. All these nitroxides have been characterised by their I. R., U. V. and E. P. R. absorption spectra. The final section contains a description of the synthesis of a stable bi-radical of the nitroxide type by condensation of 2,2, 6, 6-tetramethyl-piperid-4-one-l-oxyl with hydrazine. (author) [French] La premiere partie expose une nouvelle methode de synthase du di-t-butyl nitroxyde, par action d'halogenures de t-butyl magnesium sur le nitro-t-butane (Rdt maximum 45 pour cert, purete 86 pour cent). Une etude de radicaux. libres stables pipericliniques est faite dans une seconde partie. Ces composes sont obtenus par oxydation de derives de la triacetonamine. Les caracteristiques spectroscopiques ultra-violette, infra-rouge, et paramagnetique electronique de ces radicaux sont donnees. La grande inertie chimique du groupement nitroxyde a permis la syn-these d'un biradical stable par formation d'azine d'une cetone radicalaire, ce qui fait 1'objet de la troisieme partie. (auteur)

  8. Synthesis, crystal structure, spectroscopic and quantum chemical studies of novel 3-((2-chlorophenyl)(piperidin-1-yl)methyl)-4-hydroxy-1-phenylquinolin-2(1H)-one

    Science.gov (United States)

    Fatma, Shaheen; Bishnoi, Abha; Verma, Anil Kumar; Singh, Ramesh; Srivastava, Amrita

    2017-07-01

    A novel 3-((2-chlorophenyl)(piperidin-1-yl)methyl)-4-hydroxy-1-phenylquinolin-2(1H)-one was synthesized using Michael addition of secondary amine to the α, β-unsaturated carbonyl compound which was formed during the reaction. The crystal structure was studied by X-ray crystallography. Molecular geometry, first order hyperpolarizability, molecular electrostatic potential and vibrational analysis was carried out by using density functional theory (DFT/B3LYP) method with 6-31G (d,p) as basis set. Calculated 13C NMR and 1H NMR chemical shift values and vibrational wavenumbers showed good agreement with the experimental data. X-ray study confirmed that each molecule interacts with other molecule through Csbnd H⋯O, Csbnd C⋯Cl and Csbnd H ….C interactions. Conformational analysis of the molecule was studied by DFT/6-31G (d, p) method. Increment in wavenumber has been confirmed by AIM calculation. Stability of the molecule arising from hyperconjugative interactions and charge delocalization has been analyzed using natural bond orbital analysis. Local reactivity descriptors were calculated to explain the chemically reactive site in the molecule. Electronic absorption spectrum has been predicted and found agreement with the experimental one. Intramolecular interactions were analyzed by AIM approach. In addition, thermodynamic properties were investigated using theoretical calculations.

  9. Common Degradative Pathways of Morpholine, Thiomorpholine, and Piperidine by Mycobacterium aurum MO1: Evidence from 1H-Nuclear Magnetic Resonance and Ionspray Mass Spectrometry Performed Directly on the Incubation Medium

    Science.gov (United States)

    Combourieu, Bruno; Besse, Pascale; Sancelme, Martine; Godin, Jean-Philippe; Monteil, André; Veschambre, Henri; Delort, Anne-Marie

    2000-01-01

    In order to see if the biodegradative pathways for morpholine and thiomorpholine during degradation by Mycobacterium aurum MO1 could be generalized to other heterocyclic compounds, the degradation of piperidine by this strain was investigated by performing 1H-nuclear magnetic resonance directly with the incubation medium. Ionspray mass spectrometry, performed without purification of the samples, was also used to confirm the structure of some metabolites during morpholine and thiomorpholine degradation. The results obtained with these two techniques suggested a general pathway for degradation of nitrogen heterocyclic compounds by M. aurum MO1. The first step of the degradative pathway is cleavage of the C—N bond; this leads formation of an intermediary amino acid, which is followed by deamination and oxidation of this amino acid into a diacid. Except in the case of thiodiglycolate obtained from thiomorpholine degradation, the dicarboxylates are completely mineralized by the bacterial cells. A comparison with previously published data showed that this pathway could be a general pathway for degradation by other strains of members of the genus Mycobacterium. PMID:10919768

  10. Spiro-oxindole derivative 5-chloro-4',5'-diphenyl-3'-(4-(2-(piperidin-1-yl) ethoxy) benzoyl) spiro[indoline-3,2'-pyrrolidin]-2-one triggers apoptosis in breast cancer cells via restoration of p53 function.

    Science.gov (United States)

    Saxena, Ruchi; Gupta, Garima; Manohar, Murli; Debnath, Utsab; Popli, Pooja; Prabhakar, Yenamandra S; Konwar, Rituraj; Kumar, Sandeep; Kumar, Atul; Dwivedi, Anila

    2016-01-01

    Breast cancer remains a significant health problem due to the involvement of multiple aberrant and redundant signaling pathways in tumorigenesis and the development of resistance to the existing therapeutic agents. Therefore, the search for novel chemotherapeutic agents for effective management of breast cancer is still warranted. In an effort to develop new anti-breast cancer agents, we have synthesized and identified novel spiro-oxindole derivative G613 i.e. 5-chloro-4',5'-diphenyl-3'-(4-(2-(piperidin-1-yl) ethoxy) benzoyl) spiro[indoline-3,2'-pyrrolidin]-2-one, which has shown growth inhibitory activity in breast cancer cells. The present study was aimed to explore the mechanism of anti-tumorigenic action of this newly identified spiro-oxindole compound. Compound G613 inhibited the Mdm2-p53 interaction in breast cancer cells and tumor xenograft. It caused restoration of p53 function by activating its promoter activity, triggering its nuclear accumulation and preventing its ubiquitination and proteasomal degradation. Supportively, molecular docking studies revealed considerable homology in the docking mode of G613 and the known Mdm2 inhibitor Nutlin-3, to p53 binding pocket of Mdm2. The activation of p53 led to upregulation of p53 dependent pro-apoptotic proteins, Bax, Pumaα and Noxa and enhanced interaction of p53 with bcl2 member proteins thus triggering both transcription-dependent and transcription-independent apoptosis, respectively. Additionally, the compound decreased estrogen receptor activity through sequestration of estrogen receptor α by p53 thereby causing a decreased transcriptional activation and expression of proliferation markers. In conclusion, G613 represents a potent small-molecule inhibitor of the Mdm2-p53 interaction and can serve as a promising lead for developing a new class of anti-cancer therapy for breast cancer patients.

  11. Dissociation of the effects of MTEP [3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]piperidine] on conditioned reinstatement and reinforcement: comparison between cocaine and a conventional reinforcer.

    Science.gov (United States)

    Martin-Fardon, R; Baptista, M A S; Dayas, C V; Weiss, F

    2009-06-01

    To advance understanding of the potential of metabotropic glutamate receptor (mGluR) 5 as treatment targets for cocaine addiction, the effects of MTEP [3-[(2-methyl-1,3-thiazol-4-yl) ethynyl]piperidine] (a selective mGluR5 antagonist) on conditioned reinstatement of cocaine seeking were examined. To test whether modification of conditioned reinstatement by MTEP is selective for drug-directed behavior or reflects general actions on motivated behavior, effects of MTEP on reinstatement induced by a stimulus conditioned to palatable conventional reward, sweetened condensed milk (SCM), were also evaluated. Previous data suggest that mGluR manipulations preferentially interfere with conditioned reinstatement compared with cocaine self-administration. Therefore, the effects of MTEP on cocaine self-administration were compared with MTEP's effects on SCM-reinforced behavior using the same cocaine doses and SCM concentrations employed for establishing conditioned reinstatement. Male Wistar rats were trained to associate a discriminative stimulus (S(D)) with response-contingent availability of cocaine or SCM and subjected to reinstatement tests after extinction of cocaine or SCM-reinforced behavior. MTEP (0.3-10 mg/kg i.p.) dose-dependently attenuated the response-reinstating effects of both the cocaine S(D) and SCM S(D). MTEP also decreased cocaine self-administration without a clear graded dose-response profile and did not modify SCM-reinforced responding. The findings implicate mGluR5-regulated glutamate transmission in appetitive behavior controlled by reward-related stimuli but without selectivity for cocaine seeking. However, the data suggest a differential role for mGluR5 in the acute reinforcing effects of cocaine versus conventional reward. These observations identify mGluR5 as potential treatment targets for cocaine relapse prevention, although the profile of action of mGluR5 antagonists remains to be more closely examined for potential anhedonic effects.

  12. Prediction of the binding site of 1-benzyl-4-[(5,6-dimethoxy-1-indanon-2-yl)methyl]piperidine in acetylcholinesterase by docking studies with the SYSDOC program

    Science.gov (United States)

    Pang, Yuan-Ping; Kozikowski, Alan P.

    1994-12-01

    In the preceding paper we reported on a docking study with the SYSDOC program for predicting the binding sites of huperzine A in acetylcholinesterase (AChE) [Pang, Y.-P. and Kozikowski, A.P., J. Comput.-Aided Mol. Design, 8 (1994) 669]. Here we present a prediction of the binding sites of 1-benzyl-4-[(5,6-dimethoxy-1-indanon-2-yl)methyl]piperidine (E2020) in AChE by the same method. E2020 is one of the most potent and selective reversible inhibitors of AChE, and this molecule has puzzled researchers, partly due to its flexible structure, in understanding how it binds to AChE. Based on the results of docking 1320 different conformers of E2020 into 69 different conformers of AChE and on the pharmacological data reported for E2020 and its analogs, we predict that both the R- and the S-isomer of E2020 span the whole binding cavity of AChE, with the ammonium group interacting mainly with Trp84, Phe330 and Asp72, the phenyl group interacting mainly with Trp84 and Phe330, and the indanone moiety interacting mainly with Tyr70 and Trp279. The topography of the calculated E2020 binding sites provides insights into understanding the high potency of E2020 in the inhibition of AChE and provides hints as to possible structural modifications for identifying improved AChE inhibitors as potential therapeutics for the palliative treatment of Alzheimer's disease.

  13. Forced twin-chair conformation in 7-benzoyl- and 7-phenylacetyl-r-2,c-4,t-6,t-8-tetraphenyl-3-thia-7-azabicyclo[3.3.1]nonanes with 1,3-diaxial phenyl groups in the piperidine ring: single- and double-layered supramolecular sheets built from C-H...O and C-H...pi(arene) hydrogen bonds.

    Science.gov (United States)

    Sakthivel, Chinniah; Jeyaraman, Ramasubbu

    2010-08-01

    The crystal structures of 7-benzoyl-r-2,c-4,t-6,t-8-tetraphenyl-3-thia-7-azabicyclo[3.3.1]nonane, C(38)H(33)NOS, (I), and r-2,c-4,t-6,t-8-tetraphenyl-7-phenylacetyl-3-thia-7-azabicyclo[3.3.1]nonane [systematic name: 2-phenyl-1-(r-2,c-4,t-6,t-8-tetraphenyl-3-thia-7-azabicyclo[3.3.1]nonan-7-yl)ethanone], C(39)H(35)NOS, (II), both reveal a forced twin-chair conformation with the 1,3-diaxial phenyl groups in the piperidine ring, and flattening at the N-atom end of the piperidine ring of the bicyclic system. In the crystal structure of (I), molecules are linked into sheets by a combination of two weak C-H...O and one C-H...pi(arene) hydrogen bond, while in the crystal structure of (II), the molecules extend into double-layered sheets assisted by three C-H...pi(arene) hydrogen bonds.

  14. 以哌啶为模板剂的MCM-22分子筛合成%Synthesis of MCM-22 Molecular Sieve Using Piperidine as an Organic Template

    Institute of Scientific and Technical Information of China (English)

    张斌; 王振东; 孙洪敏; 杨为民; 吴鹏

    2013-01-01

    为合成不同硅铝比的MCM-22分子筛,对分子筛配料中的硅铝比、碱度、模板剂和晶化助剂用量等进行了考察,并用X射线衍射、扫描电镜、电感耦合等离子体发射光谱、X射线光电子能谱仪及氮气吸脱附等手段对样品进行了表征.结果表明,以哌啶(PI)为模板剂、硼酸(BA)为晶化助剂,在n(OH-)/n(SiO2)为0.03~0.20、n(PI)/n(SiO2)大于0.03及n(BA)/n(SiO2)大于0.05的条件下,可得到硅铝比为25~500的MCM-22分子筛.与以六亚甲基亚胺为模板剂相比,以哌啶为模板剂制得的MCM-22分子筛具有更小的晶粒尺寸和更大的比表面积.%For synthesizing MCM-22 molecular sieves with different silica-alumina ratio, the effects of ingredient SiO2 to A12O3 ratio, alkali concentration, and the amount of organic template and crystallization-supporting agent, on the molecular sieves were studied systematically. The obtained MCM-22 samples were characterized by X-ray diffraction, scanning electron microscopy, inductively coupled plasma-atomic emission spectrometry, X-ray photoelectron spectroscopy and N2 adsorption-desorption. The results show that, MCM-22 molecular sieves with silica-alumina ratio of 25-500 could be successfully synthesized under this condition: using piperidine (PI) as the organic template and boric acid (BA) as the crystallization-supporting agent, n(OH-)/n(SiO2) of 0.03-0.20, n(PI)/n(SiO2) > 0.03 and n(BA)/n(SiO2) > 0.05. Moreover, the obtained molecular sieves using PI as the template have a smaller particle size and a larger specific surface area than those using hexamethyleneimine as the template.

  15. In vivo evaluation of [{sup 123}I]-4-(2-(bis(4-fluorophenyl)methoxy)ethyl)-1-(4-iodobenzyl)piperidine, an iodinated SPECT tracer for imaging the P-gp transporter

    Energy Technology Data Exchange (ETDEWEB)

    De Bruyne, Sylvie; Wyffels, Leonie [Laboratory for Radiopharmacy, Ghent University, 9000 Ghent (Belgium); Boos, Terrence L. [Chemical Biology Research Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD (United States); Staelens, Steven; Deleye, Steven [IBITECH-Medisip, Ghent University-IBBT, 9000 Ghent (Belgium); Rice, Kenner C. [Chemical Biology Research Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD (United States); De Vos, Filip [Laboratory for Radiopharmacy, Ghent University, 9000 Ghent (Belgium)], E-mail: filipx.devos@ugent.be

    2010-05-15

    Introduction: P-glycoprotein (P-gp) is an energy-dependent transporter that contributes to the efflux of a wide range of xenobiotics at the blood-brain barrier playing a role in drug-resistance or therapy failure. In this study, we evaluated [{sup 123}I]-4-(2-(bis(4-fluorophenyl)methoxy)ethyl)-1-(4-iodobenzyl)piperidine ([{sup 123}I]-FMIP) as a novel single photon emission computed tomography (SPECT) tracer for imaging P-gp at the brain in vivo. Methods: The tissue distribution and brain uptake as well as the metabolic profile of [{sup 123}I]-FMIP in wild-type and mdr1a (-/-) mice after pretreatment with physiological saline or cyclosporin A (CsA) (50 mg/kg) was investigated. The influence of increasing doses CsA on brain uptake of [{sup 123}I]-FMIP was explored. {mu}SPECT images of mice brain after injection of 11.1 MBq [{sup 123}I]-FMIP were obtained for different treatment strategies thereby using the Milabs U-SPECT-II. Results: Modulation of P-gp with CsA (50 mg/kg) as well as mdr1a gene depletion resulted in significant increase in cerebral uptake of [{sup 123}I]-FMIP with only minor effect on blood activity. [{sup 123}I]-FMIP is relative stable in vivo with >80% intact [{sup 123}I]-FMIP in brain at 60 min p.i. in the different treatment regiments. A dose-dependent sigmoidal increase in brain uptake of [{sup 123}I]-FMIP with increasing doses of CsA was observed. In vivo region of interest-based SPECT measurements correlated well with the observations of the biodistribution studies. Conclusions: These findings indicate that [{sup 123}I]-FMIP can be applied to assess the efficacy of newly developed P-gp modulators. It is also suggested that [{sup 123}I]-FMIP is a promising SPECT tracer for imaging P-gp at the blood-brain barrier.

  16. Anticonvulsant mechanisms of piperine, a piperidine alkaloid.

    Science.gov (United States)

    Mishra, Awanish; Punia, Jasmine Kaur; Bladen, Chris; Zamponi, Gerald W; Goel, Rajesh Kumar

    2015-01-01

    Piperine, a natural compound isolated from the fruits of Piper, is known to modulate several neurotransmitter systems such as serotonin, norepinephrine, and GABA, all of which have been linked to the development of convulsions. Fruits of Piper species have been suggested as means for managing seizure disorders. The present study was designed to elucidate the anticonvulsant effect of piperine and its mechanisms of action using in-silico, in-vivo and in-vitro techniques.PASS software was used to determine its possible activity and mechanisms. Furthermore the latency for development of convulsions and mortality rate was recorded in different experimental mouse models of epilepsy (pentylenetetrazole, maximal electroshock, NMDA, picrotoxin, bicuculline, BAYK-8644, strychnine-induced convulsions) after administration of various doses of piperine (5, 10 and 20 mg/kg, i.p.). Finally, the effect of piperine on Na(+) and Ca(2+) channels were evaluated using the whole cell patch clamp techniqueOur results revealed that piperine decreased mortality in the MES-induced seizure model. Moreover, piperine (10 mg/kg) delayed the onset of tonic clonic convulsions in the pentylenetetrazole test and reduced associated mortality. Furthermore, an anticonvulsant dose of piperine also delayed the onset of tonic clonic seizures in strychnine, picrotoxin and BAY K-8644. Complete protection against mortality was observed in BAYK-8644 induced convulsions. Finally, whole cell patch clamp analysis suggested an inhibitory effect of piperine on Na(+) channels. Together, our data suggest Na(+) channel antagonist activity as a contributor to the complex anticonvulsant mechanisms of piperine.

  17. 含双环哌啶结构HIV-1抑制剂的设计合成及生物活性研究%Design, synthesis and biological activity of bicyclic piperidine-based HIV-1 inhibitors

    Institute of Scientific and Technical Information of China (English)

    毛文祥; 董铭心; 朱卫国; 姜世勃; 戴秋云

    2011-01-01

    目的 设计合成一系列具有新型结构特征的双环哌啶类C-C族趋化因子受体5(CCR5)抑制剂并测定其抗HIV-1活性.方法 以HIV-1辅助受体CCR5抑制剂Vicriviroc的结构为模板,通过改变左侧哌嗪结构、取代基位置等方法设计并合成一系列新化合物.并利用MS及1H-NMR谱对这些化合物进行结构表征.结果 与结论合成了15个新结构化合物,活性测试结果表明,该系列化合物具有较强的抗HIV-1 R5病毒株的活性(IC50=1.20~66.24μmol·L-1).当R1为芳基结构且两个氮原子满足标准的丙二胺结构时,化合物的活性更好.%CCR5 is a major co-receptor for HIV-1 entry into human cells and is also a good target for antiHIV-1 drug design. Based on the chemical structure of Vicriviroc, a CCR5 antagonist, a series of new compounds were designed by changing its piperazine loop and other group substitutions. In the present study,15 bicyclic piperidine-based compounds were synthesized using a convergent synthetic route, and the structures of the target compounds were confirmed by MS and 1H-NMR. The synthetic routes were as follows:N-Bocpiperidine-4-carboxylic acid, N-Boc-pyrro-3-carboxylic acid and N-Boc-ethylenediamine were coupled with theamine derivatives to give the corresponding compounds 1a- 1d,2a- 2c,3a- 3c,4-piperidinone hydrochloride reacted with 2,6-dimethylbenzoyl chloride,2,6-dichlorobenzoyl chloride and 2,4,6-trimethyl-5-pyrimidine carbonyl chloride to obtain the compounds 4a -4c. Then 4a -4c was reacted with 1a - 1d,2a -2c ,3a - 3c to give the target compounds I 1 - I 15. Furthermore, the antiviral activity and cell cytotoxicity of these compounds were evaluated with HIV-1 R5 strain in vitro. The results showed that all the target compounds exhibited potent antiviral activity against HIV-1 R5 strain( IC50 = 1.20 -66. 24 μmol· L-1 ). Preliminary analysis of the structure-activity relationship showed that some compounds with an aryl group and the 1,3-diamino

  18. Novel spiropiperidine-based stearoyl-CoA desaturase-1 inhibitors: Identification of 1'-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-5-(trifluoromethyl)-3,4-dihydrospiro[chromene-2,4'-piperidine].

    Science.gov (United States)

    Uto, Yoshikazu; Kiyotsuka, Yohei; Ueno, Yuko; Miyazawa, Yuriko; Kurata, Hitoshi; Ogata, Tsuneaki; Deguchi, Tsuneo; Yamada, Makiko; Watanabe, Nobuaki; Konishi, Masahiro; Kurikawa, Nobuya; Takagi, Toshiyuki; Wakimoto, Satoko; Kono, Keita; Ohsumi, Jun

    2010-01-15

    Cyclization of the benzoylpiperidine in lead compound 2 generated a series of novel and highly potent spiropiperidine-based stearoyl-CoA desaturase (SCD)-1 inhibitors. Among them, 1'-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-5-(trifluoromethyl)-3,4-dihydrospiro[chromene-2,4'-piperidine] (19) demonstrated the most powerful inhibitory activity against SCD-1, not only in vitro but also in vivo (C57BL/6J mice). With regard to the pharmacological evaluation, 19 showed powerful reduction of the desaturation index in the plasma of C57BL/6J mice on a non-fat diet after a 7-day oral administration (q.d.) without causing notable abnormalities in the eyes or skin up to the highest dose (3mg/kg) in our preliminary analysis. Copyright 2009 Elsevier Ltd. All rights reserved.

  19. Synthesis, crystal structure and bioactivity of 1-(4-Methylbenzyl) piperidin-4-one O-(6-chloropyridin-3-yl) methyl oxime%1-(4-甲基苄基)哌啶-4-酮-6-氯吡啶-3-甲基肟醚的合成、单晶结构分析以及生物活性的测定

    Institute of Scientific and Technical Information of China (English)

    马旭波; 尹安琴; 薛思佳

    2011-01-01

    通过1-(4-甲基苄基)哌啶-4-酮肟醚与2-氯-5-氯甲基吡啶的亲核取代反应合成了一个未见文献报道的化合物:1-(4-甲基苄基)哌啶-4-酮-6-氯吡啶-3-甲基肟醚.目标化合物的结构经过元素分析、IR、1H MNR及单晶X-射线衍射测定确定.该单晶属于单斜晶系,空间群为P2(1),a=9.486(6),b=6.317(4),c=15.027(10)(A),α=90,β=93.178(8),γ=90°,V=899.0(10)(A)3,Z=2,Dc=1.270 g/cm3,μ=0.223mm-1,M=343.85,F(000)=364,S=1.019,R=0.0732以及wR=0.1902.目标化合物的结构是非平面的,哌啶环是一个椅式结构.哌啶环与苯环的二面角为86.1(9)°.此单晶中没有分子内和分子间氢键的存在.初步杀菌活性测试表明,在浓度为1×10-4时该化合物有广谱的的杀菌活性.%A novel 1 - (4-Methylbenzyl ) piperidin-4-one O- ( 6-chloropyridin-3-yl) methyl oxime compound was synthesized by the reaction of 1-(4-methylbenzyl)piperidin-4-one oxime with 2-chloro-5-chloromethylpyridine,followed by characterization with elemental analysis, IR, 1H NMR spectra and single - crystal X-ray diffraction. The crystal belongs to the monoclinic system, space group P2 ( 1 )with a =9.486(6) ,b =6.317(4) ,c = 15. 027(10)(A),α = 90,β =93. 178(8) ,γ =90°, V = 899.0(10)(A)3 ,Z =2,Dc = 1. 270 g/cm3 ,μ =0.223 mm-1 ,M =343.85 ,F(000) =364,S = 1. 019 ,the final R =0. 0732 and wR = 0. 1902. The molecule was nonplanar, the piperidine exhibited a chair conformation. The dihedral angle made by the pyridine ring with the benzene ring was 86. 1(9)°. No intra-or intermolecular hydrogen bonds were identified in the crystal structure. Bioassays indicated that the as-prepared compound exhibited broad inhibitory activities toward fungi at the concentration of 1 × 10-4.

  20. Synthesis, spectroscopic and redox properties of the mononuclear NiII, NiII(BPh2)2 containing (B-C) bond and trinuclear CuII-NiII-CuII type-metal complexes of ,'-(4-amino-1-benzyl piperidine)-glyoxime

    Indian Academy of Sciences (India)

    Ahmet Kilic; Esref Tas; Ismail Yilmaz

    2009-01-01

    The novel vic-dioxime ligand containing the 4-amino-1-benzyl piperidine group, ,'-(4-amino-1-benzyl piperidine)-glyoxime, (LH2) has been prepared from 4-amino-1-benzyl piperidine with anti-dichloroglyoxime at -15°C in absolute THF. Mononuclear NiII metal complex has been obtained with 1 : 2 metal/ligand ratio. The NiII complex of this ligand is proposed to be square planar geometry. IR spectra show that the ligand acts in a tetradentate manner and coordinates N4 donor groups of LH2 to NiII ion. The detection of H-bonding (O-H$\\cdots$O) in the [Ni(LH))2] (${\\rm 1}$) metal complex by IR spectra supported the square-planar MN4 coordination of mononuclear complex. The disappereance of H-bonding (O-H$\\cdots$O) in the [Ni(L)2(BPh2)2] (2) complex shows that the BPh$^{+}_{2}$-capped groups (BPh$^{+}_{2}$ cation formed BPh4 anion) attaches to the main oxime core. MN4 coordination of the [Ni(LH)2] (1) and [Ni(L)2(BPh2)2] (2) metal complexes were also determined by 1H-NMR spectroscopy. In the trinuclear CuII-NiII-CuII metal complexes, the NiII ion centered into the main oxime core by the coordination of the imino groups while the two CuII ions coordinate dianionic oxygen donors of the oxime groups and linked to the ligands of 1,10-phenanthroline, 2,2'-bipyridine, and 4,4'-bipyridine. The ligand and their mono and trinuclear metal complexes were characterized by elemental analyses, FT-IR, UV-Vis, 1H and 13C-NMR spectra, magnetic susceptibility measurements, molar conductivity, cyclic voltammetry, mass spectra and X-ray powder techniques. The cyclic voltammetric results show that the cathodic peak potential of [Ni(L)2(BPh2)2] shifted toward more negative value compared to that of [Ni(LH)2], probably due to a decreasing effect of back donation of metal-oxime moieties as a result of the BPh$^{+}_{2}$-bridged complex formation. Also, the formation of the trinuclear CuII-NiII-CuII metal complexes caused considerable changes on the CV behaviour of mononuclear [Ni(LH)2] (1

  1. Discovery of 2-[1-(4,4-Difluorocyclohexyl)piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide (NMS-P118): A Potent, Orally Available, and Highly Selective PARP-1 Inhibitor for Cancer Therapy.

    Science.gov (United States)

    Papeo, Gianluca; Posteri, Helena; Borghi, Daniela; Busel, Alina A; Caprera, Francesco; Casale, Elena; Ciomei, Marina; Cirla, Alessandra; Corti, Emiliana; D'Anello, Matteo; Fasolini, Marina; Forte, Barbara; Galvani, Arturo; Isacchi, Antonella; Khvat, Alexander; Krasavin, Mikhail Y; Lupi, Rosita; Orsini, Paolo; Perego, Rita; Pesenti, Enrico; Pezzetta, Daniele; Rainoldi, Sonia; Riccardi-Sirtori, Federico; Scolaro, Alessandra; Sola, Francesco; Zuccotto, Fabio; Felder, Eduard R; Donati, Daniele; Montagnoli, Alessia

    2015-09-10

    The nuclear protein poly(ADP-ribose) polymerase-1 (PARP-1) has a well-established role in the signaling and repair of DNA and is a prominent target in oncology, as testified by the number of candidates in clinical testing that unselectively target both PARP-1 and its closest isoform PARP-2. The goal of our program was to find a PARP-1 selective inhibitor that would potentially mitigate toxicities arising from cross-inhibition of PARP-2. Thus, an HTS campaign on the proprietary Nerviano Medical Sciences (NMS) chemical collection, followed by SAR optimization, allowed us to discover 2-[1-(4,4-difluorocyclohexyl)piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide (NMS-P118, 20by). NMS-P118 proved to be a potent, orally available, and highly selective PARP-1 inhibitor endowed with excellent ADME and pharmacokinetic profiles and high efficacy in vivo both as a single agent and in combination with Temozolomide in MDA-MB-436 and Capan-1 xenograft models, respectively. Cocrystal structures of 20by with both PARP-1 and PARP-2 catalytic domain proteins allowed rationalization of the observed selectivity.

  2. Study on the Synthesis of Piperidine Dithiocarbamate Acetamidobenzene Derivatives and Their Tribological Properties%六氢吡啶二硫代氨基甲酸苯胺羰甲基酯的合成及其摩擦学性能初步研究

    Institute of Scientific and Technical Information of China (English)

    王励申; 廖俊旭; 杨攀龙; 焦叶叶

    2011-01-01

    合成了两个新型无灰六氢吡啶二硫代氨基甲酸苯胺羰甲基酯化合物;用核磁共振氢谱、核磁共振碳谱、红外光谱、紫外光谱、质谱和元素分析对其结构进行了表征;用四球摩擦机测试了其作为润滑油添加剂在液体石蜡中的极压性能;采用热重分析和油溶性实验考察了热稳定性及其在有机溶剂中的溶解性.结果表明,这两个新型化合物具有较好的承载能力和热稳定性.%Two novel ashless piperidine dithiocarbamate acetamidobenzene derivatives were synthesized and their chemical structures were characterized by 1H NMR, 13C NMR, IR, UV-vis, MS and elemental analysis. Their extreme pressure (EP) behaviors as lubricant additives in liquid paraffin were evaluated using a four-ball tester. Their thermal stabilities and compatibilities with several kinds of organic solvents were inspected by TGA test and oil solubility test. The results indicate that the two novel compounds possess excellent load-carrying capacity and thermal stability.

  3. A critical review of both the synthesis approach and the receptor profile of the 8-chloro-1-(2',4'-dichlorophenyl)-N-piperidin-1-yl-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide and analogue derivatives.

    Science.gov (United States)

    Lazzari, Paolo; Distinto, Rita; Manca, Ilaria; Baillie, Gemma; Murineddu, Gabriele; Pira, Marilena; Falzoi, Matteo; Sani, Monica; Morales, Paula; Ross, Ruth; Zanda, Matteo; Jagerovic, Nadine; Pinna, Gérard Aimè

    2016-10-04

    8-Chloro-1-(2',4'-dichlorophenyl)-N-piperidin-1-yl-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide 9a was discovered as potent and selective CB1 antagonist by part of our group few years ago. In particular it was reported to have an affinity towards the CB1 cannabinoid receptor (CB1R), expressed as Ki, of 0.00035 nM. Nevertheless significantly divergent data were reported for the same compound from other laboratories. To unequivocally define the receptor profile of 9a, we have critically reviewed both its synthesis approach and binding data. Here we report that, in contrast to our previously reported data, 9a showed a Ki value for CB1R in the order of nanomolar rather than of fentomolar range. The new determined receptor profile of 9a was also ascertained for analogue derivatives 9b-i, as well as for 12. Moreover, the structural features of the synthesized compounds necessary for CB1R were investigated. Amongst the novel series, effects on CB1R intrinsic activity was highlighted due to the substituents at the position 3 of the pyrazole ring of the 1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole scaffold. Although the cannabinoid receptor profile of 9a was reviewed in this work, the relevance of this compound in CB1R antagonist based drug discovery is confirmed.

  4. 5′′-(4-Nitrobenzylidene-7′-(4-nitrophenyl-1′′-methyl-1′,3′,5′,6′,7′,7a′-hexahydrodispiro[acenaphthylene-1,5′-pyrrolo[1,2-c][1,3]thiazole-6′,3′′-piperidine]-2,4′′(1H-dione including an unknown solvate

    Directory of Open Access Journals (Sweden)

    P. L. Nilantha Lakshman

    2013-08-01

    Full Text Available The title compound, C35H28N4O6S, crystallizes with two molecules in the asymmetric unit. In both molecules, the piperidine ring adopts a shallow-chair conformation, the thiazole ring adopts a twisted conformation about the Cm—N bond (m = methine and the pyrrole ring adopts an envelope conformation with the C atom shared with the thiazole ring as the flap. In the crystal, inversion dimers linked by pairs of C—H...O interactions generate R22(34 loops for one of the asymmetric molecules. Further C—H...O links also involving the other molecule lead to a three-dimesional network. The contribution of the highly disordered solvent to the scattering was removed with SQUEEZE option of PLATON [Spek (2009. Acta Cryst. D65, 148–155]. The solvent contribution is not included in the reported molecular weight and density.

  5. Separação de fases induzida por meio de reação química no sistema éter diglicidílico do bisfenol A e piperidina com poli(metacrilato de metila Phase separation induced by chemical reaction in the system of diglycidyl ether of bisphenol A and piperidine with poly(methyl methacrylate

    Directory of Open Access Journals (Sweden)

    Filiberto González Garcia

    2003-12-01

    Full Text Available O comportamento da separação de fases e da gelificação do sistema epoxídico, constituído pelo éter diglicidílico do bisfenol A (DGEBA e a piperidina, modificado com poli(metacrilato de metila (PMMA, foi estudado na faixa de temperatura de 60 °C - 120 °C. A concentração de PMMA e a temperatura de cura causam mudanças significativas na morfologia gerada. A massa molecular de PMMA provoca ligeiras mudanças para a observação da separação de fases e não afeta a velocidade da reação. O sistema modificado com PMMA mostra o efeito de retardação cinético e a velocidade de separação de fases é maior que a velocidade de polimerização.The phase separation and gelification behavior of epoxy system based on diglycidyl ether of bisphenol-A (DGEBA and piperidine modified with poly(methyl methacrylate (PMMA were studied in the range between 60 °C and 120 °C. The morphology is influenced by the PMMA content in the blend and also by the cure temperature. The molecular weight of PMMA provokes slight changes on cloud point and does not affect the reaction rate. The systems modified by PMMA exhibited kinetic retardation effect but the cloud point rate was higher than the polymerization rate.

  6. Actions of piperidine alkaloid teratogens at fetal nicotinic acetylcholine receptors.

    Science.gov (United States)

    Green, Benedict T; Lee, Stephen T; Panter, Kip E; Welch, Kevin D; Cook, Daniel; Pfister, James A; Kem, William R

    2010-01-01

    Teratogenic alkaloids are found in many species of plants including Conium maculatum L., Nicotiana glauca, Nicotiana tabaccum, and multiple Lupinus spp. Fetal musculoskeletal defects produced by alkaloids from these plants include arthrogyropisis, scoliosis, torticollis, kyposis, lordosis, and cleft palate. A pharmacodynamic comparison of the alkaloids ammodendrine, anabasine, anabaseine, anagyrine, and coniine in SH-SY5Y cells and TE-671 cells was made. These alkaloids and their enantiomers were more effective in depolarizing TE-671 cells which express the human fetal-muscle type nicotinic acetylcholine receptor (nAChR) relative to SH-SY5Y cells which predominately express autonomic nAChRs. The rank order of potency in TE-671 cells was: anabaseine>(+)-anabasine>(-)-anabasine > (+/-)-anabasine>anagyrine>(-)-coniine > (+/-)-coniine>(+)-coniine>(+/-)-ammodendrine>(+)-ammodendrine. The rank order potency in SH-SY5Y cells was: anabaseine>(+)-anabasine>(-)-coniine>(+)-coniine>(+)-ammodendrine>anagyrine>(-)-anabasine>(+/-)-coniine>(+/-)-anabasine>(-)-ammodendrine. The actions of these alkaloids at nAChRs in both cell lines could be distinguished by their maximum effects in depolarizing cell membrane potential. The teratogenic action of these compounds may be related to their ability to activate and subsequently desensitize nAChRs.

  7. Syntese af amino/hydroxypyrrolidines og -piperidiner fra kulhydratderivater

    DEFF Research Database (Denmark)

    Godskesen, Michael Anders

    -methyl-D-xylitol, hydrotosylate with lithium aluminium hydride.The epoxide in methyl 2,3-anhydro-5-O-p-toluenesulfonyl-beta-D-ribofuranoside was opened by diethyl aluminium cyanide with formation of methyl 3-C-cyano-5-O-p-toluenesulfonyl-beta-D-xylofuranoside. Hydrogenation of the nitrile function with palladium on carbon led...... by methyliodide. The 5-Bromo functionality was then substituted by azid, which was hydrogenated in presence of palladium on carbon. The amino-lactones rearranged to the corresponding lactams, that could be reduced to 1,2,5-trideoxy-1,5-imino-2-C-methyl-D-arabinitol, hydrotosylate and 1,2,5-trideoxy-1,5-imino-2-C...

  8. Technetium-99m labeled 1-(4-fluorobenzyl)-4-(2-mercapto-2-methyl-4-azapentyl)-4- (2-mercapto-2-methylp ropylamino)-piperidine and iodine-123 metaiodobenzylguanidine for studying cardiac adrenergic function: a comparison of the uptake characteristics in vascular smooth muscle cells and neonatal cardiac myocytes, and an investigation in rats

    Energy Technology Data Exchange (ETDEWEB)

    Samnick, Samuel E-mail: rassam@uniklinik-saarland.de; Scheuer, Claudia; Muenks, Sven; El-Gibaly, Amr M.; Menger, Michael D.; Kirsch, Carl-Martin

    2004-05-01

    In developing technetium-99m-based radioligands for in vivo studies of cardiac adrenergic neurons, we compared the uptake characteristics of the {sup 99m}Tc-labeled 1-(4-fluorobenzyl)-4-(2-mercapto-2-methyl-4-azapentyl)-4- (2-mercapto-2-methylpropylamino)-piperidine ({sup 99m}Tc-FBPBAT) with those of the clinically established meta-[{sup 123}I]iodobenzylguanidine ({sup 123}I-MIBG) in rat vascular smooth muscle cells and neonatal cardiac myocytes. Furthermore, the cardiac and extracardiac uptake of both radiopharmaceuticals was assessed in intact rats and in rats pretreated with various {alpha}- and {beta}-adrenoceptor drugs, and adrenergic reuptake blocking agents. The uptake of {sup 99m}Tc-FBPBAT and {sup 123}I-MIBG into vascular smooth muscle cells and neonatal cardiac myocytes was rapid; more than 85% of the radioactivity accumulation into the cells occurring within the first 3 minutes. Radioactivity uptake after a 60-minute incubation at 37 degree sign C (pH 7.4) varied from 15% to 65% of the total loaded activity per million cells. In all cases, {sup 99m}Tc-FBPBAT showed the higher uptake, relative to {sup 123}I-MIBG, at any given cell concentration. The cellular uptake of {sup 99m}Tc-FBPBAT was lower at 4 degree sign C and 20 degree sign C than at 37 degree sign C. In contrast, the {sup 123}I-MIBG uptake was only slightly temperature dependent. Inhibition experiments confirmed that the cellular uptake of {sup 123}I-MIBG is mediated by the uptake-I carrier, whereas {alpha}{sub 1}- and {beta}{sub 1}-adrenoceptors were predominantly involved in the uptake of {sup 99m}Tc-FBPBAT into the cardiovascular tissues. Biodistribution studies in rats showed that {sup 99m}Tc-FBPBAT accumulated in myocardium after intravenous injection. Radioactivity in rat heart amounted to 2.32% and 1.91% of the injected dose per gram at 15 and 60 minutes postinjection, compared with 3.10% and 2.21% injected dose per gram of tissue (%ID/g) in the experiment with {sup 123}I

  9. Aspiperidine oxide, a piperidine N-oxide from the filamentous fungus Aspergillus indologenus

    DEFF Research Database (Denmark)

    Petersen, Lene Maj; Kildgaard, Sara; Jaspars, Marcel;

    2015-01-01

    A novel secondary metabolite, aspiperidine oxide, was isolated from the filamentous fungus, Aspergillus indologenus. The structure of aspiperidine oxide was determined from extensive 1D and 2D NMR spectroscopic analysis supported by high-resolution mass spectrometry. The structure revealed a rare...

  10. 4-Cyano-N-ethylspiro[chromene-2,4′-piperidine]-1′-carboxamide

    Directory of Open Access Journals (Sweden)

    P. Rajalakshmi

    2013-01-01

    Full Text Available The title compound, C17H19N3O2, crystallizes with two independent molecules (A and B in the asymmetric unit. In both molecules, the pyran ring has a twisted conformation (5S4, with Q = 0.301 (3 Å, θ = 116.7 (6 and ϕ= 213.6 (7° for molecule A, and Q = 0.364 (2 Å, θ = 113.7 (3 and ϕ = 213.0 (4° for molecule B. In molecule B, the terminal ethyl group is disordered over two orientations with an occupancy ratio of 0.55 (1:0.45 (1. In the crystal, molecules A and B form very similar but separate R12(7 motifs through N—H...O and C—H...O hydrogen bonds. The resulting chains along [001] are interlinked by weaker C—H...O and C—H...π interactions, forming layers parallel to the bc plane.

  11. Synthesis and evaluation of α-fluoro analogues of capsaicin and 2-(aminomethyl)piperidine derivatives

    OpenAIRE

    Moraux, Thomas

    2011-01-01

    Chapter 1 gives an overview of the fluorine chemistry field, from its early developments to recent applications in medicinal chemistry. The development of asymmetric electrophilic or nucleophilic installation of fluorine in organic molecules is highlighten. Chapter 2 of this thesis discusses the enantioselective synthesis of α-fluoroamides. The study is applied to the synthesis of fluoroenantiomers of the bioactive molecule capsaicin and short-chain analogues. The biological activity of t...

  12. Biaryl formation from 5-(2-bromobenzyl)-substituted piperidin-2-ones via palladacycles.

    Science.gov (United States)

    Satyanarayana, Gedu; Maier, Martin E

    2008-06-19

    The reaction of piperdin-2-ones with a 2-bromobenzyl substituent in the 5-position in the presence of a palladium catalyst leads to biaryl compounds. Their formation can be explained via initial C-H insertion of the aryl palladium species into the allylic C-H bond of the piperidinone. This eventually leads to a metallacycle containing Pd(II) that inserts another aryl bromide, promoting the formation of the biaryl bond.

  13. A piperidine amide extracted from Piper longum L. fruit shows activity against Aedes aegypti mosquito larvae.

    Science.gov (United States)

    Yang, Young-Cheol; Lee, Sang-Guei; Lee, Hee-Kwon; Kim, Moo-Key; Lee, Sang-Hyun; Lee, Hoi-Seon

    2002-06-19

    Mosquito larvicidal activity of Piper longum fruit-derived materials against the fourth-instar larvae of Aedes aegypti was examined. A crude methanol extract of P. longum fruits was found to be active against the larvae, and the hexane fraction of the methanol extract showed a strong larvicidal activity of 100% mortality. The biologically active component of P. longum fruits was characterized as pipernonaline by spectroscopic analyses. The LC(50) value of pipernonaline was 0.25 mg/L. The toxicity of pipernonaline is comparable to that of pirimiphos-methyl as a mosquito larvicide. In tests with available components derived from P. longum, no activity was observed with piperettine, piperine, or piperlongumine.

  14. Bromido(2-{1-[2-(piperidin-1-ylethylimino]ethyl}phenolatocopper(II

    Directory of Open Access Journals (Sweden)

    Xiao-Fan Zhao

    2010-08-01

    Full Text Available In the title complex, [CuBr(C15H21N2O], the CuII atom is coordinated by one phenolate O, one imine N and one amine N atom of the tridentate Schiff base ligand and by one bromide ion, resulting in a distorted CuBrN2O square-planar geometry for the metal ion, with the N atoms in a cis conformation.

  15. Novel 4-(piperidin-4-yl)-1-hydroxypyrazoles as gamma-aminobutyric acidA receptor ligands

    DEFF Research Database (Denmark)

    Møller, Henriette A; Sander, Tommy; Kristensen, Jesper Langgaard;

    2010-01-01

    A series of substituted 1-hydroxypyrazole analogues of the GABA(A) receptor partial agonist 5-(4-piperidyl)-3-isoxazolol (4-PIOL) have been synthesized and pharmacologically characterized. Several of the analogues displayed K(i) in the low nanomolar range at the native GABA(A) receptors and potent...... antagonism of the alpha(1)beta(2)gamma(2) receptor. It appears that several regions situated in proximity to the core of the orthosteric binding site of the GABA(A) receptor are able to accommodate large hydrophobic substituents....

  16. Occurrence of piperidine alkaloids in Piper species collected in different areas.

    Science.gov (United States)

    Bao, Narisu; Ochir, Sarangowa; Sun, Zhaorigetu; Borjihan, Gereltu; Yamagishi, Takashi

    2014-01-01

    A simple and convenient method was established for simultaneous quantitative determination of piperine and piperlonguminine in dried fruits of Piper longum and allied plants. The average content of piperine in P. longum (18.26 mg/g, range 12.05-33.23 mg/g) was about one half that of P. nigrum (40.09 mg/g, range 29.57-54.23 mg/g), but the content of piperlonguminine in P. longum was in the range of 0.42-1.82 mg/g, and the average content of piperlonguminne (0.91 mg/g) was about seven times higher than that in P. nigrum (0.13 mg/g). A sample of P. longum from Vietnam and a sample of P. retrofractum collected in Ishigaki, Japan, showed high contents of piperine and piperlonguminine. On the other hand, a sample of P. betle collected in Taiwan showed low content of piperine, and piperlonguminine was not detected.

  17. The mechanism of pyridine hydrogenolysis on molybdenum-containing catalysts : II. Hydrogenation of pyridine to piperidine

    NARCIS (Netherlands)

    Sonnemans, J.; Berg, van den G.H.; Mars, P.

    1973-01-01

    The kinetics of pyridine hydrogenation was studied at high hydrogen pressures on a Mo-Al oxide and a Co-Mo-Al oxide catalyst. The rate equation was found to be r = kPpyrPH2n/Ppyro, in which n is 1.5 at 300 and 375 °C and 1.0 at 250 °C. This rate equation can be derived assuming strong adsorption of

  18. Piperidine, pyridine alkaloid inhibition of fetal movement in a day 40 pregnant goat model

    Science.gov (United States)

    The inhibition of fetal movement is one mechanism behind the development of multiple congenital contracture-type defects and cleft palate in developing fetuses of humans and animals. In this study, we tested the alkaloids anabasine, lobeline, and myosmine for agonist actions, and sensitivity to alp...

  19. catena-Poly[[tris(4-fluorobenzyltin(IV]-μ-2-[(piperidin-1-ylcarbothioylsulfanyl]acetato-κ2O:O′

    Directory of Open Access Journals (Sweden)

    Chun Thy Keng

    2010-08-01

    Full Text Available Adjacent units of the title polymeric complex, [Sn(C7H6F3(C8H12NO2S2], are bridged by the carboxylate ion into a helical chain running along the b axis. The Sn(IV atom shows a distorted trans-C3SnO2 trigonal-bipyramidal coordination and is displaced by 0.113 (2 Å out of the C3Sn girdle in the direction of the covalently bonded O atom. The ring is disordered of two positions with an occupancy of 0.631 (4 for the major occupied site.

  20. Synthesis and structure-activity relationship of piperidine-derived non-urea soluble epoxide hydrolase inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Pecic, Stevan; Pakhomova, Svetlana; Newcomer, Marcia E.; Morisseau, Christophe; Hammock, Bruce D.; Zhu, Zhengxiang; Rinderspacher, Alison; Deng, Shi-Xian [UCD; (LSU); (Columbia)

    2013-09-27

    A series of potent amide non-urea inhibitors of soluble epoxide hydrolase (sEH) is disclosed. The inhibition of soluble epoxide hydrolase leads to elevated levels of epoxyeicosatrienoic acids (EETs), and thus inhibitors of sEH represent one of a novel approach to the development of vasodilatory and anti-inflammatory drugs. Structure–activities studies guided optimization of a lead compound, identified through high-throughput screening, gave rise to sub-nanomolar inhibitors of human sEH with stability in human liver microsomal assay suitable for preclinical development.

  1. Synthesis of 7-oxo-dihydrospiro[indazole-5,4'-piperidine] acetyl-CoA carboxylase inhibitors.

    Science.gov (United States)

    Bagley, Scott W; Southers, James A; Cabral, Shawn; Rose, Colin R; Bernhardson, David J; Edmonds, David J; Polivkova, Jana; Yang, Xiaojing; Kung, Daniel W; Griffith, David A; Bader, Scott J

    2012-02-03

    Synthesis of oxo-dihydrospiroindazole-based acetyl-CoA carboxylase (ACC) inhibitors is reported. The dihydrospiroindazoles were assembled in a regioselective manner in six steps from substituted hydrazines and protected 4-formylpiperidine. Enhanced regioselectivity in the condensation between a keto enamine and substituted hydrazines was observed when using toluene as the solvent, leading to selective formation of 1-substituted spiroindazoles. The 2-substituted spiroindazoles were formed selectively from alkyl hydrazones by ring closure with Vilsmeier reagent. The key step in the elaboration to the final products is the conversion of an intermediate olefin to the desired ketone through elimination of HBr from an O-methyl bromohydrin. This methodology enabled the synthesis of each desired regioisomer on 50-75 g scale with minimal purification. Acylation of the resultant spirocyclic amines provided potent ACC inhibitors.

  2. Structure-Activity Relationships of 33 Piperidines as Toxicants Against Female Adults of Aedes aegypti (Diptera: Culicidae)

    Science.gov (United States)

    2007-03-01

    MEDICAL ENTOMOLOGY Vol. 44, no. 2 tigotes and amastigotes of Trypanosoma cruzi . Bioorg. Med. Chem. Lett. 14: 3555Ð3558. Rudnick, A. 1967. Aedes aegypti and...alkaloid piperine and 12 syn- thetic derivatives have been evaluated against epimas- tigote and amastigote forms of the protozoan parasite Trypanosoma ... cruzi , the etiological agent of ChagasÕ disease. Furthermore, it has been suggested that pip- erine is a suitable template for the development of new

  3. Synthesis and Biological Evaluation of New 3-Phenyl-1-[(4-arylpiperazin-1-yl)alkyl]-piperidine-2,6-diones.

    Science.gov (United States)

    Bielenica, Anna; Kossakowski, Jerzy; Struga, Marta; Dybała, Izabela; Loddo, Roberta; Ibba, Cristina; La Colla, Paolo

    2011-01-01

    A set of 13 alkyl derivatives of 3-phenylpiperidine-2,6-dione were synthesized. Newly obtained compounds were investigated in vitro against HIV-1 and other selected viruses. The benzyl 3f and fluorophenyl 3g derivatives showed moderate protection against CVB-2 and the compound 3g also against HSV-1. Derivatives were tested also for their antibacterial and antifungal activity. The molecular structures of 3a and 3d were determined by an X-ray analysis.

  4. Quantitative analysis of penicillins in porcine tissues, milk and animal feed using derivatisation with piperidine and stable isotope dilution liquid chromatography tandem mass spectrometry

    NARCIS (Netherlands)

    Holthoon, van F.L.; Mulder, P.P.J.; Bennekom, van E.O.; Heskamp, H.H.; Zuidema, T.; Rhijn, van J.A.

    2010-01-01

    Penicillins are used universally in both human and veterinary medicine. The European Union (EU) has established maximum residue levels (MRLs) for most ß-lactam antibiotics in milk and animal tissues and included them in the National Residue Monitoring Programs. In this study, a novel method is descr

  5. Halogen Bonding or Hydrogen Bonding between 2,2,6,6-Tetramethyl-piperidine-noxyl Radical and Trihalomethanes CHX3 (X=Cl, Br, I)

    Institute of Scientific and Technical Information of China (English)

    Xiao-ran Zhao; Xue Pang; Xiao-qing Yan; Wei-jun Jin

    2013-01-01

    The halogen and hydrogen bonding complexes between 2,2,6,6-tetramethylpiperidine-noxyl and trihalomethanes (CHX3,X=Cl,Br,I) are simulated by computational quantum chemistry.The molecular electrostatic potentials,geometrical parameters and interaction energy of halogen and hydrogen bonding complexes combined with natural bond orbital analysis are obtained.The results indicate that both halogen and hydrogen bonding interactions obey the order Cl<Br<I,and hydrogen bonding is stronger than the corresponding halogen bond ing.So,hydrogen bonding complexes should be dominant in trihalomethanes.However,it is possible that halogen bonding complex is competitive,even preponderant,in triiodomethane due to the similar interaction energy.This work might provide useful information on specific solvent effects as well as for understanding the mechanism of nitroxide radicals as a bioprobe to interact with the halogenated compounds in biological and biochemical fields.

  6. [Synthetic transformations of higher terpenoids. XXX. Synthesis and cytotoxic activity of betulonic acid amides with a piperidine or pyrrolidine nitroxide moiety].

    Science.gov (United States)

    Antimonova, A N; Petrenko, N I; Shults, E E; Polienko, Iu F; Shakirov, M M; Irtegova, I G; Pokrovskiĭ, M A; Sherman, K M; Grigor'ev, I A; Pokrovskiĭ, A G; Tolstikov, G A

    2013-01-01

    The reaction of betulonic acid chloride with 4-amino-2,2,6,6-tetramethylpeperidine-1-oxyl, 3-amino-2,2,5,5-tetramethylpyrrolidine-1-oxyl and 3-aminomethyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl gave corresponding triterpenoid amides. It was found that new derivatives exhibit cytotoxic activity against tumor cells CEM-13, U-937, MT-4. CCID50 value for most activity compound--N-[3-oxolup-20(29)-en-30-yl]-(2,2,6,6-tetramethylpiperidine-4-yl)-1-oxyl--was 5.7-33.1 microM.

  7. Effect of Piperidin-4-ones on the Corrosion Inhibition of Mild Steel in 1 N H2SO4

    Directory of Open Access Journals (Sweden)

    Glory Tharial Xavier

    2015-01-01

    Full Text Available The corrosion inhibition of mild steel in 1 N sulphuric acid solution by 2,6-diphenylpiperidin-4-ones with various substituents at 3- and 3,5-positions (01–06 has been tested by weight loss, potentiodynamic polarization, electrochemical impedance spectroscopic methods, and FTIR and UV absorption spectra. The surface morphology of the mild steel specimen has been analyzed by SEM. The effect of temperature (300 to 323 ± 1 K on the corrosion behavior of mild steel in the presence of the inhibitors (01–06 was studied using weight loss techniques. The effect of anions (Cl−, Br−, and I− on the corrosion behavior of mild steel in the presence of the same inhibitors was also studied by weight loss method and the synergism parameters were calculated. The adsorption characteristics of the inhibitors have been determined from the results.

  8. 5-(Piperidin-4-yl)-3-Hydroxypyrazole: A Novel Scaffold for Probing the Orthosteric γ-Aminobutyric Acid Type A Receptor Binding Site

    DEFF Research Database (Denmark)

    Krall, Jacob; Kongstad, Kenneth Thermann; Nielsen, Birgitte

    2014-01-01

    indicate that the N1-substituted analogues of 4-PIOL and 4-PHP, 2 a–k, and previously reported 3-substituted 4-PHP analogues share a common binding mode to the orthosteric binding site in the receptor. Interestingly, the core scaffold of the N2-substituted analogues of 4-PIOL and 4-PHP, 3 b......–k, are suggested to flip 180° thereby adapting to the binding pocket and addressing a cavity situated above the core scaffold....

  9. Inhibitory activities of venom alkaloids of Red Imported Fire Ant against Clavibacter michiganensis subsp. michiganensis in vitro and the application of piperidine alkaloids to manage symptom development..

    Science.gov (United States)

    Bacterial canker of tomato caused by Clavibacter michiganensis subsp. michiganensis (CMM) is a highly destructive disease and has caused major economic losses in tomato production worldwide. There are limited methods available to manage this disease. In searching for disease management alternatives,...

  10. Quinolinesulfonamides of aryloxy-/arylthio-ethyl piperidines: influence of an arylether fragment on 5-HT1A/5-HT7 receptor selectivity.

    Science.gov (United States)

    Grychowska, Katarzyna; Marciniec, Krzysztof; Canale, Vittorio; Szymiec, Michał; Glanowski, Grzegorz; Satała, Grzegorz; Maślankiewicz, Andrzej; Pawłowski, Maciej; Bojarski, Andrzej J; Zajdel, Paweł

    2013-03-01

    The solid-phase synthesis of a new series of 19 biomimetics of long-chain arylpiperazines, namely flexible quinoline sulfonamides of aryl(heteroaryl)oxy-/heteroarylthio-ethyl 4-aminomethylpiperidines, is reported. Various structural modifications applied followed by biological evaluation for 5-HT1A, 5-HT6, and 5-HT7 receptors gave further support of a possible replacement of arylpiperazine with aryloxy-/arylthio-ethyl derivatives of alicyclic amines and control of receptor selectivity upon diversification in the aryl(heteroaryl)oxy-/heteroarylthio-ethyl fragment.

  11. Crystal structure of (piperidine-1-carbodithioato-κ2S,S[2-(pyridin-2-ylphenyl-κ2C1,N]palladium(II

    Directory of Open Access Journals (Sweden)

    Mikhail Kondrashov

    2015-09-01

    Full Text Available The title compound, [Pd(C11H8N(C6H10NS2], crystallizes with three similar and discrete molecules in the asymmetric unit. The CNS2 donor set defines a distorted square-planar geometry around the PdII atom, with very small deviations from planarity. The bidentate nature of the ligands gives fairly large deviations from the ideal 90° angles; the C—Pd—N angles are all around 81° and the S—Pd—S angles are around 75°. Molecules pack via dispersion interactions.

  12. The role of weak intermolecular C-H…F interactions in supramolecular assembly: Structural investigations on 3,5- dibenzylidene-piperidin-4-one and database analysis

    Indian Academy of Sciences (India)

    R S Rathore; N S Karthikeyan; Y Alekhya; K Sathiyanarayanan; P G Aravindan

    2011-07-01

    The fluorinated and non-fluorinated dibenzylidene-4-piperidones were synthesized and their structures examined using X-ray crystallography. Interestingly, the para-fluorosubstituted dibenzylidene compound, in contrast to other analogs, is characterized by C-H…F bonded one-dimensional packing motif. To evaluate the ability of hydrogen bond donors and acceptors for forming interactions, in general and competitive situation, we have defined statistical descriptors. Analysis of Cambridge Structural Database using these newly defined parameters reveals high propensity of C-H…F interactions in organic crystals. The present structural study suggests much larger role of fluorine driven intermolecular interactions that are even though weak, but possess significant ability to direct and alter the packing.

  13. Radiosynthesis and biodistribution of a histamine H{sub 3} receptor antagonist 4-[3-(4-piperidin-1-yl-but-1-ynyl)-[{sup 11}C]benzyl]-morpholine: evaluation of a potential PET ligand

    Energy Technology Data Exchange (ETDEWEB)

    Airaksinen, Anu J. [Department of Nuclear Medicine and PET Research, Location Radionuclide Center, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam (Netherlands); Jablonowski, Jill A. [Johnson and Johnson Pharmaceutical Research and Development LLC, San Diego, CA 92121 (United States); Mey, Margreet van der [Department of Nuclear Medicine and PET Research, Location Radionuclide Center, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam (Netherlands); Barbier, Ann J. [Johnson and Johnson Pharmaceutical Research and Development LLC, San Diego, CA 92121 (United States); Klok, Rob P. [Department of Nuclear Medicine and PET Research, Location Radionuclide Center, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam (Netherlands); Verbeek, Joost [Department of Nuclear Medicine and PET Research, Location Radionuclide Center, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam (Netherlands); Schuit, Robert [Department of Nuclear Medicine and PET Research, Location Radionuclide Center, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam (Netherlands); Herscheid, Jacobus D.M. [Department of Nuclear Medicine and PET Research, Location Radionuclide Center, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam (Netherlands); Leysen, Josee E. [Department of Nuclear Medicine and PET Research, Location Radionuclide Center, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam (Netherlands); Carruthers, Nicholas I. [Johnson and Johnson Pharmaceutical Research and Development LLC, San Diego, CA 92121 (United States); Lammertsma, Adriaan A. [Department of Nuclear Medicine and PET Research, Location Radionuclide Center, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam (Netherlands); Windhorst, Albert D. [Department of Nuclear Medicine and PET Research, Location Radionuclide Center, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam (Netherlands)]. E-mail: bwindhorst@rnc.vu.nl

    2006-08-15

    The potent histamine H{sub 3} receptor antagonist JNJ-10181457 () was successfully labeled with {sup 11}C in a novel one-pot reaction sequence, with high chemical yield (decay-corrected yield, 28{+-}8%) and high specific radioactivity (56{+-}26 GBq/{mu}mol). The binding of [{sup 11}C] to H{sub 3} receptors was studied in vitro in rat brain and in vivo in rats and mice. The in vitro binding of [{sup 11}C] in rat coronal brain slices showed high binding in the striatum, and this binding was blocked by histamine and by two known H{sub 3} antagonists, JNJ-5207852 () and unlabeled Compound (), in a concentration-dependent manner. The biodistribution of [{sup 11}C] in rats was measured at 5, 10, 30 and 60 min. The uptake of [{sup 11}C] in regions rich in H{sub 3} receptors was highest at 30 min, giving 0.98%, 1.41%, 1.28% and 1.72% dose/g for the olfactory bulb, hippocampus, striatum and cerebral cortex, respectively. However, the binding of [{sup 11}C] in the rat brain could not be blocked by pretreatment with either Compound () (30 min or 24 h pretreatment) or cold Compound () (30-min pretreatment). The biodistribution of [{sup 11}C] in a second species (Balb/c mice) showed a higher overall uptake of the radioligand with an average brain uptake of 8.9% dose/g. In C57BL/6-H{sub 3}(-/-) knockout mice, a higher brain uptake was also observed. Analyses of metabolites and plasma protein binding were also undertaken. It appeared that [{sup 11}C] could not specifically label H{sub 3} receptors in rodent brain in vivo. Possible causes are discussed.

  14. Crystal structure of [propane-1,3-diylbis(piperidine-4,1-diyl]bis[(pyridin-4-ylmethanone]–4,4′-oxydibenzoic acid (1/1

    Directory of Open Access Journals (Sweden)

    Emily M. Low

    2014-09-01

    Full Text Available In the title co-crystal, C25H32N4O2·C14H10O5, molecules are connected into supramolecular chains aligned along [102] by O—H...N hydrogen bonding. These aggregate into supramolecular layers oriented parallel to (20-1 by C—H...O interactions. These layers then stack in an ABAB pattern along the c crystal direction to give the full three-dimensional crystal structure. The central chain in the dipyridylamide has an anti–anti conformation. The dihedral angle between the aromatic ring planes is 29.96 (3°. Disorder is noted in some of the residues in the structure and this is manifested in two coplanar dispositions of one statistically disordered carboxylic acid group.

  15. Spirocyclic delta opioid receptor agonists for the treatment of pain: discovery of N,N-diethyl-3-hydroxy-4-(spiro[chromene-2,4'-piperidine]-4-yl) benzamide (ADL5747).

    Science.gov (United States)

    Le Bourdonnec, Bertrand; Windh, Rolf T; Leister, Lara K; Zhou, Q Jean; Ajello, Christopher W; Gu, Minghua; Chu, Guo-Hua; Tuthill, Paul A; Barker, William M; Koblish, Michael; Wiant, Daniel D; Graczyk, Thomas M; Belanger, Serge; Cassel, Joel A; Feschenko, Marina S; Brogdon, Bernice L; Smith, Steven A; Derelanko, Michael J; Kutz, Steve; Little, Patrick J; DeHaven, Robert N; DeHaven-Hudkins, Diane L; Dolle, Roland E

    2009-09-24

    Selective, nonpeptidic delta opioid receptor agonists have been the subject of great interest as potential novel analgesic agents. The discoveries of BW373U86 (1) and SNC80 (2) contributed to the rapid expansion of research in this field. However, poor drug-like properties and low therapeutic indices have prevented clinical evaluation of these agents. Doses of 1 and 2 similar to those required for analgesic activity produce convulsions in rodents and nonhuman primates. Recently, we described a novel series of potent, selective, and orally bioavailable delta opioid receptor agonists. The lead derivative, ADL5859 (4), is currently in phase II proof-of-concept studies for the management of pain. Further structure activity relationship exploration has led to the discovery of ADL5747 (36), which is approximately 50-fold more potent than 4 in an animal model of inflammatory pain. On the basis of its favorable efficacy, safety, and pharmacokinetic profile, 36 was selected as a clinical candidate for the treatment of pain.

  16. Effects of piperidine and piperideine alkaloids from the venom of red imported fire ants, Solenopsis invicta Buren, on Pythium ultimum Trow growth in vitro and the application of piperideine alkaloids to control cucumber..

    Science.gov (United States)

    Pythium ultimum Trow is a plant pathogen that causes significant yield losses on many economically important crops. Chemical seed treatment has been used for disease control. In searching for alternatives, the venom alkaloids from red imported fire ant were tested against P. ultimum in vitro and to ...

  17. Crystal structure of 1',1''-dimethyl-4'-(4-cholorophen-yl)di-spiro-[11H-indeno[1,2-b]quinoxaline-11,2'-pyrrolidine-3',3''-piperidin]-4''-one.

    Science.gov (United States)

    Nagalakshmi, R A; Suresh, J; Malathi, K; Kumar, R Ranjith; Lakshman, P L Nilantha

    2015-02-01

    In the title compound, C30H27ClN4O, the central pyrrolidine ring adopts an envelope conformation with the methyl-ene C atom being the flap. The quinoxaline and indane rings are each essentially planar, with r.m.s. deviations of 0.027 (1) and 0.0417 (1) Å, respectively. The pyrrolidine ring forms dihedral angles of 88.25 (1) and 83.76 (1)° with the quinoxaline and indane rings, respectively. A weak intra-molecular C-H⋯N inter-action is observed. In the crystal, C-H⋯π inter-actions lead to supra-molecular chains along [101] that assemble in the ac plane. Connections along the b axis are of the type Cl⋯Cl [3.6538 (16) Å].

  18. 1′,1′′-Dimethyl-4′-(4-methylphenyldispiro[11H-indeno[1,2-b]quinoxaline-11,2′-pyrrolidine-3′,3′′-piperidin]-4′′-one

    Directory of Open Access Journals (Sweden)

    R. A. Nagalakshmi

    2013-09-01

    Full Text Available In the title compound, C31H30N4O, the central pyrrolidine ring adopts an envelope conformation with the methylene C atom being the flap. The quinoxaline and indane rings are each planar, having r.m.s. deviations of 0.030 and 0.050 Å, respectively. The pyrrolidine ring mean plane forms dihedral angles of 88.25 (1 and 83.76 (1° with the quinoxaline and indane rings, respectively. Intramolecular C—H...O and C—H...N interactions are observed. In the crystal, C—H...π interactions lead to helical supramolecular chains along the b-axis direction.

  19. 1′,1′′-Dimethyl-4′-phenyldispiro[11H-indeno[1,2-b]quinoxaline-11,2′-pyrrolidine-3′,3′′-piperidin]-4′′-one

    Directory of Open Access Journals (Sweden)

    J. Suresh

    2013-09-01

    Full Text Available In the title compound, C30H28N4O, the central pyrrolidine ring adopts an envelope conformation with the CH2 C atom as the flap. The quinoxaline and indene ring systems are planar, with r.m.s. deviations of 0.0165 and 0.0181 Å, respectively. The pyrrolidine ring mean plane forms dihedral angles of 88.84 (1 and 86.14 (1° with the quinoxaline and indene ring systems, respectively. A weak intramolecular C—H...N interaction is observed. In the crystal, C—H...O interactions lead to helical supramolecular chains along the b axis having a C(9 motif.

  20. 微波辐射六氢吡啶催化快速合成乙酰水杨酸的研究%Research on rapid synthesis of acetylsalicylic acid catalysed by piperidine under microwave radiation

    Institute of Scientific and Technical Information of China (English)

    赵士举; 金秋; 苏惠; 李伟; 徐翠莲

    2010-01-01

    以水杨酸和乙酸酐为原料,微波辐射加热,六氢吡啶为催化剂,快速合成了乙酰水杨酸.通过正交试验及直观分析,探索出了最佳合成工艺条件;通过方差分析,得出了影响次序和程度.该方法为高效、环保、低能合成乙酰水杨酸提供了新的工艺条件.

  1. Radiosynthesis of an opiate receptor-binding radiotracer for positron emission tomography: (C-11 methyl)-methyl-4-(N-(1-oxopropyl)-N-phenylamino)-4-piperidine carboxylate (C-11 4-carbomethoxyfentanyl)

    Energy Technology Data Exchange (ETDEWEB)

    Dannals, R.F.; Ravert, H.T.; Frost, J.J.; Wilson, A.A.; Burns, H.D.; Wagner, H.N. Jr.

    1984-01-01

    The development of high affinity, high specific activity tritium-labeled neurotransmitter receptor ligands has made it possible to determine the spatial distribution and relative regional concentration of several neuroreceptors by means of in vivo receptor labeling techniques in animals. This development made possible the biochemical identification of opiate receptors by autoradiographic visualization in experimental animals. The quantitation and localization of opiate receptors in man using non-invasive methods, such as positron emission tomography, could provide a means of obtaining information about a variety of receptor-linked neuropsychiatric diseases as well as normal brain mechanisms regulating pain and emotions. As part of a continuing program to identify and radiolabel high affinity, highly specific ligands for the opiate receptor, the authors have selected two derivatives of fentanyl, a well-known analgesic, as candidates for radiolabeling: R-31,833 (4-carbomethoxy-fentanyl) and R-34,995 (lofentanil). Carbon-11 labeled R-31,833 was synthesized by the methylation of the appropriate carboxylate with C-11 methyl iodide in dimethylformamide at room temperature and purified by high performance liquid chromatography. The average synthesis time from end-of-bombardment (E.O.B.) was 30 minutes. The average specific activity was determined by ultraviolet spectroscopy to be 890 mCi/..mu..mole end-of-synthesis (approx. 2500 mCi/..mu..mole E.O.B.).

  2. Neuroimaging of the vesicular acetylcholine transporter by a novel 4-[{sup 18}F]fluoro-benzoyl derivative of 7-hydroxy-6-(4-phenyl-piperidin-1-yl)-octahydro-benzo[1,4]oxazines

    Energy Technology Data Exchange (ETDEWEB)

    Sorger, Dietlind [Department of Nuclear Medicine, University of Leipzig, Leipzig 04103 (Germany)], E-mail: sord@medizin.uni-leipzig.de; Scheunemann, Matthias; Vercouillie, Johnny [Institute of Interdisciplinary Isotope Research, Leipzig 04318 (Germany); Grossmann, Udo [Department of Nuclear Medicine, University of Leipzig, Leipzig 04103 (Germany); Fischer, Steffen; Hiller, Achim; Wenzel, Barbara [Institute of Interdisciplinary Isotope Research, Leipzig 04318 (Germany); Roghani, Ali [Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock TX 39430 (United States); Schliebs, Reinhard [Paul Flechsig Institute of Brain Research, University of Leipzig, Leipzig 04109 (Germany); Steinbach, Joerg; Brust, Peter [Institute of Interdisciplinary Isotope Research, Leipzig 04318 (Germany); Sabri, Osama [Department of Nuclear Medicine, University of Leipzig, Leipzig 04103 (Germany)

    2009-01-15

    Phenylpiperidinyl-octahydro-benzo[1,4]oxazines represent a new class of conformationally restrained vesamicol analogues. Derived from this morpholine-fused vesamicol structure, a new fluorine-18-labeled 4-fluorobenzoyl derivative ([{sup 18}F]FBMV) was synthesized with an average specific activity of 75 GBq/{mu}mol and a radiochemical purity of 99%. The radiolabeling method included an exchange reaction of a 4-nitro group of the precursor by fluorine-18, a reduction procedure to eliminate excess of the nitro compound, followed by a high-performance liquid chromatography purification. [{sup 18}F]FBMV demonstrates (i) a moderate lipophilic character with a logD{sub pH7.0} 1.8{+-}0.10; (ii) a considerable binding affinity to the vesicular acetylcholine transporter (VAChT) (K{sub i}=27.5 nM), as determined using PC12 cells transfected with a VAChT cDNA, and a low affinity to {sigma}{sub 1,2} receptors (K{sub i} >3000 nM); (iii) a good uptake into the rat and pig brains; (iv) a typical accumulation in the VAChT-containing brain regions; and (v) an approximately 20% reduction in cortical tracer binding after a specific cholinergic lesion using 192IgG-saporin. [{sup 18}F]FBMV exhibits another PET marker within the group of vesamicol derivatives that demonstrates potentials in imaging brain cholinergic deficits, while its usefulness in clinical practice must await further investigation.

  3. RELATIONSHIP BETWEEN ACTION OF ACETIC-β-(N-PIPERIDINE)-ESTER ON SNAIL-KILLING AND CALCIUM ION%乙酸β-哌啶乙酯的灭螺作用与钙离子的关系

    Institute of Scientific and Technical Information of China (English)

    王少林; 夏国瑾; 李桂玲; 吴世玉; 田先翔

    2001-01-01

    目的研究乙酸β-哌啶乙酯(Ape)的杀螺作用与Ca2+的关系. 方法采用完全浸泡和离体钉螺足平滑肌的实验方法,研究Ape杀螺效果及其对Ca2+的影响.结果0.1 mg/L和0.5 mg/LApe均有杀螺作用(P均<0.05),且呈浓度依赖性.不同浓度的Ape对钉螺足平滑肌的收缩效应曲线呈双相性.低浓度时(10-7~3×10-6mol/L)可增强其收缩幅度,且能被钙通道阻滞剂维拉帕米所拮抗;高浓度时(10-5~10-4mol/L)则能拮抗钙通道激动剂Bay K 8644增强钉螺足平滑肌的收缩幅度.结论Ape具有一定的杀螺作用,其影响平滑肌收缩的结果表明,高浓度有阻Ca2+作用.

  4. Crystal structure of chlorido{4,5-dimethoxy-2-[(2,3-η-2-prop-2-en-1-yl]phenyl-κC1}(piperidine-κNplatinum(II ethanol monosolvate

    Directory of Open Access Journals (Sweden)

    Peter Mangwala Kimpende

    2014-11-01

    Full Text Available In the title compound, [Pt(C11H13O2Cl(C5H11N]·C2H5OH, the PtII cation is pentacoordinated in a distorted square-planar geometry. In the crystal, inversion dimers showing C—H...Cl and C—H...π interactions are further stacked in columns along the a axis via C—H...π interactions. The ethanol solvate molecule interacts with neighbouring methoxy groups of methyleugenol through O—H...O hydrogen bonds.

  5. Potent heteroarylpiperidine and carboxyphenylpiperidine 1-alkyl-cyclopentane carboxamide CCR2 antagonists.

    Science.gov (United States)

    Pasternak, Alexander; Goble, Stephen D; Vicario, Pasquale P; Di Salvo, Jerry; Ayala, Julia M; Struthers, Mary; DeMartino, Julie A; Mills, Sander G; Yang, Lihu

    2008-02-01

    This report describes replacement of the 4-(4-fluorophenyl)piperidine moiety in our CCR2 antagonists with 4-heteroaryl piperidine and 4-(carboxyphenyl)-piperidine subunits. Some of the resulting analogs retained potency in our CCR2 binding assay and had improved selectivity versus the I(Kr) channel; poor selectivity against I(Kr) had been a liability of earlier analogs in this series.

  6. Ab Initio Studies on the Preferred Site of Protonation in Cytisine in the Gas Phase and Water

    Directory of Open Access Journals (Sweden)

    Małgorzata Darowska

    2005-01-01

    Full Text Available Abstract: Ab initio calculations (HF, MP2, DFT for isolated and PCM for solvated molecules were performed for cytisine (1 and its model compounds: N-methyl-2-pyridone (2 and piperidine (3. Among three heteroatomic functions (carbonyl oxygen, pyridone and piperidine nitrogens considered as the possible sites of protonation in 1, surprisingly the carbonyl oxygen takes preferentially the proton in the gas phase whereas in water the piperidine nitrogen is firstly protonated. For model compounds, the piperidine nitrogen in 3 is more basic than the carbonyl oxygen in 2 in both, the gas phase and water.

  7. Synthesis and in vitro affinities of various MDL 100907 derivatives as potential F-18-radioligands for 5-HT2A receptor imaging with PET

    DEFF Research Database (Denmark)

    Herth, Matthias Manfred; Kramer, Vasko; Piel, Markus

    2009-01-01

    Radiolabelled piperidine derivatives such as [(11)C]MDL 100907 and [(18)F]altanserin have played an important role in diagnosing malfunction in the serotonergic neurotransmission. A variety of novel piperidine MDL 100907 derivatives, possible to label with (18)F-fluorine, were synthesized to impr...

  8. Racemic methyl 3,10-dioxa-2-azatricyclo[6.2.1.02,6]undecane-4- carboxylate

    KAUST Repository

    Moosa, Basem

    2011-04-29

    The structure of the racemic title compound, C10H 15NO4, consists of a tricyclic skeleton comprising a six-membered piperidine ring and five-membered isoxazolidine and tetrahydrofuran rings. The piperidine ring adopts a distorted chair conformation, while the isoxazolidine and tetrahydrofuran rings have envelope conformations.

  9. Antidepressant-like effects of piperine and its derivate,3,4-methylene dioxy cinnamoyl piperidine%胡椒碱及其衍生物3,4-次甲二氧桂皮酰哌啶的抗抑郁作用

    Institute of Scientific and Technical Information of China (English)

    李崧; 王澈; 李巍; 小池一男; 二阶堂保; 王敏伟

    2006-01-01

    目的研究胡椒碱及其衍生物3,4-次甲二氧桂皮酰哌啶的抗抑郁作用,并对其作用机理进行初步探讨.方法 利用小鼠强制游泳实验、悬尾实验等考察胡椒碱和3,4次甲二氧桂皮酰哌啶的抗抑郁作用,并通过测定不同脑区内单胺类神经递质质量浓度以及全脑单胺氧化酶活性变化,探讨作用机制.结果 胡椒碱和3,4-次甲二氧桂皮酰哌啶(10、20 mg·kg-1)长期给药后,能明显缩短小鼠在行为学实验中的不动状态时间,并且该作用随剂量增大效应逐渐降低,高剂量(80 mg·kg-1)表现出明显的中枢神经抑制作用;能显著提高脑内5-羟色胺水平,而对脑内肾上腺素递质水平未见明显影响;具有较弱的单胺氧化酶抑制作用.结论 胡椒碱和3,4-次甲二氧桂皮酰哌啶具有较好的抗抑郁作用,其作用是通过上调中枢神经系统5-羟色胺或多巴胺水平实现的.

  10. Crystal structure of 1′,1′′-dimethyl-4′-(4-cholorophenyldispiro[11H-indeno[1,2-b]quinoxaline-11,2′-pyrrolidine-3′,3′′-piperidin]-4′′-one

    Directory of Open Access Journals (Sweden)

    R.A. Nagalakshmi

    2015-02-01

    Full Text Available In the title compound, C30H27ClN4O, the central pyrrolidine ring adopts an envelope conformation with the methylene C atom being the flap. The quinoxaline and indane rings are each essentially planar, with r.m.s. deviations of 0.027 (1 and 0.0417 (1 Å, respectively. The pyrrolidine ring forms dihedral angles of 88.25 (1 and 83.76 (1° with the quinoxaline and indane rings, respectively. A weak intramolecular C—H...N interaction is observed. In the crystal, C—H...π interactions lead to supramolecular chains along [101] that assemble in the ac plane. Connections along the b axis are of the type Cl...Cl [3.6538 (16 Å].

  11. Synthesis of novel chiral tetraaza ligands and their application in enantioselective transfer hydrogenation of ketones

    Institute of Scientific and Technical Information of China (English)

    Shen Luan Yu; Yan Yun Li; Zhen Rong Dong; Jing Xing Gao

    2012-01-01

    Novel chiral tetraaza ligands (R)-N,N'-bis[2-(piperidin-l-yl)benzylidene]propane-1,2-diamine 6 and (S)-N-[2-(piperidin-1-yl)benzylidene]-3-{ [2-(piperidin-1-yl)benzylidene]amino}-alanine sodium salt 7 have been synthesized and fully characterized by NMR,IR,MS and CD spectra.The catalytic property of the ligands was investigated in Ir-catalyzed enantioselective transfer hydrogenation of ketones.The corresponding optical active alcohols were obtained with high yields and moderate ees under mild reaction conditions.

  12. Formation of nitrate and ammonium ions in titanium dioxide mediated photocatalytic degradation of organic compounds containing nitrogen atoms

    Energy Technology Data Exchange (ETDEWEB)

    Low, G.K.-C.; McEvoy, S.R.; Matthews, R.W. (CSIRO Division of Coal and Energy Technology, Menai (Australia))

    1991-03-01

    The photocatalytic oxidation of a related series of primary, secondary, and tertiary amines and other nitrogen- and sulfur-containing organic compounds over a UV-illuminated film of TiO{sub 2} has been studied. The compounds were as follows: n-pentylamine, piperidine, pyridine, phenylalanine, desipramine, thioridazine, penicillamine, isosorbide dinitrate, 4-nitrocatechol, 2,4-dinitrophenol, cyclophosphamide, 5-fluorouracil, atrazine, ethylenediaminetetracetic acid, and tetrabutylammonium phosphate. Both ammonium and nitrate ions were formed. The relative concentration of the two ions depended on the nature of the nitrogen in a compound, but was also influenced by the illumination time and concentration of the solute. It was found that for n-pentylamine, piperidine and pyridine, the rate of formation of ammonium ions was n-pentylamine {much gt} pyridine > piperidine. The order of rates of nitrate formation was pyridine = piperidine {much gt} pentylamine. For n-pentylamine the rate of formation of ammonium ions was {approximately}100 times that of nitrate.

  13. 76 FR 23626 - Importer of Controlled Substances; Notice of Registration

    Science.gov (United States)

    2011-04-27

    ... 15, 2011, and published in the Federal Register on February 23, 2011, 76 FR 10067, Sigma Aldrich... Dimethyltryptamine (7435) I Psilocybin (7437) I Psilocyn (7438) I 1- piperidine (7470)..... I N-Benzylpiperazine...

  14. 76 FR 35243 - Manufacturer of Controlled Substances; Notice of Registration

    Science.gov (United States)

    2011-06-16

    ... January 18, 2011, and published in the Federal Register on February 2, 2011, 76 FR 5829, Sigma Aldrich...) I (7405). Psilocybin (7437) I 5-Methoxy-N,N-diisopropyltryptamine (7439). I 1- piperidine (TCP)...

  15. 78 FR 39339 - Importer of Controlled Substances; Notice of Registration; SA INTL GMBH C/O., Sigma Aldrich Co., LLC

    Science.gov (United States)

    2013-07-01

    ..., 78 FR 19015, SA INTL GMBH C/O., Sigma Aldrich Co. LLC., 3500 Dekalb Street, St. Louis, Missouri 63118... (7435) I Psilocybin (7437) I Psilocyn (7438) I 1- piperidine I (7470). N-Benzylpiperazine (7493)...

  16. 76 FR 10067 - Importer of Controlled Substances; Notice of Application

    Science.gov (United States)

    2011-02-23

    ... September 23, 1975, (40 FR 43745-46), all applicants for registration to import a basic class of any... Dimethyltryptamine (7435) I Psilocybin (7437) I Psilocyn (7438) I 1- piperidine I (7470). N-Benzylpiperazine...

  17. 75 FR 44286 - Manufacturer of Controlled Substances; Notice of Registration

    Science.gov (United States)

    2010-07-28

    ... 16, 2010, and published in the Federal Register on March 24, 2010, (75 FR 14190), Sigma Aldrich...) I (7405). Psilocybin (7437) I 5-Methoxy-N,N-diisopropyltryptamine (7439). I 1- piperidine (TCP)...

  18. 75 FR 14188 - Importer of Controlled Substances; Notice of Application

    Science.gov (United States)

    2010-03-24

    ... Register on September 23, 1975, (40 FR 43745-46), all applicants for registration to import a basic class... Dimethyltryptamine (7435) I Psilocybin (7437) I Psilocyn (7438) I 1- piperidine I (7470). N-Benzylpiperazine...

  19. 1,5-Anhydro-D-fructose as Chiral Building Block: A Novel Approach to 1-Deoxymannojirimycin

    DEFF Research Database (Denmark)

    Maier, Peter; Andersen, Søren Møller; Lundt, Inge

    2006-01-01

    A novel six-step synthesis of 1-deoxymannojirimycin from 1,5-anhydro-D-fructose in 35% overall yield is reported. The key steps are nucleophilic piperidine ring formation and subsequent Lewis acid induced pyran ether cleavage.......A novel six-step synthesis of 1-deoxymannojirimycin from 1,5-anhydro-D-fructose in 35% overall yield is reported. The key steps are nucleophilic piperidine ring formation and subsequent Lewis acid induced pyran ether cleavage....

  20. Synthesis of deuterium-labelled methylphenidate, p-hydroxy-methylphenidate, ritalinic acid and p-hydroxyritalinic acid

    Energy Technology Data Exchange (ETDEWEB)

    Patrick, K.; Kilts, C.; Breese, G. (North Carolina Univ., Chapel Hill (USA). School of Medicine)

    1982-04-01

    The synthesis of threo-dl-methylphenidate (Ritalin 1), threo-dl-p-hydroxy-methylphenidate (3), threo-dl-ritalinic acid (2), and threo-dl-p-hydroxyritalinic acid (4) with deuterium incorporated in the piperidine ring is described. These compounds were synthesized for use as internal standards for mass fragmentographic assays of methylphenidate and its metabolites. The synthetic scheme described resulted in less than 0.05% /sup 2/H/sub 0/ in the piperidine ring in any of the preparations.

  1. Benzamide derivatives and their constrained analogs as histamine H3 receptor antagonists.

    Science.gov (United States)

    Nirogi, Ramakrishna; Shinde, Anil; Tiriveedhi, Vinaykumar; Kota, Laxman; Saraf, Sangram Keshari; Badange, Rajesh Kumar; Mohammed, Abdul Rasheed; Subramanian, Ramkumar; Muddana, Nageshwararao; Bhyrapuneni, Gopinadh; Abraham, Renny

    2016-01-27

    A series of 4-(1-substituted piperidin-4-yloxy) benzamides and 6-(1-substituted piperidin-4-yloxy)-3,4-dihydro-2H-isoquinolin-1-one derivatives have been synthesized and tested for their binding affinity towards H3 receptor. Most of these synthesized compounds have displayed potent binding affinity for H3 receptor when tested in in vitro binding assay. Preliminary SAR studies, functional activity, pharmacokinetic profile and efficacy profile constitute the subject matter of this communication.

  2. [4 + 2] cycloadditions of N-alkenyl iminium ions: structurally complex heterocycles from a three-component Diels-Alder reaction sequence.

    Science.gov (United States)

    Sarkar, Nihar; Banerjee, Abhisek; Nelson, Scott G

    2008-07-23

    N-Alkenyl iminium ions serve as conduits to three-component [4 + 2] cycloaddition reactions accessing structurally and stereochemically diverse piperidine derivatives. These cationic 2-azadienes participate in endo- or exo-selective [4 + 2] cycloadditions with electron-rich and neutral alkene dienophiles to generate a tetrahydropyridinium ion as the initial cycloadduct. In situ nucleophilic addition to the cycloaddition-derived iminium ion completes the three-component coupling sequence and affords a versatile synthesis of structurally complex piperidines.

  3. Tandem Aza

    Science.gov (United States)

    Tailor; Hall

    2000-11-16

    The alpha-hydroxyalkyl piperidine unit is common to several naturally occurring alkaloids and azasugar analogues. Polysubstituted piperidine derivatives of this kind (3), embodying four stereogenic centers, are formed in just a single operation from the highly stereocontrolled reaction of 4-borono-1-azadienes (1), maleimides, and aldehydes. This novel multicomponent reaction which affords as many as four elements of diversity should prove highly valuable in combinatorial chemistry and natural product synthesis.

  4. Plant alkaloids that cause developmental defects through the disruption of cholinergic neurotransmission.

    Science.gov (United States)

    Green, Benedict T; Lee, Stephen T; Welch, Kevin D; Panter, Kip E

    2013-12-01

    The exposure of a developing embryo or fetus to alkaloids from plants, plant products, or plant extracts has the potential to cause developmental defects in humans and animals. These defects may have multiple causes, but those induced by piperidine and quinolizidine alkaloids arise from the inhibition of fetal movement and are generally referred to as multiple congenital contracture-type deformities. These skeletal deformities include arthrogyrposis, kyposis, lordosis, scoliosis, and torticollis, associated secondary defects, and cleft palate. Structure-function studies have shown that plant alkaloids with a piperidine ring and a minimum of a three-carbon side-chain α to the piperidine nitrogen are teratogenic. Further studies determined that an unsaturation in the piperidine ring, as occurs in gamma coniceine, or anabaseine, enhances the toxic and teratogenic activity, whereas the N-methyl derivatives are less potent. Enantiomers of the piperidine teratogens, coniine, ammodendrine, and anabasine, also exhibit differences in biological activity, as shown in cell culture studies, suggesting variability in the activity due to the optical rotation at the chiral center of these stereoisomers. In this article, we review the molecular mechanism at the nicotinic pharmacophore and biological activities, as it is currently understood, of a group of piperidine and quinolizidine alkaloid teratogens that impart a series of flexure-type skeletal defects and cleft palate in animals.

  5. Visualizing the 16-membered ring macrolides tildipirosin and tilmicosin bound to their ribosomal site.

    Science.gov (United States)

    Poehlsgaard, Jacob; Andersen, Niels M; Warrass, Ralf; Douthwaite, Stephen

    2012-08-17

    The veterinary antibiotic tildipirosin (20,23-dipiperidinyl-mycaminosyl-tylonolide, Zuprevo) was developed recently to treat bovine and swine respiratory tract infections caused by bacterial pathogens such as Pasteurella multocida. Tildipirosin is a derivative of the naturally occurring compound tylosin. Here, we define drug-target interactions by combining chemical footprinting with structure modeling and show that tildipirosin, tylosin, and an earlier tylosin derivative, tilmicosin (20-dimethylpiperidinyl-mycaminosyl-tylonolide, Micotil), bind to the same macrolide site within the large subunit of P. multocida and Escherichia coli ribosomes. The drugs nevertheless differ in how they occupy this site. Interactions of the two piperidine components, which are unique to tildipirosin, distinguish this drug from tylosin and tilmicosin. The 23-piperidine of tildipirosin contacts ribosomal residues on the tunnel wall while its 20-piperidine is oriented into the tunnel lumen and is positioned to interfere with the growing nascent peptide.

  6. 2-(4-Carbonylphenyl)benzoxazole inhibitors of CETP: attenuation of hERG binding and improved HDLc-raising efficacy.

    Science.gov (United States)

    Sweis, Ramzi F; Hunt, Julianne A; Sinclair, Peter J; Chen, Ying; Eveland, Suzanne S; Guo, Qiu; Hyland, Sheryl A; Milot, Denise P; Cumiskey, Anne-Marie; Latham, Melanie; Rosa, Raymond; Peterson, Larry; Sparrow, Carl P; Anderson, Matt S

    2011-05-01

    The development of 2-phenylbenzoxazoles as inhibitors of cholesteryl ester transfer protein (CETP) is described. Efforts focused on finding suitable replacements for the central piperidine with the aim of reducing hERG binding: a main liability of our benchmark benzoxazole (1a). Replacement of the piperidine with a cyclohexyl group successfully attenuated hERG binding, but was accompanied by reduced in vivo efficacy. The approach of substituting a piperidine moiety with an oxazolidinone also attenuated hERG binding. Further refinement of this latter scaffold via SAR at the pyridine terminus and methyl branching on the oxazolidinone led to compounds 7e and 7f, which raised HDLc by 33 and 27mg/dl, respectively, in our transgenic mouse PD model and without the hERG liability of previous series.

  7. Discovery of novel (4-piperidinyl)-piperazines as potent and orally active acetyl-CoA carboxylase 1/2 non-selective inhibitors: F-Boc and triF-Boc groups are acid-stable bioisosteres for the Boc group.

    Science.gov (United States)

    Chonan, Tomomichi; Wakasugi, Daisuke; Yamamoto, Daisuke; Yashiro, Miyoko; Oi, Takahiro; Tanaka, Hiroaki; Ohoka-Sugita, Ayumi; Io, Fusayo; Koretsune, Hiroko; Hiratate, Akira

    2011-03-01

    Novel (4-piperidinyl)-piperazine derivatives were synthesized and evaluated as ACC1/2 non-selective inhibitors. Optimization of the substituents on the nitrogen of the piperidine ring led to the identification of the fluorine substituted tert-butoxycarbonyl group. Advanced analog, 1,1,1-trifluoro-2-methylpropan-2-yl 4-{4-[(2-amino-6-methyl-1-benzothiophen-3-yl)carbonyl]piperazin-1-yl}piperidine-1-carboxylate (12c) showed potent inhibitory activities in enzyme-assay and cell-based assays. Compound 12c also exhibited reduction of hepatic de novo fatty acid synthesis in rats after oral administration.

  8. BH3-Amine and B(CH3)3-Amine Adducts as Additives for Liquid/Gel Hypergols and Solid Hybrid Rocket Motor Fuels: Property and Performance Predictions

    Science.gov (United States)

    2013-12-01

    adduct might be analogous to reacting highly corrosive nitric acid (HNO3) with ammonia (NH3). The NH3 + HNO3 reaction produces a noncorrosive...Although the application for these compounds was not mentioned in the cited publications, the researchers later patented syntheses involving the...triaazabicyclo[4.3.0]non-6-ene C6H11N3 MMA methanamine or monomethylamine CH5N NH3 ammonia H3N piperidine piperidine C5H11N pyridine pyridine C5H5N

  9. Pellitorine, a Potential Anti-Cancer Lead Compound against HL60 and MCT-7 Cell Lines and Microbial Transformation of Piperine from Piper Nigrum

    Directory of Open Access Journals (Sweden)

    Gwendoline Cheng Lian Ee

    2010-04-01

    Full Text Available Pellitorine (1, which was isolated from the roots of Piper nigrum, showed strong cytotoxic activities against HL60 and MCT-7 cell lines. Microbial transformation of piperine (2 gave a new compound 5-[3,4-(methylenedioxyphenyl]-pent-2-ene piperidine (3. Two other alkaloids were also found from Piper nigrum. They are (E-1-[3’,4’-(methylenedioxycinnamoyl]piperidine (4 and 2,4-tetradecadienoic acid isobutyl amide (5. These compounds were isolated using chromatographic methods and their structures were elucidated using MS, IR and NMR techniques.

  10. Pellitorine, a potential anti-cancer lead compound against HL6 and MCT-7 cell lines and microbial transformation of piperine from Piper Nigrum.

    Science.gov (United States)

    Ee, Gwendoline Cheng Lian; Lim, Chyi Meei; Rahmani, Mawardi; Shaari, Khozirah; Bong, Choon Fah Joseph

    2010-04-05

    Pellitorine (1), which was isolated from the roots of Piper nigrum, showed strong cytotoxic activities against HL60 and MCT-7 cell lines. Microbial transformation of piperine (2) gave a new compound 5-[3,4-(methylenedioxy)phenyl]-pent-2-ene piperidine (3). Two other alkaloids were also found from Piper nigrum. They are (E)-1-[3',4'-(methylenedioxy)cinnamoyl]piperidine (4) and 2,4-tetradecadienoic acid isobutyl amide (5). These compounds were isolated using chromatographic methods and their structures were elucidated using MS, IR and NMR techniques.

  11. Unexpected Formation of Highly Functionalized Dihydropyrans via Addition-Cyclization Reactions Between Dimethyl Oxoglutaconate and α,β-Unsaturated Hydrazones.

    Science.gov (United States)

    Mullins, Jason E; Etoga, Jean-Louis G; Gajewski, Mariusz; Degraw, Joseph I; Thompson, Charles M

    2009-05-20

    The condensation between dienophiles and α,β-unsaturated hydrazone azadienes was previously reported to afford piperidines. During an attempt to adapt this reaction to the preparation of piperidine-based conformationally-restricted analogs of glutamate, it was discovered that the electrophile, dimethyl oxoglutaconate (DOG) led to highly substituted dihydropyrans in 20-50% yield. The unexpected pyran product likely results from an initial 1,4-addition of the hydrazone to the oxoglutaconate followed by intramolecular cyclization of the resultant enolate oxygen to the α,β-unsaturated iminium ion. Further manipulations afford substituted tetrahydropyran 6-methamino-2,4-dicarboxylic acids.

  12. A configurational switch based on iridium-catalyzed allylic cyclization: application in asymmetric total syntheses of prosopis, dendrobate, and spruce alkaloids.

    Science.gov (United States)

    Gnamm, Christian; Brödner, Kerstin; Krauter, Caroline M; Helmchen, Günter

    2009-10-12

    A method for the stereoselective synthesis of 2,6-disubstituted piperidines has been developed that is based on the use of an intramolecular iridium-catalyzed allylic substitution as a configurational switch. The procedure allows the preparation of 2-vinylpiperidines with enantiomeric excesses (ee) of greater than 99%. As applications, total syntheses of piperidine alkaloids have been elaborated, most often by using Ru-catalyzed cross-metatheses as a key step for introduction of a side chain. Asymmetric total syntheses of the prosopis alkaloids (+)-prosopinine, (+)-prosophylline, (+)-prosopine, and of the dendrobate alkaloid (+)-241D and its C6 epimer are described.

  13. Discovery and optimization of adamantyl carbamate inhibitors of 11β-HSD1.

    Science.gov (United States)

    Tice, Colin M; Zhao, Wei; Krosky, Paula M; Kruk, Barbara A; Berbaum, Jennifer; Johnson, Judith A; Bukhtiyarov, Yuri; Panemangalore, Reshma; Scott, Boyd B; Zhao, Yi; Bruno, Joseph G; Howard, Lamont; Togias, Jennifer; Ye, Yuan-Jie; Singh, Suresh B; McKeever, Brian M; Lindblom, Peter R; Guo, Joan; Guo, Rong; Nar, Herbert; Schuler-Metz, Annette; Gregg, Richard E; Leftheris, Katerina; Harrison, Richard K; McGeehan, Gerard M; Zhuang, Linghang; Claremon, David A

    2010-11-15

    Synthesis of 2-adamantyl carbamate derivatives of piperidines and pyrrolidines led to the discovery of 9a with an IC(50) of 15.2 nM against human 11β-HSD1 in adipocytes. Optimization for increased adipocyte potency, metabolic stability and selectivity afforded 11k and 11l, both of which were >25% orally bioavailable in rat.

  14. The Development of an Aza-C-Glycoside Library Based on a Tandem Staudinger/Aza-Wittig/Ugi Three-Component Reaction

    NARCIS (Netherlands)

    Wennekes, T.; Bonger, K.M.; Vogel, K.; Berg, van den S.A.; Strijland, A.; Donker-Koopman, W.E.; Aerts, J.; Marel, van der A.; Overkleeft, H.S.

    2012-01-01

    We report the tandem Staudinger/aza-Wittig/Ugi three-component reaction mediated synthesis of a 64-member compound library of aza-C-glycosides. The library is composed of four pyrrolidine and three piperidine scaffolds, onto which a number of functional groups is grafted to form seven sublibraries.

  15. 78 FR 55099 - Established Aggregate Production Quotas for Schedule I and II Controlled Substances and...

    Science.gov (United States)

    2013-09-09

    ... assessment of annual needs for 1- piperidine, carfentanil, cathinone, dihydromorphine, dimethyltryptamine...-methylenedioxyamphetamine 25 5-Methoxy-N,N-diisopropyltryptamine 25 5-Methoxy-N,N-dimethyltryptamine 25 Acetyl-alpha... 200 Desomorphine 5 Diethyltryptamine 25 Difenoxin 50 Dihydromorphine 3,990,000 Dimethyltryptamine 35...

  16. Towards the total synthesis of keramaphidin B

    Science.gov (United States)

    Jakubec, Pavol; Farley, Alistair J M

    2016-01-01

    Summary The enantio- and diastereoselective Michael addition of a δ-valerolactone-derived pronucleophile to a substituted furanyl nitroolefin catalysed by a bifunctional cinchonine-derived thiourea has been used as the key stereocontrolling step in a new synthetic strategy to the heavily functionalised piperidine core of keramaphidin B. PMID:27340496

  17. A Facile Synthesis for Novel Loperamide Analogs as Potential μ Opioid Receptor Agonists

    Directory of Open Access Journals (Sweden)

    Xiaofeng Bao

    2012-12-01

    Full Text Available A facile synthesis for novel loperamide analogs as potential μ opioid receptors is described. The synthetic procedure for compound 5, which contains two 4-phenyl piperidine scaffolds, was optimized, and this compound was synthesized in excellent yield. We also describe a mild and highly efficient protocol for the synthesis of compounds 6 and 7.

  18. Asymmetric Synthesis of (-)-Incarvillateine Employing an Intramolecular Alkylation via Rh-Catalyzed Olefinic C-H Bond Activation

    Energy Technology Data Exchange (ETDEWEB)

    Tsai, Andy; Bergman, Robert; Ellman, Jonathan

    2008-02-18

    An asymmetric total synthesis of (-)-incarvillateine, a natural product having potent analgesic properties, has been achieved in 11 steps and 15.4% overall yield. The key step is a rhodium-catalyzed intramolecular alkylation of an olefinic C-H bond to set two stereocenters. Additionally, this transformation produces an exocyclic, tetrasubstituted alkene through which the bicyclic piperidine moiety can readily be accessed.

  19. Inwerking van kaliumamide op enige chloorpyrazinen

    NARCIS (Netherlands)

    Lont, P.J.

    1973-01-01

    Sinds 1960 wordt in het Laboratorium voor Organische Chemie te Wageningen het gedrag van halogeenmonoaza- en halogeen-1,3-diaza-aromaten t.o.v. sterke nucleofiele reagentia, met name kaliumamide in vloeibare ammoniak en lithiumpiperidide in piperidine, bestudeerd. Uit dit onderzoek is gebleken dat

  20. 76 FR 44359 - Manufacturer of Controlled Substances; Notice of Registration

    Science.gov (United States)

    2011-07-25

    ... Enforcement Administration Manufacturer of Controlled Substances; Notice of Registration By Notice dated April... Administration (DEA) to be registered as a bulk manufacturer of 4-Anilino-N-Phenethyl-4-Piperidine (8333), a... accordance with 21 CFR 1301.33, the above named company is granted registration as a bulk manufacturer of...

  1. 76 FR 53961 - Manufacturer of Controlled Substances; Notice of Registration

    Science.gov (United States)

    2011-08-30

    ... Enforcement Administration Manufacturer of Controlled Substances; Notice of Registration By Notice dated April... Enforcement Administration (DEA) to be registered as a bulk manufacturer of 4-Anilino-N-phenethyl-4-Piperidine... controlled substance in the manufacturer of another controlled substance. No comments or objections have...

  2. Enaminonitriles in Heterocyclic Synthesis: A Route to 1,3-Diaryl-4-aminopyrazole Derivatives

    Directory of Open Access Journals (Sweden)

    Abdellatif Mohamed Salaheldin

    2013-01-01

    Full Text Available Benzylcyanide and 4-nitrobenzylcyanide condensed with triethyl orthoformate and piperidine or morpholine to yield 2-aryl-2-piperidinyl or 2-morpholinylacrylonitriles. These coupled with aromatic diazonium salts to yield the 2-arylhydrazno-2-arylethane nitriles in good yields. The latter were converted into 4-aminopyrazoles in good yields using the Thorpe-Ziegler cyclization.

  3. Crystal structure of S-(4-methylbenzyl piperidinedithiocarbamate

    Directory of Open Access Journals (Sweden)

    Z. A. Rahima

    2015-09-01

    Full Text Available The title compound, C14H19NS2, crystallizes in the thione form with the presence of a C=S bond. The piperidine ring adopts a chair conformation. The dihedral angle between the essentially planar dithiocarbamate and p-tolyl fragments is 74.46 (10°

  4. 75 FR 37295 - Control of Immediate Precursor Used in the Illicit Manufacture of Fentanyl as a Schedule II...

    Science.gov (United States)

    2010-06-29

    ... 812(b). ANPP is the immediate chemical intermediary in the synthesis process currently used by... Enforcement Administration 21 CFR Part 1308 RIN 1117-AB16 Control of Immediate Precursor Used in the Illicit... the precursor chemical, 4-anilino-N-phenethyl-4-piperidine (ANPP) as an immediate precursor for the...

  5. Intermolecular interactions in rifabutin—2-hydroxypropyl-β-cyclodextrin—water solutions

    Science.gov (United States)

    Anshakova, A. V.; Yermolenko, Yu. V.; Konyukhov, V. Yu.; Polshakov, V. I.; Maksimenko, O. O.; Gelperina, S. E.

    2015-05-01

    The possibility of a intermolecular complex rifabutin (RB)-2-hydroxypropyl-β-cyclodextrin (HP-β-CD) formed as a result of the interaction of the piperidine fragment of the RB molecule and the hydrophobic cavity of the HP-β-CD molecule was found. The stability constant of the intermolecular complex was determined.

  6. The Studies of Rhodium-catalyzed Ring Opening Reaction of N-Boc azabenzonorbornadiene with Heteroatom Nucleophiles

    Institute of Scientific and Technical Information of China (English)

    Er Chang LIU; Ding Qiao YANG; Ying Feng HAN; Jian Xia DONG

    2006-01-01

    A rhodium-catalyzed ring opening reaction of N-Boc-azabenzonorbornadiene with heteroatom nucleophiles was described. Piperidine and piperazine's derivatives were nucleophiles in this reaction. The yields of the products 2a-f are good and the regioselectivity are excellent.

  7. Anagyrine desensitization of peripheral nicotinic acetylcholine receptors. A potential biomarker of quinolizidine alkaloid teratogenesis in cattle.

    Science.gov (United States)

    Anagyrine, a teratogenic quinolizidine alkaloid found in certain Lupinus spp., has been proposed to undergo metabolism by pregnant cattle to a piperidine alkaloid which acts inhibit fetal movement, the putative mechanism behind crooked calf syndrome. The objective of this study was to test the hypot...

  8. Aza-Claisen rearrangement of 2-C-hydroxymethyl glycals as a versatile strategy towards synthesis of isofagomine and related biologically important azasugars.

    Science.gov (United States)

    Reddy, Y Suman; Kancharla, Pavan K; Roy, Rashmi; Vankar, Yashwant D

    2012-04-14

    Synthesis of isofagomine has been achieved by implementation of aza-Claisen rearrangement of 2-C-hydroxymethyl glycals as a key step. The above rearrangement has also been utilized in the synthesis of biologically important polyhydroxylated piperidine frameworks such as isogalactofagomine, ent-isogalactofagomine and their analogues and some other azasugars as glycosidase inhibitors.

  9. Development of radiotracers for imaging NR2B subtype NMDA receptors with positron emission tomography; Developpement de radiotraceurs pour la visualisation des recepteurs NMDA de sous-type NR2B par tomographie par emission de positons

    Energy Technology Data Exchange (ETDEWEB)

    Labas, R

    2007-07-01

    The aim of this thesis was to develop new radioactive tracers for imaging NR2B subtype NMDA receptors with positron emission tomography. Several compounds including 4-(4-fluoro-benzyl)piperidine and presenting interesting in vivo biological properties were the object of a labelling with a positrons emitter atom ({sup 11}C or {sup 18}F)

  10. A facile synthesis of the spiroindoline-based growth hormone secretagogue, MK-677

    Institute of Scientific and Technical Information of China (English)

    Xian Liang Qi; Er Qun Yang; Jun Tao Zhang; Tao Wang; Xiao Ping Cao

    2012-01-01

    A facile and improved route for the synthesis of the orally active spiroindoline-based growth hormone secretagogue,MK-677 was described.The key step adopted the Fischer indole/reduction strategy.The preparation of the key intermediates N-protected piperidine carboxaldehyde 5 and the N-Boc-O-benzyl-D-serine (2) are also optimized.

  11. Reações de 1,2-dicloro-4,5-dinitrobenzeno com aminas: monossubstituição de nitro e dissubstituição de cloro e nitro Reactions of 1,2-dichloro-4,5-dinitrobenzene with amines: monosubstitution of chlorine and disubstitution of chlorine and nitro

    Directory of Open Access Journals (Sweden)

    Fabrício Gava Menezes

    2007-04-01

    Full Text Available 1,2-dichloro-4,5-dinitrobenzene (DCDNB reacts with primary and secondary amines, in acetonitrile, at room temperature, to give a monosubstituted nitro product with a yield of 85 to 95%. The chloro-nitro-disubstituted product is formed with excess amine under reflux. Piperidine, pyrroline, dimethylamine and methylamine were the most reactive reagents in both mono- and disubstitution.

  12. Total enantioselective synthesis of (-)-cytisine.

    Science.gov (United States)

    Danieli, Bruno; Lesma, Giordano; Passarella, Daniele; Sacchetti, Alessandro; Silvani, Alessandra; Virdis, Andrea

    2004-02-19

    [reaction: see text] The first total enantiosynthesis of the biologically active alkaloid (-)-cytisine is reported, featuring a ruthenium-catalyzed RCM reaction as the key step. The approach relies on readily available cis-piperidine-3,5-dimethanol monoacetate as the chiral building block, and it is suited for achieving the target compound in both enantiomeric forms.

  13. Microwave-Assisted Synthesis and Biological Evaluation of Dihydropyrimidinone Derivatives as Anti-Inflammatory, Antibacterial, and Antifungal Agents

    Directory of Open Access Journals (Sweden)

    Anjna Bhatewara

    2013-01-01

    Full Text Available A simple protocol for the efficient preparation of aryl and heteroaryl substituted dihydropyrimidinone has been achieved via initial Knoevenagel, subsequent addition, and final cyclization of aldehyde, ethylcyanoacetate, and guanidine nitrate in the presence of piperidine as a catalyst in solvent-free under microwave irradiation. The synthesized compounds showed a good anti-inflammatory, antibacterial, and antifungal activity.

  14. Asymmetric Synthesis of (-)-Incarvillateine Employing an Intramolecular Alkylation via Rh-Catalyzed Olefinic C-H Bond Activation

    Energy Technology Data Exchange (ETDEWEB)

    Tsai, Andy; Bergman, Robert; Ellman, Jonathan

    2008-02-18

    An asymmetric total synthesis of (-)-incarvillateine, a natural product having potent analgesic properties, has been achieved in 11 steps and 15.4% overall yield. The key step is a rhodium-catalyzed intramolecular alkylation of an olefinic C-H bond to set two stereocenters. Additionally, this transformation produces an exocyclic, tetrasubstituted alkene through which the bicyclic piperidine moiety can readily be accessed.

  15. Asymmetric Hydrogenation of 3-Substituted Pyridinium Salts

    NARCIS (Netherlands)

    Renom-Carrasco, Marc; Gajewski, Piotr; Pignataro, Luca; de Vries, Johannes G.; Piarulli, Umberto; Gennari, Cesare; Lefort, Laurent

    2016-01-01

    The use of an equivalent amount of an organic base leads to high enantiomeric excess in the asymmetric hydrogenation of N-benzylated 3-substituted pyridinium salts into the corresponding piperidines. Indeed, in the presence of Et3N, a Rh-JosiPhos catalyst reduced a range of pyridinium salts with ee

  16. Reversed binding of a small molecule ligand in homologous chemokine receptors - differential role of extracellular loop 2

    DEFF Research Database (Denmark)

    Jensen, P C; Thiele, S; Steen, A;

    2012-01-01

    The majority of small molecule compounds targeting chemokine receptors share a similar pharmacophore with a centrally located aliphatic positive charge and flanking aromatic moieties. Here we describe a novel piperidine-based compound with structural similarity to previously described CCR8-specific...

  17. Complexation of roxatidine acetate hydrochloride with beta-cyclodextrin: NMR spectroscopic study.

    Science.gov (United States)

    Ali, S M; Maheshwari, A; Asmat, F

    2004-08-01

    A NMR spectroscopic study of mixtures of varying ratios of roxatidine acetate hydrochloride (RAH) and beta-cyclodextrin (beta-CD) in D2O revealed the formation of a 1:1 inclusion compound. The aromatic ring of RAH selectively penetrates the beta-CD cavity in preference to the piperidine ring.

  18. An Efficient Method for Racemization of (S)-3-Carbamoylmethyl-5-methylhexanoic Acid

    Institute of Scientific and Technical Information of China (English)

    WU,Ting; GAO,Man; YE,Bo; SHEN,Yongjia

    2009-01-01

    (S)-3-Carbamoylmethyl-5-methylhexanoic acid was heated in xylene and converted into 4-isobutyl-piperidine- 2,6-dione, which was hydrolyzed in aqueous solution of sodium hydroxide to afford the racemate. Our process is much advantageous over the traditional one, with not only less time (ca. 20 h) but also higher yield (76.4%).

  19. Tolperisone: a typical representative of a class of centrally acting muscle relaxants with less sedative side effects.

    Science.gov (United States)

    Quasthoff, Stefan; Möckel, Claudia; Zieglgänsberger, Walter; Schreibmayer, Wolfgang

    2008-01-01

    Tolperisone, a piperidine derivative, is assigned to the group of centrally acting muscle relaxants and has been in clinical use now for decades. The review summarizes the known pharmacokinetics, pharmacodynamics, toxicology and side effects in humans and the clinical use of tolperisone. A future perspective for further exploration of this drug is given.

  20. Synthesis and Antimicrobial Activities of Some Pyrazoline Derivatives

    Directory of Open Access Journals (Sweden)

    Ganguly Sushmita S

    2012-10-01

    Full Text Available An efficient synthesis of 3, 5-disubstituted-2-pyrazoline was carried out by the condensation of chalcones with hydrazine hydrate in ethanol in presence of piperidine. The newly synthesized compounds were characterized by 1H NMR spectroscopy, IR spectroscopy, MS, elemental analysis and screened for their antimicrobial activity against various strains of bacteria and fungi.

  1. Electron Spin Resonance (ESR) Studies on the Formation of Roasting-Induced Antioxidative Structures in Coffee Brews at Different Degrees of Roast

    NARCIS (Netherlands)

    Bekedam, E.K.; Schols, H.A.; Cämmerer, B.; Kroh, L.W.; Boekel, van M.A.J.S.; Smit, G.

    2008-01-01

    The antioxidative properties of coffee brew fractions were studied using electron spin resonance spectroscopy using 2,2,6,6-tetramethyl-1-piperidin-1-oxyl (TEMPO) and Fremy¿s salt (nitrosodisulfonate) as stabilized radicals. TEMPO was scavenged by antioxidants formed during roasting and not by chlor

  2. Electron Spin Resonance (ESR) Studies on the Formation of Roasting-Induced Antioxidative Structures in Coffee Brews at Different Degrees of Roast

    NARCIS (Netherlands)

    Bekedam, E.K.; Schols, H.A.; Cämmerer, B.; Kroh, L.W.; Boekel, van M.A.J.S.; Smit, G.

    2008-01-01

    The antioxidative properties of coffee brew fractions were studied using electron spin resonance spectroscopy using 2,2,6,6-tetramethyl-1-piperidin-1-oxyl (TEMPO) and Fremy¿s salt (nitrosodisulfonate) as stabilized radicals. TEMPO was scavenged by antioxidants formed during roasting and not by

  3. Spectaline, cassine and semi-synthetic analogues as potential candidate drugs for the treatment of Alzheimer disease [Espectalina, cassina e análogos semissintéticos como potenciais candidatos a fármacos para o tratamento da doença de Alzheimer

    OpenAIRE

    Bolzani,Vanderlan da S.; Alberto J. Cavalheiro; Ian Castro-Gamboa; Luciana de A. Santos; Claudio Viegas Jr; Silva,Dulce H. S.; Barreiro, Eliezer J.; Carlos A. M. Fraga; Rocha, Monica S.; Maria Claudia M. Young; Marcos Pivatto; Castro, Newton G.

    2010-01-01

    This paper describes the main steps in the study of Senna spectabilis, as part of our bioprospection studies, with the isolation of spectaline, cassine and other piperidine alkaloids, as well as the preparation of semi-synthetic analogues, and the studies of their pharmacological and toxicological properties, which led to the establishment of two candidate drugs for the treatment of Alzheimer disease.

  4. Toxicity of some bis Mannich bases and corresponding piperidinols in the brine shrimp (Artemia salina) bioassay.

    Science.gov (United States)

    Gul, H Inci; Gul, Mustafa; Erciyas, Ercin

    2003-01-01

    Some acetophenone-derived bis Mannich bases were synthesized: bis[beta-benzoylethyl]ethylamine hydrochloride (IIa), bis[beta-(p-methylbenzoyl)ethyl]ethylamine hydrochloride (IIb), bis[beta-(p-chlorobenzoyl)ethyl]ethy- lamine hydrochloride (IId), bis[(2-thienylcarbonyl)ethyl]ethylamine hydrochloride (IIe); some corresponding piperidinol derivatives: 3-benzoyl-1-ethyl-4-phenyl-4-piperidinol hydrochloride (IIIa), 1-ethyl-3-(p-methyl- benzoyl)-4-(p-methylphenyl)-4-piperidinol hydrochloride (IIIb), 1-ethyl-3-(p-methoxybenzoyl)-4-(p-methoxy- phenyl)-4-piperidinol hydrochloride (IIIc), 1-ethyl-3-(p-chlorobenzoyl)-4-(p-chlorophenyl)-4-piperidinol hydrochloride (IIId), 1-ethyl-4-(2-thienyl)-3-(2-thienylcarbonyl)-4-piperidinol hydrochloride (IIIe); and some representative quaternary piperidinols: 3-benzoyl-1-ethyl-4-hydroxy-1-methyl-4-phenylpiperidinium iodide (IIIf), 1-ethyl-4-hydroxy-1-methyl-3-(p-methylbenzoyl)-4-(p-methylphenyl)piperidinium iodide (IIIg). Toxicity was tested by the brine shrimp bioassay as an intermediate test before further in vivo animal experiments. Piperidine derivatives were found to be more potent than bis Mannich bases. Quaternary piperidine derivatives IIIf and IIIg and also non-quaternary piperidine derivatives IIIb, IIIe, IIIc and IIId were more toxic than 5-fluorouracil in brine shrimp bioassay. Except for IIe, bis Mannich bases were not effective. Quaternization and conversion of bis Mannich bases to corresponding piperidines improved the toxicity. The lipid solubility of the compounds may not affect the toxicity. From these findings the quaternary piperidine derivatives IIIf and IIIg could be used in further drug development and also for in vivo experiments.

  5. Alkaloids Induce Programmed Cell Death in Bloodstream Forms of Trypanosomes (Trypanosoma b. brucei

    Directory of Open Access Journals (Sweden)

    Michael Wink

    2008-10-01

    Full Text Available The potential induction of a programmed cell death (PCD in Trypanosoma b. brucei by 55 alkaloids of the quinoline, quinolizidine, isoquinoline, indole, terpene, tropane, steroid, and piperidine type was studied by measuring DNA fragmentation and changes in mitochondrial membrane potential. For comparison, the induction of apoptosis by the same alkaloids in human leukemia cells (Jurkat APO-S was tested. Several alkaloids of the isoquinoline, quinoline, indole and steroidal type (berberine, chelerythrine, emetine, sanguinarine, quinine, ajmalicine, ergotamine, harmine, vinblastine, vincristine, colchicine, chaconine, demissidine and veratridine induced programmed cell death, whereas quinolizidine, tropane, terpene and piperidine alkaloids were mostly inactive. Effective PCD induction (EC50 below 10 µM was caused in T. brucei by chelerythrine, emetine, sanguinarine, and chaconine. The active alkaloids can be characterized by their general property to inhibit protein biosynthesis, to intercalate DNA, to disturb membrane fluidity or to inhibit microtubule formation.

  6. Synthesis and characterization of oxovanadium (IV) dithiocarbamates with pyridine

    Energy Technology Data Exchange (ETDEWEB)

    Doadrio, Antonio L.; Sotelo, Jose; Fernandez-Ruano, Ana [Universidad Complutense, Madrid (Spain). Facultad de Farmacia. Dept. de Quimica Inorganica y Bioinorganica]. E-mail: antoniov@farm.ucm.es

    2002-07-01

    We report the synthesis and study of a new series of oxovanadium (IV) dithiocarbamate adducts and derivatives with pyridine and cyclohexyl, di-iso-butyl, di-n-propyl, aniline, morpholine, piperidine and di-iso-propyl amines. The complexes have been characterized by analytical, magneto chemical, IR, visible-UV spectral and thermal studies, and are assigned the formulas [VO(L){sub 2}].py, where L=cyclohexyl, di-iso-butyl, di-n-propyl, aniline dithiocarbamate and [VO(OH)(L)(py){sub 2}] OH.H{sub 2}O (L=morpholine, piperidine and di-iso-propyl dithiocarbamate). The effect of the adduct formation on the p{sub V=0} bound is discussed in terms of the IR (V=O, V-S and V-N stretching frequencies) and electronic spectra (d-d transitions). (author)

  7. Novel Mannich bases bearing pyrazolone moiety. Synthesis, characterization and electrochemical studies

    Directory of Open Access Journals (Sweden)

    KRISHNA NAIK

    2013-04-01

    Full Text Available The present investigation describes a series of new {4-[3-Methyl-5-oxo-4-(4|-substituted phenyl hydrazono-4,5-dihydro-pyrazol-1-yl]-phenoxy}-acetic acid (2-oxo-1-piperidine-1-ylmethyl-1,2-dihydro–indol-3-ylidene-hydrazides synthesized by the Mannich reaction of {4-[3-Methyl-5-oxo-4-(4|-substituted phenyl hydrazono-4,5-dihydro-pyrazol-1-yl]-phenoxy}-acetic acid (2-oxo-1,2-dihydro-indol-3-ylidene-hydrazide with aqueous formaldehyde and a solution of piperidine in dimethylformamide. These novel Mannich bases were characterized by elemental analysis, IR, 1H NMR and mass spectral data. Electrochemical behavior of these compounds were studied by two techniques namely polarography and cyclic voltammetry. The results from both the techniques were compared and the reduction mechanism in acidic as well as basic medium was proposed.

  8. Synthesis of bicyclic alkaloids from the iridoid antirrhinoside

    DEFF Research Database (Denmark)

    Frederiksen, Signe Maria

    The present thesis describes the isolation of the iridoid glucoside antirrhinoside from Antirrhinum majus, and the approaches made towards its transformation into analogues of biologically active compounds, with special interest in syntheses of bicyclic alkaloids.A synthetic piperidine monoterpene...... alkaloid was prepared from antirrhinoside by means of an enzymatic cleavage to afford the aglucone, followed by a double reductive amination with benzylamine hydrochloride and sodium cyanoborohydride. The resulting piperidine was modified by opening of the epoxide on the cyclopropane ring by azide...... strategy was therefore abandoned.A one-pot reaction involving ozonolysis and subsequent reduction of the 5,6-O-isopropylidene-2',3',4',6'-tetra-O-acetyl antirrhinoside yielded a diol, which was considered a potential intermediate in the preparation of enantiopure 3-azabicyclo[3.3.0]octane alkaloids...

  9. Human Acid β-Glucosidase Inhibition by Carbohydrate Derived Iminosugars: Towards New Pharmacological Chaperones for Gaucher Disease.

    Science.gov (United States)

    Parmeggiani, Camilla; Catarzi, Serena; Matassini, Camilla; D'Adamio, Giampiero; Morrone, Amelia; Goti, Andrea; Paoli, Paolo; Cardona, Francesca

    2015-09-21

    A collection of carbohydrate-derived iminosugars belonging to three structurally diversified sub-classes (polyhydroxylated pyrrolidines, piperidines, and pyrrolizidines) was evaluated for inhibition of human acid β-glucosidase (glucocerebrosidase, GCase), the deficient enzyme in Gaucher disease. The synthesis of several new pyrrolidine analogues substituted at the nitrogen or α-carbon atom with alkyl chains of different lengths suggested an interpretation of the inhibition data and led to the discovery of two new GCase inhibitors at sub-micromolar concentration. In the piperidine iminosugar series, two N-alkylated derivatives were found to rescue the residual GCase activity in N370S/RecNcil mutated human fibroblasts (among which one up to 1.5-fold). This study provides the starting point for the identification of new compounds in the treatment of Gaucher disease.

  10. Studies toward labeling cytisine with [11C]phosgene: rapid synthesis of a delta-lactam involving a new chemoselective lithiation-annulation method.

    Science.gov (United States)

    Rouden, Jacques; Seitz, Thomas; Lemoucheux, Laurent; Lasne, Marie-Claire

    2004-05-28

    With the aim of the radiolabeling of cytisine, a potent agonist of nicotinic receptors, with [(11)C]phosgene, the rapid synthesis of a lactam model of our target has been studied. The key step of the delta-lactam formation is a new chemoselective lithiation-annulation method, under high dilution, of a suitable piperidinylcarbamoyl chloride. This precursor was obtained from (2-hydroxyethyl)piperidine in a linear synthetic sequence involving a Corey-Fuchs olefination of the corresponding aldehyde, followed by a selective reduction, using a diimide equivalent, of an iodoalkyne into a (Z)-iodopropene piperidine. This alkene served as main precursor to study the cyclization according to several procedures using phosgene as the required carbonylating reagent.

  11. Synthesis and characterization of oxovanadium (IV dithiocarbamates with pyridine

    Directory of Open Access Journals (Sweden)

    Antonio L. Doadrio

    2002-07-01

    Full Text Available We report the synthesis and study of a new series of oxovanadium (IV dithiocarbamate adducts and derivatives with pyridine and cyclohexyl, di-iso-butyl, di-n-propyl, anilin, morpholin, piperidin and di-iso-propyl amines. The complexes have been characterized by analytical, magnetochemical, IR, visible-UV spectral and thermal studies, and are assigned the formulas [VO(L2].py, where L=cyclohexyl, di-iso-butyl, di-n-propyl, anilin dithiocarbamate and [VO(OH(L(py2]OH.H2O (L=morpholin, piperidin and di-iso-propyl dithiocarbamate. The effect of the adduct formation on the pV=0 bound is discussed in terms of the IR (V=O, V-S and V-N stretching frequencies and electronic spectra (d-d transitions.

  12. Ethyl 1-[2-(1,3-benzoxazol-2-ylsulfanylacetyl]-4-hydroxy-2,6-diphenyl-1,2,5,6-tetrahydropyridine-3-carboxylate

    Directory of Open Access Journals (Sweden)

    G. Aridoss

    2011-07-01

    Full Text Available In the title compound, C29H26N2O5S, the piperidine ring adopts a half-chair conformation. The phenyl rings are oriented at dihedral angles of 75.76 (12 and 86.64 (9° with respect to the best plane through the piperidine ring. The dihedral angle between the two phenyl rings is 30.81 (13°. The benzoxazole ring system is approximately planar [maximum deviation = 0.016 (4 Å]. The atoms of the ethyl side chain are disordered over two sets of sites [site occupancies = 0.376 (9 and 0.624 (9]. The molecular conformation is stabilized by an intramolecular O—H...O hydrogen bond, generating an S(6 motif. The crystal packing is stabilized by intermolecular C—H...O interactions, generating a chain running along the a axis.

  13. Kinetics of proton transfer from tetra( m-trifluoromethylphenyl)dibenzotetraazaporphin to nitrogen-containing bases in a benzene-dimethyl sulfoxide system

    Science.gov (United States)

    Petrov, O. A.

    2015-02-01

    The acid-base interaction between tetra( m-trifluoromethylphenyl)dibenzotetraazaporphin with pyridine, 2-methylpyridine, morpholine, piperidine, n-butylamine, diethylamine, and triethylamine is studied in the benzene-dimethyl sulfoxide system. It is found that intermolecular transfer of protons of NH-groups from of tetra( m-trifluoromethylphenyl)dibenzotetraazaporphin to n-butylamine and piperidine is characterized by unusually low values of the rate constants. The effect the structure of tetra( m-trifluoromethylphenyl)dibenzotetraazaporphin, hexa( m-trifluoromethylphenyl)benzotetraazaporphin, and octa( m-trifluoromethylphenyl)tetraazaporphin has on the kinetic parameters of acid-base interaction is demonstrated, along with that of the nature of the base and solvent. A structure is proposed for the charge-transfer complexes of the substituted tetraazaporphyrins. It is found that they undergo destruction over time.

  14. Inhibition of diacylglycerol acyltransferase by alkamides isolated from the fruits of Piper longum and Piper nigrum.

    Science.gov (United States)

    Lee, Seung Woong; Rho, Mun-Chual; Park, Hye Ran; Choi, Jung-Ho; Kang, Ji Yun; Lee, Jung Won; Kim, Koanhoi; Lee, Hyun Sun; Kim, Young Kook

    2006-12-27

    Pharmacological inhibition of acyl CoA:diacylglycerol acyltransferase (DGAT, EC 2.3.1.20) has emerged as a potential therapy for the treatment of obesity and type 2 diabetes. Bioassay-guided isolation of CHCl3 extracts of the fruits of Piper longum and Piper nigum (Piperaceae), using an in vitro DGAT inhibitory assay, lead to isolation of a new alkamide named (2E,4Z,8E)-N-[9-(3,4-methylenedioxyphenyl)-2,4,8-nonatrienoyl]piperidine (2), together with four known alkamides: retrofractamide C (1), pipernonaline (3), piperrolein B (4), and dehydropipernonaline (5). Compounds 2-5 inhibited DGAT with IC50 values of 29.8 (2), 37.2 (3), 20.1 (4), and 21.2 (5) microM, respectively, but the IC50 value for 1 was more than 900 microM. This finding indicates that compounds possessing piperidine groups (2-5) can be potential DGAT inhibitors.

  15. Quantitative analysis of alkaloidal constituents in imported fire ants by gas chromatography.

    Science.gov (United States)

    Yu, Yu-Ting; Wei, Hong-Yi; Fadamiro, Henry Y; Chen, Li

    2014-06-25

    A method based on silica gel chromatography and GC-MS/GC-FID analyses was developed for the quantitation of alkaloidal compounds in imported fire ants, Solenopsis richteri, S. invicta, and their hybrid found in the southern United States. The cis and trans alkaloids from fire ant body extracts were successfully separated by silica gel chromatography, identified by GC-MS, and quantitated by GC-FID. Piperideine compounds were eluted together with the cis and trans piperidines, but were well-resolved on a nonpolar GC column. Eight pairs of piperidine isomers and 12 piperideines were quantitated. The ratios of trans alkaloids to corresponding cis isomers ranged from 87 to 378:1 in S. invicta and were significantly higher than in S. richteri and hybrid ants. The results were discussed in relation to the evolution of fire ant venom alkaloids and their role as host location cues for parasitic Pseudacteon phorid flies.

  16. The role of the alcohol and carboxylic acid in directed ruthenium-catalyzed C(sp3)-H α-alkylation of cyclic amines.

    Science.gov (United States)

    Bergman, Sheba D; Storr, Thomas E; Prokopcová, Hana; Aelvoet, Karel; Diels, Gaston; Meerpoel, Lieven; Maes, Bert U W

    2012-08-13

    A general directed Ru-catalyzed C(sp(3))-H α-alkylation protocol for piperidines (less-reactive substrates than the corresponding five-membered cyclic amines) has been developed. The use of a hindered alcohol (2,4-dimethyl-3-pentanol) as the solvent and catalyst activator, and a catalytic amount of trans-1,2-cyclohexanedicarboxylic acid is necessary to achieve a high conversion to product. This protocol was used to effectively synthesize a number of 2-hexyl- and 2,6-dihexyl piperidines, as well as the alkaloid (±)-solenopsin A. Kinetic studies have revealed that the carboxylic acid additive has a significant effect on catalyst initiation, catalyst longevity, and reverses the reaction selectivity compared with the acid-free reaction (promotes alkylation versus competing alkene reduction).

  17. An Expeditious Stereoselective Synthesis of (−)-Pinidinone from Ethyl Acetoacetate

    Energy Technology Data Exchange (ETDEWEB)

    Damodar, Kongara; Jun, Jong-Gab [Hallym University, Chuncheon (Korea, Republic of)

    2016-04-15

    An expeditious stereoselective synthesis of a naturally occurring 2,6-disubstituted piperidine alkaloid, (−)-pinidinone, has been accomplished with an overall yield of 31% in total eight steps. The synthesis involves ethyl acetoacetate as the starting material and the stereoselective α-aminoallylation of aldehyde with (S)-tert-butanesulfinamide, allyl bromide, and indium and Grubbs' olefin cross-metathesis as the pivotal steps.

  18. Controlled shift in the tautomeric equilibrium of 4-​((phenylimino)​methyl)​naphthalen-​1-​ol

    DEFF Research Database (Denmark)

    Kamounah, Fadhil S.; Deneva, V; Manolova, y

    2013-01-01

    -​((Phenylimino)​methyl)​naphthalen-​1-​ol and 4-​((phenylimino)​methyl)​-​2-​(piperidin-​1-​ylmethyl)​naphthalen-​1-​ol have been synthesized and their tautomeric properties were investigated using mol. spectroscopy (UV-​vis absorption​/emission and NMR)​, X-​ray crystallog. anal. and quantum...

  19. A facile stereospecific synthesis of (Z)-2-sulfonyl-substituted 1,3-enynes via Sonogashira coupling of (E)-α-iodovinyl sulfones with 1-alkynes

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    (E)-α-Iodovinyl sulfones 1 underwent the Sonogashira coupling reactions with terminal alkynes 2 in piperidine at room temperature in the presence of 5 mol% of Pd(PPh3)4 and 10 mol% of CuI to stereospecifically afford the corresponding (Z)-2-sulfonyl-substituted 1,3-enynes 3 in high yields.(C) 2007 Ming Zhong Cai. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.

  20. Exploring architectures displaying multimeric presentations of a trihydroxypiperidine iminosugar

    Directory of Open Access Journals (Sweden)

    Camilla Matassini

    2015-12-01

    Full Text Available The synthesis of new multivalent architectures based on a trihydroxypiperidine α-fucosidase inhibitor is reported herein. Tetravalent and nonavalent dendrimers were obtained by means of the click chemistry approach involving the copper azide-alkyne-catalyzed cycloaddition (CuAAC between suitable scaffolds bearing terminal alkyne moieties and an azido-functionalized piperidine as the bioactive moiety. A preliminary biological investigation is also reported towards commercially available and human glycosidases.

  1. 2-(Dibutylamino-3-(4-fluorophenyl-5,6,7,8-tetrahydro-7-methyl-6,8-diphenylpyridine[3′,4′:2,3]thieno[5,4-d]pyrimidin-4(3H-one

    Directory of Open Access Journals (Sweden)

    Yang-gen Hu

    2008-02-01

    Full Text Available In the crystal structure of the title compound, C36H39FN4OS, the two fused rings of the thienopyrimidine system are coplanar. The 4-fluorophenyl ring is twisted with respect to the heterocyclic pyrimidinone ring by 67.21 (14°. The piperidine ring shows a half-chair conformation. One of the n-butyl chains is disordered equally over two sites. The crystal packing is stabilized by C—H...O hydrogen bonds.

  2. Racemochrysone, a dihydroanthracenone from Senna racemosa.

    Science.gov (United States)

    Mena-Rejón, Gonzalo J; Pérez-Rivas, Karla; Sansorez-Peraza, Pablo; Rios, Tirso; Quijano, Leovigildo

    2002-01-01

    From the hexane extract of the bark of the stems of Senna racemosa (syn. Cassia racemosa) a new dihydroanthracenone derivative, named racemochrysone, was isolated. Its structure was established as 8,9-dihydroxy-3-methoxy-2,2,6-trimethyl-(2H)-anthracen-1-one based on spectroscopical data, mainly 1D and 2D NMR experiments. In addition beta-sitosterol, stigmasterol, chrysophanol and physcion were obtained. From the leaves extracts the piperidine alkaloid cassine and the hexitol pinitol were obtained.

  3. Influence of ring size on the cognition-enhancing activity of DM235 and MN19, two potent nootropic drugs.

    Science.gov (United States)

    Guandalini, L; Martini, E; Di Cesare Mannelli, L; Dei, S; Manetti, D; Scapecchi, S; Teodori, E; Ghelardini, C; Romanelli, M N

    2012-03-01

    A series of analogs of DM235 and MN19, characterized by rings with different size, have been prepared and evaluated for their nootropic activity in the mouse passive-avoidance test. It was found that the optimal ring size for the analogs of DM235, showing endocyclic both amidic groups, is 6 or 7 atoms. For the compounds structurally related to MN19, carrying an exocyclic amide group, the piperidine ring is the moiety which gives the most interesting compounds.

  4. Piperidinium 3-hydroxy-2-naphthoate

    Directory of Open Access Journals (Sweden)

    Wen-Zhu Wan

    2008-09-01

    Full Text Available The crystals of the title salt, C5H12N+·C11H7O3−, were obtained from a methanol/water solution of 3-hydroxy-2-naphthoic acid and piperidine at room temperature. In the crystal structure, the piperidinium cations display a chair conformation and link with hydroxynaphthoate anions via N—H...O and C—H...O hydrogen bonds. An intramolecular O—H...O interaction is also present.

  5. 4-Azaniumyl-2,2,6,6-tetramethylpiperidin-1-ium dinitrate

    Directory of Open Access Journals (Sweden)

    Hammouda Chebbi

    2014-06-01

    Full Text Available In the crystal structure of the title salt, C9H22N22+·2NO3−, the piperidine ring of the dication adopts a chair conformation and the orientation of the C—NH3 bond is equatorial. The ions are linked by normal and bifurcated N—H...O hydrogen bonds in R22(6, two R42(8 and R34(14 graf-set motifs, generating a three-dimensional network.

  6. Synthesis of 13-amino telekin derivatives and their cytotoxic activity.

    Science.gov (United States)

    Wang, Xiujie; Zhang, Xiumei; Zheng, Beibei; Hu, Nan; Xie, Weidong; Row, Kyungho

    2015-01-01

    Telekin is a eudesmane sesquiterpene-lactone naturally occurring in many medicinal plants with antitumour and anti-inflammatory activity. In this study, a series of 13-amino derivatives of telekin have been synthesised through Michael addition reaction, and their relative configurations were exemplified by the single crystal X-ray diffraction of the dimethylamine adduct. The in vitro cytotoxicity against three tumour cell lines of these amine derivatives was evaluated. The piperidine and 4-hydroxypiperidine adducts displayed stronger cytotoxic activity than telekin.

  7. beta-1,2,3-Triazolyl-nucleosides as nicotinamide riboside mimics.

    Science.gov (United States)

    Amigues, E J; Armstrong, E; Dvorakova, M; Migaud, M E; Huang, M

    2009-03-01

    The synthesis of a series of pyridine- and piperidine-substituted 1,2,3-triazolides linked to a riboside moiety is described. The presence of a triazolide substituent on the pyridine moiety permitted the facile reduction of the latter under mild hydrogenation conditions. These analogues were modelled as to define their similarity to nicotinamide riboside and quantify their ability to bind NAD-dependent protein deacetylases.

  8. Rh(III)-Catalyzed C-H Bond Addition/Amine-Mediated Cyclization of Bis-Michael Acceptors.

    Science.gov (United States)

    Potter, Tyler J; Ellman, Jonathan A

    2016-08-01

    A Rh(III)-catalyzed C-H bond addition/primary amine-promoted cyclization of bis-Michael acceptors is reported. The C-H bond addition step occurs with high chemoselectivity, and the subsequent intramolecular Michael addition, mediated by a primary amine catalyst, sets three contiguous stereocenters with high diastereoselectivity. A broad range of directing groups and both aromatic and alkenyl C-H bonds were shown to be effective in this transformation, affording functionalized piperidines, tetrahydropyrans, and cyclohexanes.

  9. European Scientific Notes, Volume 37, Number 3,

    Science.gov (United States)

    1983-03-31

    as glycine , ß-alanine, aspartic acid, glutamic acid, and piperidinic acid. There was a pronounced maximum in the curve of anticoagulant activity...presented by research- ers from the Technical Institute of Munich and the Max Planck Institute in Stuttgart. By correlating the concentration of...of transition metal impurities in InP. Their reported work concentrated on manganese and copper. Both ion-implan- tation and diffusion techniques

  10. Prospective, Controlled, Multicentre Study of Loperimide in Pregnancy

    Directory of Open Access Journals (Sweden)

    A Einarson

    2000-01-01

    Full Text Available BACKGROUND: Loperamide is a synthetic piperidine derivative used for the treatment of both acute and chronic diarrhea. Little is known about its safety and risk in pregnancy. Human data are limited to one surveillance study of Michigan Medicaid patients, with 108 women exposed in the first trimester. In this study there were six major birth defects, three of which were cardiovascular anomalies.

  11. Aldonolactones as Chiral Synthons

    DEFF Research Database (Denmark)

    Lundt, Inge

    1997-01-01

    as the sulfonylated, lactones are suitable starting materials for the preparation of hydroxylated and amino substituted pyrrolidines and piperidines, obtained by simple treatment with ammonia. Boiling in water transformed the activated lactones into hydroxylated tetrahydrofurans. Radical-initiated internal ring...... closure of brominated aldonolactones with unsaturation yields functionalized cyclopentanes regio- and stereospecifically. This results in the synthesis of optically pure carbasugars. Easy manipulation of the hydroxy groups in the cyclopentane-lactones obtained, gives access to other hydroxy...

  12. Equilibrium study between condensed phases by isoplethic thermal analysis when a miscibility gap is observed

    OpenAIRE

    Labarthe, Emilie; Bougrine, Anne-Julie; Delalu, Henri; Berthet, Jacques; Counioux, Jean-Jacques

    2009-01-01

    International audience; Isoplethic thermal analysis was used to determine the solid-liquid-liquid equilibria in the ternary system water-sodium sulfate-piperidine. The changes in state observed on the thermogram recorded during the displacement in a quasi-binary section permit the identification of the different phases and the delimitation of the corresponding equilibrium domains. Two isotherms were established at 25°C and 40°C because these temperatures frame the peritectic decomposition of ...

  13. Characterization of trimethylsilyl ethers of iminosugars by gas chromatography-mass spectrometry.

    Science.gov (United States)

    Rodríguez-Sánchez, S; Ruiz-Matute, A I; Sanz, M L; Soria, A C

    2014-11-01

    A combination of gas chromatographic retention data (linear retention indices) on two different stationary phases (100% methyl- and 50% phenylmethylsilicone) and electron impact mass spectrometric relative abundances for characteristic m/z ratios of 12 trimethylsilylated piperidine and pyrrolidine iminosugars are reported. These results have been related to their structural features and applied to the characterization of iminosugar composition of an Aglaonema treubii root extract. Seven iminosugars were detected in this extract, two of them were described for the first time.

  14. Conformational studies of 3-amino-1-alkyl-cyclopentane carboxamide CCR2 antagonists leading to new spirocyclic antagonists.

    Science.gov (United States)

    Pasternak, Alexander; Goble, Stephen D; Doss, George A; Tsou, Nancy N; Butora, Gabor; Vicario, Pasquale P; Ayala, Julia Marie; Struthers, Mary; Demartino, Julie A; Mills, Sander G; Yang, Lihu

    2008-02-15

    In an effort to shed light on the active binding conformation of our 3-amino-1-alkyl-cyclopentane carboxamide CCR2 antagonists, we prepared several conformationally constrained analogs resulting from backbone cyclization. Evaluation of CCR2 binding affinities for these analogs gave insight into the optimal relative positions of the piperidine and benzylamide moieties while simultaneously leading to the discovery of a new, potent lead type based upon a spirocyclic acetal scaffold.

  15. USSR Report, Chemistry.

    Science.gov (United States)

    2007-11-02

    Polytechnic Institute, imeni V.V. Kuybyshev] .[Abstract] A study is reported of processes of development, movement and condensation of aerosols formed...8217-(3,4-dichlorophenyl)-N2-methyl-N2-(2,2,6,6-tetramethyl- piperidine) -urea (TMPM). Activity of these agents was evaluated on chlorella and chloroplasts ...to be related with the movement of electrons and holes rather than charge carriers, contrary to the Rouse-Fowler-Weisberg theory. The delayed

  16. Encapsulation and characterization of proton-bound amine homodimers in a water-soluble, self-assembled supramolecular host

    OpenAIRE

    Pluth, Michael D.; Fiedler, Dorothea; Mugridge, Jeffrey S.; Bergman, Robert G.; Raymond, Kenneth N.

    2009-01-01

    Cyclic amines can be encapsulated in a water-soluble self-assembled supramolecular host upon protonation. The hydrogen-bonding ability of the cyclic amines, as well as the reduced degrees of rotational freedom, allows for the formation of proton-bound homodimers inside of the assembly that are otherwise not observable in aqueous solution. The generality of homodimer formation was explored with small N-alkyl aziridines, azetidines, pyrrolidines, and piperidines. Proton-bound homodimer formatio...

  17. Directing Group in Decarboxylative Cross-Coupling: Copper-Catalyzed Site-Selective C-N Bond Formation from Nonactivated Aliphatic Carboxylic Acids.

    Science.gov (United States)

    Liu, Zhao-Jing; Lu, Xi; Wang, Guan; Li, Lei; Jiang, Wei-Tao; Wang, Yu-Dong; Xiao, Bin; Fu, Yao

    2016-08-03

    Copper-catalyzed directed decarboxylative amination of nonactivated aliphatic carboxylic acids is described. This intramolecular C-N bond formation reaction provides efficient access to the synthesis of pyrrolidine and piperidine derivatives as well as the modification of complex natural products. Moreover, this reaction presents excellent site-selectivity in the C-N bond formation step through the use of directing group. Our work can be considered as a big step toward controllable radical decarboxylative carbon-heteroatom cross-coupling.

  18. Sonogashira coupling reaction of homopropargyl ether with aryl bromides and synthesis of 2,5-disubstituted 3-bromofurans

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    This paper presents Sonogashira coupling reaction of aryl bromides with protected homopropargyl alcohols such as tert-butyldimethyl(1-phenylbut-3-ynyloxy)silane and tert-butyldimethyl(1-(2,4-dichlorophenyl)but-3-ynyloxy)silane in piperidine catalyzed by PdCl2/PPh3 without copper(Ⅰ). The coupling products, disubstituted acetylene, are obtained in good or excellent yields. These products can be further used for the synthesis of 2,5-disubstituted 3-bromofurans.

  19. SYNTHESIS OF A HYPERBRANCHED POLY(AROYLARYLENE) CONTAINING TRIAZOLE AND FLUORENE FUNCTIONALITIES BY CLICK CHEMISTRY AND METAL-FREE, REGIOSELECTIVE POLYCYCLOTRIMERIZATION

    Institute of Scientific and Technical Information of China (English)

    An-jun Qin; Cathy,K. W. Jim; Jacky,W. Y. Lam; Jing-zhi Sun; Ben Zhong Tang

    2009-01-01

    A new bis(aroylacetylene) containing tfiazole and fluorene moieties is synthesized by click chemistry.Polycyclotrimerization of the monomer is catalyzed by piperidine in refluxed dioxane,furnishing a regioregular poly(aroylarylene) in a satisfactory yield.The hyperbranched structure of the polymer is characterized spectroscopically with satisfactory results.The polymer enjoys no metal detriment and is soluble in common organic solvents such as tetrahydrofuran (THF), chloroform, dichloromethane (DCM), and N,N-dimethylformamide (DMF).

  20. Synthesis, inhibition and binding of simple non-nitrogen inhibitors of monoamine transporters.

    Science.gov (United States)

    Petersen, Mikkel Due; Boye, Søren Valdgård; Nielsen, Erik Holm; Willumsen, Jeanette; Sinning, Steffen; Wiborg, Ove; Bols, Mikael

    2007-06-15

    A series of simple truncated analogues of phenyl tropanes, 2-arylcycloalk-1-enyl carboxylic acid methylesters, were prepared and investigated for their activity towards the dopamine, serotonin and norepinephrine transporters. The compounds were prepared from cyclic ketoesters, which were converted to enolic triflates and reacted with arylboronates using the Suzuki coupling. For comparison the corresponding piperidines were also made and investigated. The new compounds inhibit monoamine-transporters with Ki values ranging from 0.1 to 1000 microM.

  1. Basic Aspects of the Pharmacodynamics of Tolperisone, A Widely Applicable Centrally Acting Muscle Relaxant

    OpenAIRE

    Tekes, Kornelia

    2014-01-01

    Tolperisone (2-methyl-1-(4-methylphenyl)-3-piperidin-1-ylpropan-1-one hydro-chloride) was introduced in the clinical practice more than forty years ago and is still evaluated as a widely applicable compound in pathologically elevated skeletal muscle tone (spasticity) and related pains of different origin. In the present review, basic pharmacodynamic effects measured on whole animals, analyses of its actions on cell and tissue preparations and molecular mechanism of action on sodium and calciu...

  2. Synthesis and Antimicrobial Activity of Some Novel Chalcones of 2-Hydroxy -1-Acetonapthone and 3-Acetyl Coumarin

    OpenAIRE

    2006-01-01

    Five novel chalcones were synthesised by condensing 2-hydroxy-1-acetonaphthone with aldehyde derivatives in dilute ethanolic potassium hydroxide solution at room temperature according to Claisen-Schmidt condensation and another five novel chalcones were prepared by refluxing 3-acetyl coumarin with aldehydes in the presence of piperidine in ethanol. All these compounds were characterised by means of their IR, 1H NMR spectroscopic data and microanalyses. The antimicrobial activity of these comp...

  3. Synthesis and Antimicrobial Activity of Some Novel Chalcones of 2-Hydroxy -1-Acetonapthone and 3-Acetyl Coumarin

    Directory of Open Access Journals (Sweden)

    Y. Rajendra Prasad

    2006-01-01

    Full Text Available Five novel chalcones were synthesised by condensing 2-hydroxy-1-acetonaphthone with aldehyde derivatives in dilute ethanolic potassium hydroxide solution at room temperature according to Claisen-Schmidt condensation and another five novel chalcones were prepared by refluxing 3-acetyl coumarin with aldehydes in the presence of piperidine in ethanol. All these compounds were characterised by means of their IR, 1H NMR spectroscopic data and microanalyses. The antimicrobial activity of these compounds were evaluated by the cup plate method.

  4. Cyclic Voltammetry And Linear Sweep Voltammetry Study Of Cyclic Tertiary Amines

    Institute of Scientific and Technical Information of China (English)

    ZHAO Ping; TIAN JinPing; YIN YingWu

    2001-01-01

    @@ Cyclic six membered a-aminonitrile have proved to be very versatile synthetic intermediates and have been widely used in the construction of a large number of indole alkaloids. In order to obtain some information about the mechanisn of electrochemical synthesis of aaminonitrile. Electrochemistry behaviors that include cyclic voltammetry and linear sweep voltammetry of cyclic tertiary amines which including N-benzylpiperidine (NBP), 1-(l-Methoxycarbonyl ethyl) piperidine (MCEP), N-methylcarbonylppiperidine (NMCP), Nethylpiperidine(NEP) was studied.

  5. Cyclic Voltammetry And Linear Sweep Voltammetry Study Of Cyclic Tertiary Amines

    Institute of Scientific and Technical Information of China (English)

    ZHAO; Ping

    2001-01-01

    Cyclic six membered a-aminonitrile have proved to be very versatile synthetic intermediates and have been widely used in the construction of a large number of indole alkaloids. In order to obtain some information about the mechanisn of electrochemical synthesis of aaminonitrile. Electrochemistry behaviors that include cyclic voltammetry and linear sweep voltammetry of cyclic tertiary amines which including N-benzylpiperidine (NBP), 1-(l-Methoxycarbonyl ethyl) piperidine (MCEP), N-methylcarbonylppiperidine (NMCP), Nethylpiperidine(NEP) was studied.……

  6. Stereochemical basis for a unified structure activity theory of aromatic and heterocyclic rings in selected opioids and opioid peptides.

    Science.gov (United States)

    Goldberg, Joel S

    2010-02-18

    This paper presents a novel unified theory of the structure activity relationship of opioids and opioid peptides. It is hypothesized that a virtual or known heterocyclic ring exists in all opioids which have activity in humans, and this ring occupies relative to the aromatic ring of the drug, approximately the same plane in space as the piperidine ring of morphine. Since the rings of morphine are rigid, and the aromatic and piperidine rings are critical structural components for morphine's analgesic properties, the rigid morphine molecule allows for approximations of the aromatic and heterocyclic relationships in subsequent drug models where bond rotations are common. This hypothesis and five propositions are supported by stereochemistry and experimental observations.Proposition #1 The structure of morphine provides a template. Proposition #2 Steric hindrance of some centric portion of the piperidine ring explains antagonist properties of naloxone, naltrexone and alvimopam. Proposition #3 Methadone has an active conformation which contains a virtual heterocyclic ring which explains its analgesic activity and racemic properties. Proposition #4 The piperidine ring of fentanyl can assume the morphine position under conditions of nitrogen inversion. Proposition #5 The first 3 amino acid sequences of beta endorphin (l-try-gly-gly) and the active opioid dipeptide, l-tyr-pro, (as a result of a peptide turn and zwitterion bonding) form a virtual piperazine-like ring which is similar in size, shape and location to the heterocyclic rings of morphine, meperidine, and methadone. Potential flaws in this theory are discussed.This theory could be important for future analgesic drug design.

  7. Polyethylene glycol(PEG-400): An efficient and recyclable reaction medium for the synthesis of novel 1,5-benzodiazepines and their antimicrobial activity

    Institute of Scientific and Technical Information of China (English)

    Shankaraiah G. Konda; Baseer M. Shaikh; Sanjay A. Chavan; Bhaskar S. Dawane

    2011-01-01

    A new series of imidazole-containing 1,5-benzodiazepines have been synthesized by the condensation of chalcones with ophenylenediamine using piperidine in polyethylene glycol(PEG-400)as an efficient and green reaction solvent.The advantages of this protocol are environmental friendliness,easy work-up,high yields,mild reaction condition and avoidance of expensive catalyst.Furthermore,newly synthesized compounds were evaluated for their antimicrobial activity.

  8. The discovery of potent blockers of the canonical transient receptor channels, TRPC3 and TRPC6, based on an anilino-thiazole pharmacophore.

    Science.gov (United States)

    Washburn, David G; Holt, Dennis A; Dodson, Jason; McAtee, Jeff J; Terrell, Lamont R; Barton, Linda; Manns, Sharada; Waszkiewicz, Anna; Pritchard, Christina; Gillie, Dan J; Morrow, Dwight M; Davenport, Elizabeth A; Lozinskaya, Irina M; Guss, Jeffrey; Basilla, Jonathan B; Negron, Lorena Kallal; Klein, Michael; Willette, Robert N; Fries, Rusty E; Jensen, Timothy C; Xu, Xiaoping; Schnackenberg, Christine G; Marino, Joseph P

    2013-09-01

    Lead optimization of piperidine amide HTS hits, based on an anilino-thiazole core, led to the identification of analogs which displayed low nanomolar blocking activity at the canonical transient receptor channels 3 and 6 (TRPC3 & 6) based on FLIPR (carbachol stimulated) and electrophysiology (OAG stimulated) assays. In addition, the anilino-thiazole amides displayed good selectivity over other TRP channels (TRPA1, TRPV1, and TRPV4), as well as against cardiac ion channels (CaV1.2, hERG, and NaV1.5). The high oxidation potential of the aliphatic piperidine and aniline groups, as well as the lability of the thiazole amide group contributed to the high clearance observed for this class of compounds. Conversion of an isoquinoline amide to a naphthyridine amide markedly reduced clearance for the bicyclic piperidines, and improved oral bioavailability for this compound series, however TRPC3 and TRPC6 blocking activity was reduced substantially. Although the most potent anilino-thiazole amides ultimately lacked oral exposure in rodents and were not suitable for chronic dosing, analogs such as 14-19, 22, and 23 are potentially valuable in vitro tool compounds for investigating the role of TRPC3 and TRPC6 in cardiovascular disease.

  9. Workers and alate queens of Solenopsis geminata share qualitatively similar but quantitatively different venom alkaloid chemistry

    Directory of Open Access Journals (Sweden)

    Qun-Hui eShi

    2015-07-01

    Full Text Available Solenopsis geminata group (Hymenoptera: Formicidae encompasses ant species commonly called fire ants because of their painful sting. The many physiological effects of the venom are caused by 2-methyl-6-alkyl and/or alkenylpiperidine alkaloids. The variation in piperidine alkaloid structures has useful taxonomic characters. The most well studied Solenopsis species is S. invicta, which was accidentally imported into the USA in the 1930s from South America. It quickly spread throughout the southern USA and is now a major invasive pest ant in the USA and in other parts of the world. Interestingly, the invasive S. invicta has largely displaced a native USA fire ant, S. geminata, from the southern USA. We explore the possibility that differences in venom chemistry could be correlated with this displacement. The cis and trans alkaloids from body extracts of workers and alate queens of S. geminata were separated by silica gel chromatography, identified, and quantitated by GC-MS analysis. Both workers and alate queens produce primarily cis- and trans-2-methyl-6-n-undecyl-piperidines, as well as other minor alkaloid components. Imported fire ant, S. invicta, alate queens produce the same alkaloids as S. geminata alate queens, but in contrast S. invicta workers produce piperidine alkaloids with longer side chains, which are purported to be physiologically more effective. These results are discussed in relation to the evolutionary progression of fire ant venom alkaloids and displacement of S. geminata by S. invicta in the USA.

  10. Role of choline and glycine betaine in the formation of N,N-dimethylpiperidinium (mepiquat) under Maillard reaction conditions.

    Science.gov (United States)

    Bessaire, Thomas; Tarres, Adrienne; Stadler, Richard H; Delatour, Thierry

    2014-01-01

    This study is the first to examine the role of choline and glycine betaine, naturally present in some foods, in particular in cereal grains, to generate N,N-dimethylpiperidinium (mepiquat) under Maillard conditions via transmethylation reactions involving the nucleophile piperidine. The formation of mepiquat and its intermediates piperidine - formed by cyclisation of free lysine in the presence of reducing sugars - and N-methylpiperidine were monitored over time (240°C, up to 180 min) using high-resolution mass spectrometry in a model system comprised of a ternary mixture of lysine/fructose/alkylating agent (choline or betaine). The reaction yield was compared with data recently determined for trigonelline, a known methylation agent present naturally in coffee beans. The role of choline and glycine betaine in nucleophilic displacement reactions was further supported by experiments carried out with stable isotope-labelled precursors (¹³C- and deuterium-labelled). The results unequivocally demonstrated that the piperidine ring of mepiquat originates from the carbon chain of lysine, and that either choline or glycine betaine furnishes the N-methyl groups. The kinetics of formation of the corresponding demethylated products of both choline and glycine betaine, N,N-demethyl-2-aminoethanol and N,N-dimethylglycine, respectively, were also determined using high-resolution mass spectrometry.

  11. Spectroscopic properties and antimicrobial activity of dioxomolybdenum(VI complexes with heterocyclic S,S’-ligands

    Directory of Open Access Journals (Sweden)

    Sovilj Sofija P.

    2012-01-01

    Full Text Available Five new dioxomolybdenum(VI complexes of the general formula[MoO2(Rdtc2], 1-5, where Rdtc-refer to piperidine- (Pipdtc, 4-morpholine-(Morphdtc, 4-thiomorpholine-(Timdtc, piperazine- (Pzdtc or Nmethylpiperazine- (N-Mepzdtc dithiocarbamates, respectively, have been prepared. Elemental analysis, conductometric measurements, electronic, IR and NMR spectroscopy have been employed to characterize them. Complexes 1-5 contain a cis-MoO2 group and are of an octahedral geometry. Two dithiocarbamato ions join as bidentates with both the sulphur atoms to the molybdenum atom. The presence of different heteroatom in the piperidinо moiety influences the v(C----N and v(C----S vibrations, which decrease in the order of the complexes with: Pipdtc > N-Mepipdtc > Morphdtc > Pzdtc > Timdtc ligands. On the basis of spectral data, molecular structures of complexes 1-5 were optimized on semiempirical molecular-orbital level, and the geometries, as obtained from calculations, described. Antimicrobial activity was tested against nine different laboratory control strains of bacteria and two strains of yeast Candida albicans. All tested strains were sensitive. Complexes bearing heteroatom in position 4 of piperidine moiety are significantly more potent against bacteria tested comparing to corresponding ligands.

  12. Crystal structure of 1-cyclopropanecarbonyl-3-methyl-2,6-di-p-tolylpiperidin-4-one

    Directory of Open Access Journals (Sweden)

    A. Kamaraj

    2014-09-01

    Full Text Available The title compound, C24H27NO2, crystallizes with two independent molecules (A and B in the asymmetric unit. The two molecules have very similar conformations and each exhibits an intramolecular C—H...π interaction. The central piperidine rings adopt boat conformations and the p-tolyl rings are inclined to the mean plane of the piperidine ring by 71.21 (11 and 89.86 (12° in molecule A and by 68.01 (12 and 89.33 (12° in molecule B. The cyclopropanecarbonyl group is oriented at an angle of 68.5 (2° with respect to the mean plane of the piperidine ring in molecule A and 66.2 (2° in molecule B. In the crystal, the A and B molecules are linked by C—H...O hydrogen bonds, enclosing R21(6 ring motifs, forming ribbons running along the a-axis direction.

  13. The metabolism of roxatidine acetate hydrochloride in rat and dog liver homogenates.

    Science.gov (United States)

    Iwamura, S; Shibata, K; Kawabe, Y; Tsukamoto, K; Honma, S

    1987-06-01

    The metabolites were identified by gas chromatography-mass spectrometry (GC-MS). When an equimolar mixture of roxatidine acetate hydrochloride and its deuterated compound, labeled with ten deuterium atoms in the piperidine ring, was incubated with the 9000 X g supernatant (S-9) fraction of either rat or dog liver homogenate, the oxygenated metabolites of the piperidine ring such as the 3-hydroxypiperidine derivative (M1) and the 2-oxopiperidine derivative (M2) were isolated from rats but M2 was not isolated from dogs. These results suggested that the species differences in the metabolism of the piperidine ring in vitro are similar to that in vivo. The deuterium isotope effect (H/D) was 1.34 for M1 and 1.47 for M2 in rats, while the value for M1 in dogs was 1.69. On the other hand, the formation of these oxidative metabolites was inhibited by carbon monoxide in incubations using hepatic microsomes, suggesting that the reaction was catalyzed by cytochromes P-450.

  14. Identification of fentanyl metabolites in rat urine by gas chromatography-mass spectrometry with stable-isotope tracers

    Energy Technology Data Exchange (ETDEWEB)

    Goromaru, T.; Matsuura, H.; Furuta, T.; Baba, S.; Yoshimura, N.; Miyawaki, T.; Sameshima, T.

    The metabolites of fentanyl (l), which has been widely used as a neuroleptic analgesic agent, were identified in urine of rats by gas chromatography-mass spectrometry combined with a stable-isotope tracer technique. After the oral administration of an equimolar mixture of l and deuterium-labeled l (l/l-d5), the urinary metabolites were extracted with chloroform at pH 9.0. Extracts were derivatized and analyzed by GC/MS. Metabolites were identified by the presence of doublet ion peaks separated by 5 amu, and chemical structures were established from analyses of fragmentation pathways. The metabolites were identified as 4-N-(N-propionylanilino)-piperidine, 4-N-(N-hydroxypropionylanilino)piperidine, 4-N-(N-propionylanilino) hydroxypiperidine, 1-(2-phenethyl)-4-N-(N-hydroxypropionylanilino)piperidine and 1-(2-phenethyl)-4-N-(N-propionylanilino)hydroxypiperidine. These metabolites, together with unchanged l, were also detected in urine of rats receiving l/l-d5 intravenously, by selected-ion monitoring of the specific cluster ions.

  15. Hemlock alkaloids from Socrates to poison aloes.

    Science.gov (United States)

    Reynolds, Tom

    2005-06-01

    Hemlock (Conium maculatum L. Umbelliferae) has long been known as a poisonous plant. Toxicity is due to a group of piperidine alkaloids of which the representative members are coniine and gamma-coniceine. The latter is the more toxic and is the first formed biosynthetically. Its levels in relation to coniine vary widely according to environmental conditions and to provenance of the plants. Surprisingly, these piperidine alkaloids have turned up in quite unrelated species in the monocotyledons as well as the dicotyledons. Aloes, for instance, important medicinal plants, are not regarded as poisonous although some species are very bitter. Nevertheless a small number of mostly local species contain the alkaloids, especially gamma-coniceine and there have been records of human poisoning. The compounds are recognized by their characteristic mousy smell. Both acute and chronic symptoms have been described. The compounds are neurotoxins and death results from respiratory failure, recalling the effects of curare. Chronic non-lethal ingestion by pregnant livestock leads to foetal malformation. Both acute and chronic toxicity are seen with stock in damp meadows and have been recorded as problems especially in North America. The alkaloids derive biosynthetically from acetate units via the polyketide pathway in contrast to other piperidine alkaloids which derive from lysine.

  16. Ruthenium-catalyzed α-(hetero)arylation of saturated cyclic amines: reaction scope and mechanism.

    Science.gov (United States)

    Peschiulli, Aldo; Smout, Veerle; Storr, Thomas E; Mitchell, Emily A; Eliáš, Zdeněk; Herrebout, Wouter; Berthelot, Didier; Meerpoel, Lieven; Maes, Bert U W

    2013-07-29

    Transition-metal-catalyzed sp(3) C-H activation has emerged as a powerful approach to functionalize saturated cyclic amines. Our group recently disclosed a direct catalytic arylation reaction of piperidines at the α position to the nitrogen atom. 1-(Pyridin-2-yl)piperidine could be smoothly α-arylated if treated with an arylboronic ester in the presence of a catalytic amount of [Ru3(CO)12] and one equivalent of 3-ethyl-3-pentanol. A systematic study on the substrate and reagent scope of this transformation is disclosed in this paper. The effect of substitution on both the piperidine ring and the arylboronic ester has been investigated. Smaller (pyrrolidine) and larger (azepane) saturated ring systems, as well as benzoannulated derivatives, were found to be compatible substrates with the α-arylation protocol. The successful use of a variety of heteroarylboronic esters as coupling partners further proved the power of this direct functionalization method. Mechanistic studies have allowed for a better understanding of the catalytic cycle of this remarkable transformation featuring an unprecedented direct transmetalation on a Ru(II)-H species.

  17. C(8) substituted 1-azabicyclo[3.3.1]non-3-enes and C(8) substituted 1-azabicyclo[3.3.1]nonan-4-ones: novel muscarinic receptor antagonists.

    Science.gov (United States)

    Kim, Myoung Goo; Bodor, Erik T; Wang, Chen; Harden, T Kendall; Kohn, Harold

    2003-05-22

    Expedient syntheses of C(8) substituted 1-azabicyclo[3.3.1]non-3-enes and C(8) substituted 1-azabicyclo[3.3.1]nonan-4-ones are reported to begin with 2,5-disubstituted pyridines. Catalytic reduction of the pyridine to the piperidine followed by treatment with ethyl acrylate and Dieckmann cyclization gave diastereomeric mixtures of C(8) substituted 3-ethoxycarbonyl-4-hydroxy-1-azabicyclo[3.3.1]non-3-enes, which were separable by chromatography. We found that the catalytic reduction (PtO2, H2) procedure provided the cis-substituted piperidine but that pyridine reduction was accompanied by competitive cleavage of the C(2) pyridyl substituent. Accordingly, an alternative route was devised that afforded a diastereomeric mixture of the cis- and trans-2,5-disubstituted piperidine. Treatment of the substituted pyridine with m-CPBA gave the pyridine N-oxide, which was reduced to the piperidine by sequential reduction with ammonium formate in the presence of Pd-C followed by NaBH3CN. Addition of ethyl acrylate completed the synthesis of the substituted piperidine. The overall four-step reaction gave higher yields (57%) than the two-step procedure (13%) with little cleavage of the C(2) pyridyl substituent. Acid decarboxylation of the bicyclo[3.3.1]non-3-enes provided the C(8) substituted 1-azabicyclo[3.3.1]nonan-4-ones. Structural studies revealed diagnostic 13C NMR signals that permit assignment of the orientation of the C(8) substituent. Pharmacological investigations documented that 3-ethoxycarbonyl-4-hydroxy-1-azabicyclo[3.3.1]non-3-enes efficiently bind to the human M1-M5 muscarinic receptors and function as antagonists. We observed that exo-8-benzyloxymethyl-3-ethoxycarbonyl-4-hydroxy-1-azabicyclo[3.3.1]non-3-ene (3) displayed the highest affinity, exhibiting Ki values at all five muscarinic receptors that were approximately 10-50 times lower than carbachol and approximately 30-230 times lower than arecoline. Receptor selectivity was observed for 3. Compound 3 contained

  18. Propiverinium picrate

    Directory of Open Access Journals (Sweden)

    Jerry P. Jasinski

    2009-08-01

    Full Text Available The title compound [systematic name: 4-(2,2-diphenyl-2-propoxyacetoxy-1-methylpiperidin-1-ium picrate], C23H30NO3+·C6H2N3O7−, crystallizes as a salt with one cation–anion (propiverinium picrate pair in the asymmetric unit. A significant number of conformational changes are observed between the crystalline environment of this cation–anion salt and that of a density functional theory (DFT calculation of the geometry-optimized structure. The angle between the dihedral planes of the two benzyl rings in the propiverinium cation increases by 14.4 (0° from that of the crystalline environment. The dihedral angles between the mean planes of each of the benzyl rings and the mean plane of the piperidine increase by 2.0 (8 and 12.3 (5°. The angles between the mean plane of the acetate group and the mean planes of the interconnected piperidine group and the two benzyl rings decrease by 0.2 (1, 7.4 (6 and 3.2 (2°, respectively. The mean plane of the phenolate group in the anion changes by +22.6 (9, +22.1 (1 and −2.8 (6° from the mean planes of the piperidine and benzyl rings in the cation, respectively. In the crystal, a bifurcated N—H...(O,O hydrogen bond and a weak C—H...π ring interaction help to establish the packing. The two O atoms of the p-NO2 group are disordered with occupancies 0.825 (10:0.175 (10.

  19. 3-(4-Chlorobenzoyl-4-(4-chlorophenyl-1-phenethylpiperidin-4-ol

    Directory of Open Access Journals (Sweden)

    Abdullah Aydın

    2011-06-01

    Full Text Available In the title compound, C26H25Cl2NO2, the piperidine ring adopts a chair conformation with a cis configuration of the carbonyl and hydroxy substituents. The dihedral angle between the aromatic rings of the chlorobenzene groups is 24.3 (2°. The phenyl ring forms dihedral angles of 59.4 (3 and 44.1 (3° with the benzene rings. In the crystal, molecules are linked by intermolecular O—H...N and C—H...O hydrogen bonds and C—H...π interactions into layers parallel to the bc plane.

  20. Synthesis, characterization, crystal structure, in-vitro antimicrobial evaluation and molecular docking studies of 1-(furan-2-carbonyl)-3-alkyl-2,6-diphenylpiperidin-4-one derivatives

    Science.gov (United States)

    Srikanth, R.; Sivarajan, A.; Venkatesan, C. S.; Maheshwaran, V.; Sugumar, P.; Rajitha, G.; Varalakshmi, J. C.; Ponnuswamy, M. N.

    2016-12-01

    A new class of various furoyl derivatives of 2,6-disubstituted piperidin-4-ones were synthesized and characterized by FTIR, NMR, mass and single crystal X-ray diffraction methods. The synthesized compounds were subjected to in-vitro antibacterial and antifungal activities against pathogenic microbial strains. The results pointed out that compounds 11, 12 & 14 displayed pronounced activity towards gram positive bacteria, whereas the compounds 9, 13 & 14 showed a superior inhibition activity against gram negative bacteria. The compound 9 showed a moderate activity towards the fungi. In addition, molecular docking experiments were also carried out.

  1. Discovery of the first small-molecule opioid pan antagonist with nanomolar affinity at mu, delta, kappa, and nociceptin opioid receptors.

    Science.gov (United States)

    Zaveri, Nurulain T; Journigan, V Blair; Polgar, Willma E

    2015-04-15

    The trans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine scaffold is a known pharmacophore for mu opioid (MOP), kappa opioid (KOP), and delta opioid (DOP) receptor antagonists; however, it has not been explored in nociceptin opioid (NOP/ORL-1) receptor ligands. We recently found that the selective KOP antagonist JDTic, (3R)-7-hydroxy-N-((1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide, containing this opioid antagonist pharmacophore, has significant binding affinity at the NOP receptor (Ki 16.67 ± 0.76 nM), with no intrinsic activity in the [(35)S]GTPγS functional assay. Since this is the first ligand containing the trans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine opioid antagonist pharmacophore to have affinity for the NOP receptor, we explored the structural determinants of its NOP binding affinity. When rational chemical modifications of JDTic were carried out, based on our previously established NOP pharmacophoric structure-activity relationship (SAR) model, most modifications led to a significant decrease in NOP and opioid binding affinity compared to JDTic. Interestingly, however, removal of the 3,4-dimethyl groups of the trans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine antagonist scaffold of JDTic increased the binding affinity at NOP by 10-fold (Ki 1.75 ± 0.74 nM) while maintaining comparable affinity for KOP, MOP, and DOP receptors (Ki 1.14 ± 0.63, 1.67 ± 0.6, and 19.6 ± 1.3 nM, respectively). In vitro functional efficacy studies using the [(35)S]GTPγS assay showed that this compound AT-076 functions as an antagonist at all four opioid receptors. Detailed characterization of the antagonist activity of AT-076 shows that it has a noncompetitive antagonist profile at the NOP and KOP receptors (insurmountable antagonism), but is a potent competitive antagonist at the MOP and DOP receptors, with Ke values 3-6-fold more potent than those of JDTic. AT-076 is the

  2. Microwave-assisted rapid synthesis of methyl 2,4,5-trimethoxyphenylpropionate, a metabolite of Cordia alliodora.

    Science.gov (United States)

    Sinha, A K; Joshi, B P; Sharma, A; Kumar, J K; Kaul, V K

    2003-12-01

    Microwave assisted condensation of asaronaldehyde (2) with malonic acid in piperidine-AcOH provides 2,4,5-trimethoxycinnamic acid (3) in 87% yield within 4 min, which upon further reduction with PdCl2- HCOOH-aq. NaOH gives 3-(2,4,5-trimethoxy)phenyl propionic acid (4) in 88% yield within 3 min. Esterification of 4 with MeOH-H+ gives methyl 2,4,5-trimethoxyphenylpropionate (1), a metabolite of Cordia alliodora, in 94% yield within 3 min (overall 69% yield).

  3. Pyrrolidine analogues of lobelane: relationship of affinity for the dihydrotetrabenazine binding site with function of the vesicular monoamine transporter 2 (VMAT2).

    Science.gov (United States)

    Vartak, Ashish P; Nickell, Justin R; Chagkutip, Jaturaporn; Dwoskin, Linda P; Crooks, Peter A

    2009-12-10

    Ring size reduction of the central piperidine ring of lobelane yielded pyrrolidine analogues that showed marked inconsistencies in their ability to bind to the dihydrotetrabenazine (DTBZ) binding site on the vesicular monoamine transporter-2 (VMAT2) and their ability to inhibit VMAT2 function. The structure-activity relationships indicate that structural modification within the pyrrolidine series resulted in analogues that interact with two different sites, i.e., the DTBZ binding site and an alternative site on VMAT2 to inhibit transporter function.

  4. Pyrrolidine analogs of lobelane: Relationship of affinity for the dihydrotetrabenazine binding site with function of the vesicular monoamine transporter 2 (VMAT2)

    Science.gov (United States)

    Vartak, Ashish P.; Nickell, Justin R.; Chagkutip, Jaturaporn; Dwoskin, Linda P.; Crooks, Peter A.

    2013-01-01

    Ring size reduction of the central piperidine ring of lobelane yielded pyrrolidine analogs that showed marked inconsistencies in their ability to bind to the dihydrotetrabenazine (DTBZ) binding site on the vesicular monoamine transporter-2 (VMAT2) and their ability to inhibit VMAT2 function. The structure activity relationships indicate that structural modification within the pyrrolidine series resulted in analogs that interact with two different sites, i.e., the DTBZ binding site and an alternative site on VMAT2 to inhibit transporter function. PMID:19691331

  5. Preparation of iodine-123 labeled AM251: a potential SPECT radioligand for the brain cannabinoid CB1 receptor

    Energy Technology Data Exchange (ETDEWEB)

    Lan, Ruoxi; Makriyannis, Alexandros [Connecticut Univ., Molecular and Cell Biology Dept., Storrs, CT (United States); Gatley, S.J. [Brookhaven National Lab., Medical Dept., Upton, NY (United States)

    1996-10-01

    We report the synthesis and labeling with iodine-123 of N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251). This compound is an analog of the recently described cannabinoid receptor antagonist, SR141716A, in which a 4-chlorophenyl group is replaced by 4-iodophenyl. Labeling in good yield (62%) and radiochemical purity (> 95%), and high specific activity (> 2500 Ci/mmol) was achieved by an iododestannylation reaction using the tributyltin precursor, no carrier added I-123 iodide, and chloramine-T. (author).

  6. (-)-7-hydroxycassine: a new 2,6-dialkylpiperidin-3-ol alkaloid and other constituents isolated from flowers and fruits of Senna spectabilis (Fabaceae)

    Energy Technology Data Exchange (ETDEWEB)

    Viegas Junior, Claudio, E-mail: viegas@unifal-mg.edu.br, E-mail: cvjviegas@gmail.com [Universidade Federal de Alfenas (UNIFAL), MG (Brazil). Instituto de Quimica. Laboratorio de Fitoquimica e Quimica Medica; Pivatto, Marcos [Universidade Federal de Uberlandia, MG (Brazil). Instituto de Quimica; Rezende, Amanda de; Hamerski, Lidilhone; Silva, Dulce Helena Siqueira; Bolzani, Vanderlan da Silva [Universidade Estadual Paulista Julio de Mesquita Filho (NuBBE/UNESP), Araraquara, SP (Brazil). Instituto de Quimica. Nucleo de Bioensaios, Biossintese e Ecofiologia de Produtos Naturais

    2013-02-15

    The phytochemical study of flowers and green fruits of Senna spectabilis furnished a new substituted 2,6-dialkylpiperidin-3-ol alkaloid, named (-)-7-hydroxycassine, along with five known piperidine alkaloids: (-)-cassine, (-)-spectaline, (-)-3-O-acetylspectaline, (-)-7-hydroxyspectaline and (-)-iso-6-spectaline. In addition to non-alkaloidal, chemical constituents from other chemical classes were also identified, including the steroid {beta}-sitosterol, the flavonoids luteolin and 3-methoxyluteolin, the triterpene betulinic acid and trans-cinnamic acid. To our knowledge, compounds are being reported for the first time in this species. (author)

  7. Synthesis, conformational preferences and antimicrobial evaluation of N-piperazinoacetyl-r-2,c-6-diphenylpiperidin-4-ones

    Science.gov (United States)

    Akila, A.; Jeganathan, P.; Ponnuswamy, S.

    2016-09-01

    Five new N-piperazinoacetyl-r-2,c-6-diphenylpiperidin-4-ones 11-15 have been synthesized and characterized using IR, 1H, 13C, DEPT & 2D NMR and mass spectral studies. The NMR spectral data indicate that the N-piperazinoacetyl-r-2,c-6-diphenylpiperidin-4-ones 11-15 prefer to exist in an equilibrium between B1 and B2 conformations. Furthermore, the antibacterial and antifungal studies were carried out. The results show that the piperazinoacetyl piperidin-4-ones 11-15 exhibit good activity against the selected bacterial and fungal strains.

  8. Vapor-liquid equilibria of coal-derived liquids; 3: Binary systems with tetralin at 200 mmHg

    Energy Technology Data Exchange (ETDEWEB)

    Blanco, B.; Beltran, S.; Cabezas, J.L. (University Coll., Burgos (Spain). Dept. of Chemical Engineering); Coca, J. (Univ. of Oviedo (Spain). Dept. of Chemical Engineering)

    1994-01-01

    Isobaric vapor-liquid equilibrium data are reported for binary systems of tetralin with p-xylene, [gamma]-picoline, piperidine, and pyridine; all systems were measured at 26.66 kPa (200 mmHg) with a recirculation still. Liquid-phase activity coefficients were correlated using the Van Laar, Wilson, NRTL, and UNIQUAC equations. Vapor-phase nonidealities were found negligible under the experimental conditions of this work, and deviations of the liquid phase from the ideal behavior, as described by Raoult's law, were found to be slightly positive for all the systems.

  9. Synthesis, Characterization and Photophysical Properties of Pyridine-Carbazole Acrylonitrile Derivatives

    OpenAIRE

    Gabriel Ramos-Ortiz; Enrique Pérez-Gutiérrez; José Luis Maldonado; Chapela, Víctor M.; Margarita Cerón; M. Judith Percino

    2011-01-01

    We synthesized three novel highly fluorescent compounds, 2-(2’-pyridyl)-3-(N-ethyl-(3’-carbazolyl))acrylonitrile, 2-(3”-pyridyl)-3-(N-ethyl-(3’-carbazolyl))acrylonitrile, and 2-(4-pyridyl)-3-(N-ethyl-(3’-carbazolyl))acrylonitrile by Knoevenagel condensation. The first two were synthesized without solvent in the presence of piperidine as a catalyst; the third was synthesized without a catalyst and with N,N-dimethylformamide as a solvent. In solution, the molar absorption coefficients showed ab...

  10. New Perfluorophtalate Complexes of Platinum(II) With Chemotherapeutic Potential

    OpenAIRE

    de Oliveira, M. B.; J. Miller; Banks, R. E.; Kelland, L R; McAuliffe, C. A.; Mahmood, N; Rowland, I. J.

    1996-01-01

    Two new platinum(II) complexes have been synthesized and their anti-tumour and anti-HIV activities have been evaluated. The new complexes are: (i) cis-tetrafluorophthalate-ammine-morpholine-platinum(II) or MMF3 and (ii) cis-tetrafluorophthalate- ammine-piperidine-platinum(II) or MPF4. They were characterized by elemental analysis, IR spectra and 1H and 13C NMR spectra. They were tested against five human ovarian carcinoma cell lines, viz., CH1, CH1cisR, A2780, A2780cisR and SKOV-3. They were ...

  11. Enzymatic Kinetic Resolution of 2-Piperidineethanol for the Enantioselective Targeted and Diversity Oriented Synthesis

    Directory of Open Access Journals (Sweden)

    Dario Perdicchia

    2015-12-01

    Full Text Available 2-Piperidineethanol (1 and its corresponding N-protected aldehyde (2 were used for the synthesis of several natural and synthetic compounds. The existence of a stereocenter at position 2 of the piperidine skeleton and the presence of an easily-functionalized group, such as the alcohol, set 1 as a valuable starting material for enantioselective synthesis. Herein, are presented both synthetic and enzymatic methods for the resolution of the racemic 1, as well as an overview of synthesized natural products starting from the enantiopure 1.

  12. Isolation and structural elucidation of a new tadalafil analogue in health supplements: bisprenortadalafil.

    Science.gov (United States)

    Lee, Ji Hyun; Park, Han Na; Ganganna, Bogonda; Jeong, Ji Hye; Park, Sung-Kwan; Lee, Jongkook; Baek, Sun Young

    2016-06-01

    A new tadalafil analogue was found, along with nortadalafil, using HPLC-DAD during the inspection of a health product sold without official approval. The analogue was separated using a semi-preparative HPLC system and its structure was determined by a combination of mass spectrometry and NMR spectroscopy. The compound was identified as a tadalafil analogue in which the N-methyl group of tadalafil was replaced with a tadalafil precursor moiety. Nuclear Overhauser effect spectroscopy experiments suggested a cis-relationship between the substituents on a piperidine ring in the tadalafil moiety.

  13. Complexing ability of (-)-cytisine--synthesis, spectroscopy and crystal structures of the new copper and zinc complexes.

    Science.gov (United States)

    Przybył, Anna K; Kubicki, Maciej; Jastrzab, Renata

    2014-09-01

    For the first time the NMR spectra of quinolizidine alkaloid with Cu(II) are studied. Structures of new complexes of (-)-cytisine with Cu(+2) and Zn(+2) cations are visualized, discussed in detail and characterized by spectroscopic methods: ESI-MS, NMR, UV-vis, EPR and crystallographic methods. In solution metal coordinates through the protonated nitrogen atoms of secondary amino groups (in piperidine ring) of cytisine molecule. While in solid state the most stable structures of the complexes are those in which the coordination of Cu(II) and Zn(II) salts is realized solely through the lactam carbonyl oxygen atom.

  14. Combination of gold catalysis and Selectfluor for the synthesis of fluorinated nitrogen heterocycles

    Directory of Open Access Journals (Sweden)

    Antoine Simonneau

    2011-10-01

    Full Text Available We herein report the synthesis of 3-fluoro-2-methylene-pyrrolidine (3a and -piperidine (3b from 1,5- and 1,6-aminoalkynes, respectively, using a combination of a gold-catalyzed hydroamination reaction followed by electrophilic trapping of an intermediate cyclic enamine by Selectfluor. Careful attention was paid to the elucidation of the mechanism and Selectfluor was suggested to play the double role of promoting the oxidation of gold(I to a gold(III active species and also the electrophilic fluorination of the enamine intermediates.

  15. Conversion of 3-Carbethoxy-4-methyl Coumarin Derivatives into Several New Annelated Coumarin Derivatives

    Institute of Scientific and Technical Information of China (English)

    BAKEER; HadeerMohammed

    2003-01-01

    The reaction of ethyl esters of 4-methyl-2-oxo-2H-l-benzo(naphtho) pyran.3-carboxylic acids (1) with aromatic aldehy-des in the presence of piperidine yielded 4-styryl-3-carboxami-dopiperidyl connmrin derivatives 4. The reaction of hydrazlne hydrate with 1 gave acetophenone hydrozone derivatives 5 and acetophenone azine derivatives 6. The reaction of 1 with prima-ry amines afforded compomlds 7—9. And the treatment of la with Grignard reagents afforded 3-aroyl-4-methyl coumarin derivatives 10.

  16. Synthesis and Some Reactions of 1-aryl-4-acetyl-5-methyl-1,2,3-triazole Derivatives with Anticonvulsant Activity.

    Science.gov (United States)

    Nassar, Ekhlass M; Abdelrazek, Fathy M; Ayyad, Rezk R; El-Farargy, Ahmed F

    2016-01-01

    The triazoles 3a-d underwent condensation reactions with 4-(piperidin-1-yl)-benzaldehyde to afford the chalcones 5a-d. Chalcone derivatives 5a-d were reacted with 2,3-diaminomaleonitrile, thiourea and hydrazine hydrate to afford the novel diazepine-dicarbonitrile derivatives 7a-d, the pyrimidine-2-thiol derivatives 9a-d and hydrazino-pyrimidines 10a-d respectively. Structures of the prepared compounds were elucidated by physical and spectral data like FT-IR, (1)H NMR, (13)C NMR, and mass spectroscopy. Some of the synthesized compounds were screened for their anticonvulsant activity and SAR.

  17. Identification of nitrogen compounds and amides from spent hydroprocessing catalyst

    Energy Technology Data Exchange (ETDEWEB)

    Choi, J.H.K.; Gray, M.R. (University of Alberta, Edmonton, AB (Canada). Dept. of Chemical Engineering)

    1991-06-01

    A spent commercial naphtha hydrotreating catalyst was analyzed to identify compounds which had accumulated on the catalyst surface during its active life. The catalyst was extracted with methylene chloride, methanol and pyridine to remove adsorbed organic material, which was rich in nitrogen and oxygen. A series of quinolones were identified in the methanol extract after enrichment with HCl-modified silica gel adsorption and subsequent silica gel chromatography. Tetra- and hexahydroquinolones with alkyl substituents up to C{sub 3} were identified. Similar amides have been identified in asphaltenes, and are very resistant to hydrogenation. Tetrahydroquinolines and piperidines were detected in the pyridine extract. 36 refs., 8 figs., 2 tabs.

  18. Homoserine as an Aspartic Acid Precursor for Synthesis of Proteoglycan Glycopeptide Containing Aspartic Acid and a Sulfated Glycan Chain.

    Science.gov (United States)

    Yang, Weizhun; Ramadan, Sherif; Yang, Bo; Yoshida, Keisuke; Huang, Xuefei

    2016-12-02

    Among many hurdles in synthesizing proteoglycan glycopeptides, one challenge is the incorporation of aspartic acid in the peptide backbone and acid sensitive O-sulfated glycan chains. To overcome this, a new strategy was developed utilizing homoserine as an aspartic acid precursor. The conversion of homoserine to aspartic acid in the glycopeptide was successfully accomplished by late stage oxidation using (2,2,6,6-tetramethyl-piperidin-1-yl)oxyl (TEMPO) and bis(acetoxy)iodobenzene (BAIB). This is the first time that a glycopeptide containing aspartic acid and an O-sulfated glycan was synthesized.

  19. Metathesis access to monocyclic iminocyclitol-based therapeutic agents

    Directory of Open Access Journals (Sweden)

    Albert Demonceau

    2011-05-01

    Full Text Available By focusing on recent developments on natural and non-natural azasugars (iminocyclitols, this review bolsters the case for the role of olefin metathesis reactions (RCM, CM as key transformations in the multistep syntheses of pyrrolidine-, piperidine- and azepane-based iminocyclitols, as important therapeutic agents against a range of common diseases and as tools for studying metabolic disorders. Considerable improvements brought about by introduction of one or more metathesis steps are outlined, with emphasis on the exquisite steric control and atom-economical outcome of the overall process. The comparative performance of several established metathesis catalysts is also highlighted.

  20. Synthesis and evaluation of ligands for D2-like receptors: the role of common pharmacophoric groups.

    Science.gov (United States)

    Sikazwe, Donald M N; Nkansah, Nancy T; Altundas, Ramazan; Zhu, Xue Y; Roth, Bryan L; Setola, Vincent; Ablordeppey, Seth Y

    2009-02-15

    Arylcycloalkylamines, such as phenyl piperidines and piperazines and their arylalkyl substituents, constitute pharmacophoric groups exemplified in several antipsychotic agents. A review of previous reports indicates that arylalkyl substituents can improve the potency and selectivity of the binding affinity at D(2)-like receptors. In this paper, we explored the contributions of two key pharmacophoric groups, that is, 4'-fluorobutyrophenones and 3-methyl-7-azaindoles, to the potency and selectivity of synthesized agents at D(2)-like receptors. Preliminary observation of binding affinities indicates that there is little predictability of specific effects of the arylalkyl moieties but the composite structure is responsible for selectivity and potency at these receptors.

  1. Synthetic studies of neoclerodane diterpenes from Salvia divinorum: role of the furan in affinity for opioid receptors.

    Science.gov (United States)

    Simpson, Denise S; Lovell, Kimberly M; Lozama, Anthony; Han, Nina; Day, Victor W; Dersch, Christina M; Rothman, Richard B; Prisinzano, Thomas E

    2009-09-21

    Further synthetic modification of the furan ring of salvinorin A (1), the major active component of Salvia divinorum, has resulted in novel neoclerodane diterpenes with opioid receptor affinity and activity. A computational study has predicted 1 to be a reproductive toxicant in mammals and is suggestive that use of 1 may be associated with adverse effects. We report in this study that piperidine 21 and thiomorpholine 23 have been identified as selective partial agonists at kappa opioid receptors. This indicates that additional structural modifications of 1 may provide ligands with good selectivity for opioid receptors but with reduced potential for toxicity.

  2. Opportunities and challenges for direct C–H functionalization of piperazines

    Directory of Open Access Journals (Sweden)

    Zhishi Ye

    2016-04-01

    Full Text Available Piperazine ranks within the top three most utilized N-heterocyclic moieties in FDA-approved small-molecule pharmaceuticals. Herein we summarize the current synthetic methods available to perform C–H functionalization on piperazines in order to lend structural diversity to this privileged drug scaffold. Multiple approaches such as those involving α-lithiation trapping, transition-metal-catalyzed α-C–H functionalizations, and photoredox catalysis are discussed. We also highlight the difficulties experienced when successful methods for α-C–H functionalization of acyclic amines and saturated mono-nitrogen heterocyclic compounds (such as piperidines and pyrrolidines were applied to piperazine substrates.

  3. Synthesis and NLO Properties of Chromophores with 1,8-Dimethoxy-9,10-dihydroanthracene and Thiobarbituric acid Moieties

    Institute of Scientific and Technical Information of China (English)

    WU De-Lin; JIA Zhao-Li; SHI Jie-Ping; SHI Zheng-Wei; LU Guo-Yuan

    2008-01-01

    The new chromophore molecules with nonlinear optical (NLO) properties were prepared by Knoevenagel condensation from 4,5-diformyl-1,8-dimethoxy-9,10-dihydroanthracene and thiobarbituric acid derivatives in the presence of piperidine and acetic acid. In these chromophores, the ring-locked triene employed as a conjugation bridge and the thiobarbituric acid moiety was as an electron acceptor in a D-π-A units. The solvatochromism and UV spectra indicate that they have higher second-order nonlinear polarizability μβ values than the corresponding reference compound, without causing a large red shift of the charge transfer band.

  4. Sonogashira couplin8 reaction of homoproparsyl ether with aryl bromides and synthesis of 2,5-disubstituted 3-bromofurans

    Institute of Scientific and Technical Information of China (English)

    WANG Xin; LIU LingYan; CHANG WeiXing; LI Jing

    2009-01-01

    This paper presents Sonogashira coupling reaction of aryl bromides with protected homopropargyl alcohols such as tert-butyldimethyl(1-phenylbut-3-ynyloxy)silane and tert-butyldimethyl(1-(2,4-dichlorophenyl)but-3-ynyloxy)silane in piperidine catalyzed by PdCl2/PPh3 without copper(Ⅰ).The coupling products,disubstituted acetylene,are obtained in good or excellent yields.These products can be further used for the synthesis of 2,5-disubstituted 3-bromofurans.

  5. Alkaloids from Piper sarmentosum and Piper nigrum.

    Science.gov (United States)

    Ee, G C L; Lim, C M; Lim, C K; Rahmani, M; Shaari, K; Bong, C F J

    2009-01-01

    Detailed chemical studies on the roots of Piper sarmentosum and Piper nigrum have resulted in several alkaloids. The roots of P. sarmentosum gave a new aromatic compound, 1-nitrosoimino-2,4,5-trimethoxybenzene (1). Piper nigrum roots gave pellitorine (2), (E)-1-[3',4'-(methylenedioxy)cinnamoyl]piperidine (3), 2,4-tetradecadienoic acid isobutyl amide (4), piperine (5), sylvamide (6), cepharadione A (7), piperolactam D (8) and paprazine (9). Structural elucidation of these compounds was achieved through NMR and MS techniques. Cytotoxic activity screening of the plant extracts indicated some activity.

  6. Fullerene-Based Macro-Heterocycle Prepared through Selective Incorporation of Three N and Two O Atoms into C60.

    Science.gov (United States)

    Li, Yanbang; Zhang, Gaihong; Wang, Dian; Xu, Beidi; Xu, Dan; Lou, Ning; Gan, Liangbing

    2016-11-14

    A 14-membered heterocycle is created on the C60 cage skeleton through a multistep procedure. Key steps involve repeated PCl5 -induced hydroxylamino N-O bond cleavage leading to insertion of nitrogen atoms, and also piperidine-induced peroxo O-O bond cleavage leading to insertion of oxygen atoms. The hetero atoms form one pyrrole, two pyran, and one diazepine rings in conjunction with the C60 skeleton carbon atoms. The fullerene-based macrocycle showed unique reactivities towards fluoride ion and copper salts. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. Basic aspects of the pharmacodynamics of tolperisone, a widely applicable centrally acting muscle relaxant.

    Science.gov (United States)

    Tekes, Kornelia

    2014-01-01

    Tolperisone (2-methyl-1-(4-methylphenyl)-3-piperidin-1-ylpropan-1-one hydro-chloride) was introduced in the clinical practice more than forty years ago and is still evaluated as a widely applicable compound in pathologically elevated skeletal muscle tone (spasticity) and related pains of different origin. In the present review, basic pharmacodynamic effects measured on whole animals, analyses of its actions on cell and tissue preparations and molecular mechanism of action on sodium and calcium channels are summarized as recently significantly new data were reported.

  8. 2,6-Diiminopiperidin-1-ol: an overlooked motif relevant to uranyl and transition metal binding on poly(amidoxime) adsorbents

    Energy Technology Data Exchange (ETDEWEB)

    Kennedy, Zachary C.; Cardenas, Allan J.; Corbey, Jordan F.; Warner, Marvin G.

    2016-06-06

    Glutardiamidoxime, a structural motif on sorbents used in uranium extraction from seawater, was discovered to cyclize in situ at room temperature to 2,6-diimino-piperidin-1-ol in the presence of uranyl nitrate. The new diimino motif was also generated when exposed to competing transition metals Cu(II) and Ni(II). Multinuclear μ-O bridged U(VI), Cu(II), and Ni(II) complexes featuring bound diimino ligands were isolated. A Cu(II) complex with the historically relevant cyclic imide dioxime motif is also reported for structural comparison to the reported diimino complexes.

  9. THE EFFECTS OF SOLVENTS ON SUB-BITUMINOUS COAL BELOW ITS PYROLYSIS TEMPERATURE

    Energy Technology Data Exchange (ETDEWEB)

    Grens III., Edward A.; Dorighi, Gary P.; Lindsey, David

    1979-12-01

    The action of organic solvents on a sub-bituminous coal has been examined over the temperature range of 150-350°C. The solvents studied included benzene, tetralin, pyridine, quinoline, piperidine, and ethylenediamine. The yield of extracted material varied widely with solvent and temperature, exceeding 60% (daf) for ethylenediamine at 250°C. The extracts were anlayzed for molecular weight, elemental composition and proton aromaticity. When mixtures of strong amine-type solvents with toluene were used, the yield of extract was linearly related mol fraction of strong solvent in the mixture.

  10. Facile synthesis of some novel 2-substituted-4,6-diarylpyrimidines using 4 ' -hydroxy-3 ' ,5 ' -dinitrochalcones and S-benzylthiouronium chloride

    Directory of Open Access Journals (Sweden)

    K. L. Ameta

    2012-01-01

    Full Text Available Various 4'-hydroxy-3',5'-dinitro substituted chalcones 1 and S-benzylthiouronium chloride (SBT 2 in the presence of DMF-organic bases (morpholine/ pyrrolidine/ piperidine gave 4,6-diaryl-2-(4-morpholinyl / 1-pyrrolidinyl /1-piperidinyl- pyrimidines 4, 5 and 6 in a facile one-pot conversion. In an another attempt reactants 1 and 2 yielded intermediate 2-benzylthiopyrimidines 3, in presence of DMF, which on treatment with heterocyclic secondary amines gave products 4, 5 and 6 in an alternate two-step process.

  11. Synthesis and Antibacterial Activity of Thiophenes

    Directory of Open Access Journals (Sweden)

    Wedad M. Al-Adiwish

    2012-01-01

    Full Text Available 2-[Bis(methylthiomethylene]propanedinitrile 1a reacted in one-pot successively with piperidine, sodium sulfide, chloroacetonitrile, and potassium carbonate to afford 3-amino-5-(1-piperidinyl-2,4-thiophenedicarbonitrile 2a. Similar reaction using the last three reagents with ethyl 2-cyano-3,3-bis(methylthioacrylate 1b produced ethyl 4-amino-5-cyano-2-(methylthiothiophene-3-carboxylate 2b. The synthesized compounds were characterized by using FT-IR, 1H-NMR, 13C-NMR, and mass spectral data. Antibacterial activities of the synthesized compounds are also reported.

  12. 2-Hydroxy-11-methyl-16-[(E-4-methylbenzylidene]-13-(4-methylphenyl-1,11-diazapentacyclo[12.3.1.02,10.03,8.010,14]octadeca-3(8,4,6-triene-9,15-dione

    Directory of Open Access Journals (Sweden)

    Raju Suresh Kumar

    2010-09-01

    Full Text Available In the title compound, C32H30N2O3, the piperidin-4-one and the two fused pyrrolidine rings adopt envelope conformations. The two methylphenyl rings are oriented at dihedral angle of 20.36 (7 and 56.24 (7°, respectively, with respect to the indanone ring system. In the crystal structure, intermolecular O—H...N and C—H...O hydrogen bonds link the molecules into chains propagating along [001]. Weak C—H...π interactions are also observed.

  13. Synthesis and characterization of curdlan piperinic ester%凝胶多糖胡椒酸酯的合成及表征

    Institute of Scientific and Technical Information of China (English)

    韩景芬; 兰景波; 孟和; 娜日苏; 昭日格图; 博日吉汗格日勒图

    2013-01-01

    Curdlan piperinic ester was synthesized from piper-idine and water soluble curdlan in the present of N, N-carbon-yldiimidazole as catalyst. This novel conjugate was characterized by FT-IR,1HNMR and 13CNMR.%以胡椒碱和凝胶多糖为原料,在羰基二咪唑的作用下合成了凝胶多糖胡椒酸酯,并用FT-IR、1HNMR和13CNMR进行了结构表征.

  14. Crystal structures of four δ-keto esters and a Cambridge Structural Database analysis of cyano-halogen interactions.

    Science.gov (United States)

    Kamal, Kulsoom; Maurya, Hardesh K; Gupta, Atul; Vasudev, Prema G

    2015-10-01

    The revived interest in halogen bonding as a tool in pharmaceutical cocrystals and drug design has indicated that cyano-halogen interactions could play an important role. The crystal structures of four closely related δ-keto esters, which differ only in the substitution at a single C atom (by H, OMe, Cl and Br), are compared, namely ethyl 2-cyano-5-oxo-5-phenyl-3-(piperidin-1-yl)pent-2-enoate, C19H22N2O3, (1), ethyl 2-cyano-5-(4-methoxyphenyl)-5-oxo-3-(piperidin-1-yl)pent-2-enoate, C20H24N2O4, (2), ethyl 5-(4-chlorophenyl)-2-cyano-5-oxo-3-(piperidin-1-yl)pent-2-enoate, C19H21ClN2O3, (3), and the previously published ethyl 5-(4-bromophenyl)-2-cyano-5-oxo-3-(piperidin-1-yl)pent-2-enoate, C19H21BrN2O3, (4) [Maurya, Vasudev & Gupta (2013). RSC Adv. 3, 12955-12962]. The molecular conformations are very similar, while there are differences in the molecular assemblies. Intermolecular C-H...O hydrogen bonds are found to be the primary interactions in the crystal packing and are present in all four structures. The halogenated derivatives have additional aromatic-aromatic interactions and cyano-halogen interactions, further stabilizing the molecular packing. A database analysis of cyano-halogen interactions using the Cambridge Structural Database [CSD; Groom & Allen (2014). Angew. Chem. Int. Ed. 53, 662-671] revealed that about 13% of the organic molecular crystals containing both cyano and halogen groups have cyano-halogen interactions in their packing. Three geometric parameters for the C-X...N[triple-bond]C interaction (X = F, Cl, Br or I), viz. the N...X distance and the C-X...N and C-N...X angles, were analysed. The results indicate that all the short cyano-halogen contacts in the CSD can be classified as halogen bonds, which are directional noncovalent interactions.

  15. Tert-butyl 3-oxo-2,3,4,5,6,7-hexahydro-1H-pyrazolo[4,3-c]pyridine-5-carboxylate

    Directory of Open Access Journals (Sweden)

    Tara Shahani

    2010-01-01

    Full Text Available In the title compound, C11H17N3O3, the pyrazole ring is approximately planar, with a maximum deviation of 0.005 (2 Å, and forms a dihedral angle of 5.69 (13° with the plane through the six atoms of the piperidine ring. In the crystal, pairs of intermolecular N—H...O hydrogen bonds form dimers with neighbouring molecules, generating R22(8 ring motifs. These dimers are further linked into two-dimensional arrays parallel to the bc plane by intermolecular N—H...O and C—H...O hydrogen bonds.

  16. An Efficient Preparation of 1,2-Diamino-1-phenylheptane

    Directory of Open Access Journals (Sweden)

    P. T. Perumal

    2002-06-01

    Full Text Available A convenient four-step method for the preparation of the lipophilic vicinal diamine 1,2-diamino-1-phenylheptane is described. Condensation involving octan-2-one, benzaldehyde and ammonia is reported. Regioselective Schmidt rearrangement of 2,6-diphenyl-3-pentyl-piperidin-4-one (1 to 2,7-diphenyl-3-pentyl hexahydrodiazapin-5-one (3 is presented. Hydrolysis of 2,7-diphenyl-3-pentyl hexahydrodiazapin-5-one to 1,2-diamino-1-phenylheptane (4 is also reported for the first time.

  17. Methyl trans-rac-2-hexyl-1-oxo-3-(2-pyridyl-1,2,3,4-tetrahydroisoquinoline-4-carboxylate

    Directory of Open Access Journals (Sweden)

    Orhan Büyükgüngör

    2008-10-01

    Full Text Available The title compound, C22H26N2O3, was synthesized by esterification of trans-rac-2-hexyl-1-oxo-3-(2-pyridyl-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid in the presence of H2SO4 in methanol. The dihedral angle between the benzene and pyridine rings is 84.46 (17°. The piperidine ring adopts a screw-boat conformation. In the crystal, inversion dimers linked by two C—H...O bonds occur.

  18. New, Substituted Derivatives of Dicarboximides and their Cytotoxic Properties.

    Science.gov (United States)

    Kuran, Bożena; Napiórkowska, Mariola; Kossakowski, Jerzy; Cieślak, Marcin; Kaźmierczak-Barańska, Julia; Królewska, Karolina; Nawrot, Barbara

    2016-01-01

    A large group of aminoalkyl and aminoalkanol derivatives of selected dicarboximides were synthesized and characterized by 1HNMR, 13CNMR and ESI MS spectra analysis. The thirty nine new compounds were tested for their cytotoxic properties in human chronic (K562), acute leukemia (HL-60), and cervical cancer cells (HeLa) as well as in normal endothelial cells (HUVEC). The most promising compounds are 4-[2-(dimethylamino)ethyl]-, (diethylamino) ethyl]-, 4-[2-(piperidin-1-yl)ethyl]-, 4-[3-(dimethylamino)propyl]- and 4-[2-hydroxy-3-(propan- 2-ylamino)propyl]- derivatives of 1,7-diethyl-8,9-diphenyl-4-azatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5,10-trione exhibiting high and selective cytotoxicity towards K562 and HL-60 cells (IC50 in the range of 1-10 µM) while being non-toxic towards HUVEC and HeLa cells (IC50> 100 μM). Moreover, the preliminary studies have showed that 4-[2-(piperidin-1-yl)ethyl]- 1,7-diethyl-8,9-diphenyl-4-azatricyclo [5.2.1.0(2,6)]dec-8-ene-3,5,10-trione induces programmed cell death (apoptosis) in leukemia cells.

  19. Synthesis and evaluation of novel azetidine analogs as potent inhibitors of vesicular [3H]dopamine uptake.

    Science.gov (United States)

    Ding, Derong; Nickell, Justin R; Deaciuc, Agripina G; Penthala, Narsimha Reddy; Dwoskin, Linda P; Crooks, Peter A

    2013-11-01

    Lobelane analogs that incorporate a central piperidine or pyrrolidine moiety have previously been reported by our group as potent inhibitors of VMAT2 function. Further central ring size reduction of the piperidine moiety in lobelane to a four-membered heterocyclic ring has been carried out in the current study to afford novel cis-and trans-azetidine analogs. These azetidine analogs (15a-15c and 22a-22c) potently inhibited [(3)H]dopamine (DA) uptake into isolated synaptic vesicles (Ki⩽66nM). The cis-4-methoxy analog 22b was the most potent inhibitor (Ki=24nM), and was twofold more potent that either lobelane (2a, Ki=45nM) or norlobelane (2b, Ki=43nM). The trans-methylenedioxy analog, 15c (Ki=31nM), was equipotent with the cis-analog, 22b, in this assay. Thus, cis- and trans-azetidine analogs 22b and 15c represent potential leads in the discovery of new clinical candidates for the treatment of methamphetamine abuse.

  20. Multidrug resistance-selective antiproliferative activity of Piper amide alkaloids and synthetic analogues.

    Science.gov (United States)

    Wang, Yue-Hu; Goto, Masuo; Wang, Li-Ting; Hsieh, Kan-Yen; Morris-Natschke, Susan L; Tang, Gui-Hua; Long, Chun-Lin; Lee, Kuo-Hsiung

    2014-10-15

    Twenty-five amide alkaloids (1-25) from Piper boehmeriifolium and 10 synthetic amide alkaloid derivatives (39-48) were evaluated for antiproliferative activity against eight human tumor cell lines, including chemosensitive and multidrug-resistant (MDR) cell lines. The results suggested tumor type-selectivity. 1-[7-(3,4,5-Trimethoxyphenyl)heptanoyl]piperidine (46) exhibited the best inhibitory activity (IC50=4.94 μM) against the P-glycoprotein (P-gp)-overexpressing KBvin MDR sub-line, while it and all other tested compounds, except 9, were inactive (IC50 >40 μM) against MDA-MB-231 and SK-BR-3. Structure-activity relationships (SARs) indicated that (i) 3,4,5-trimethoxy phenyl substitution is critical for selectivity against KBvin, (ii) the 4-methoxy group in this pattern is crucial for antiproliferative activity, (iii) double bonds in the side chain are not needed for activity, and (iv), in arylalkenylacyl amide alkaloids, replacement of an isobutylamino group with pyrrolidin-1-yl or piperidin-1-yl significantly improved activity. Further study on Piper amides is warranted, particularly whether side chain length affects the ability to overcome the MDR cancer phenotype.

  1. GC/MS analysis of piperidinocyclohexanecarbonitrile (PCC) smoking products

    Energy Technology Data Exchange (ETDEWEB)

    Lue, L.P.; Scimeca, J.A.; Thomas, B.F.; Martin, B.R.

    1986-03-05

    Piperidinocyclohexanecarbonitrile (PCC), an intermediate in phencyclidine (PCP) synthesis, is a major contaminant of illicit PCP. Due to the frequent abuse of PCP by smoking, this study was conducted to determine the PCC pyrolysis products delivered in smoke. Marihuana placebo cigarettes were impregnated with /sup 3/H-piperidino-/sup 14/C-cyano-PCC (synthesized in the lab and recrystallized twice, m.p. 67/sup 0/C) and burned under conditions which simulated smoking. Mainstream smoke was passed through glass wool filters and H/sub 2/SO/sub 4/ and NaOH traps. Tritium and /sup 14/C were recovered as 83%, and 56%, respectively, of the starting material. Seventy-six percent of the recovered tritium was found in the glass wool trap followed by 13, 7 and 4% in the acid trap, base trap and in the ash/unburned butt, respectively. Seventy-three percent of the recovered /sup 14/C was found in the glass wool filter and 16 and 8% were found in the acid and base traps, respectively. GC/MS analysis revealed the presence of 1-piperidinocyclohexene (30%), PCC (24%), piperidine (7%), and 1-acetyl-piperidine (5%).

  2. Microwave Spectroscopy of Alkaloids: the Conformational Shapes of Nicotine

    Science.gov (United States)

    Grabow, Jens-Uwe; Mata, S.; López, J. C.; Peńa, I.; Cabezas, C.; Blanco, S.; Alonso, J. L.

    2010-06-01

    Nicotinoid alkaloids consist of two ring systems connected via a C-C σ-bond: Joining pyridine either with a (substituted) pyrrolidine or piperidine ring system, pyrrolidinic or piperidinic nicotinoids are formed. Nicotine itself, consisting of pyridine and N-methylpyrrolidine, is the prototype pyrrolidinic nicotinoid. Its coupled heteoaromatic and heteroaliphatic ring systems exhibit three sites that allow for conformational flexibility: (I) puckering of the pyrrolidine ring (Eq./Ax. positions of the pyridine), (II) inversion of the N-methyl group (Eq./Ax. positions of the hydrogen), and (III) relative orientation of the two rings (Syn-Anti). Two conformations of nicotine have been observed using the In-phase/quadrature-phase-Modulation Passage-Acquired-Coherence Technique (IMPACT) Fourier Transform Microwave (FTMW) spectrometer in Valladolid. The preferred conformations are characterized by an equatorial (Eq.) pyridine moiety and equatorial (Eq.) N-CH_3 stereochemistry. The planes of two rings are almost perpendicular with respect to each other while exhibiting two low energy conformations, Syn and Anti, that differ by a 180° rotation about the C-C σ-bond. The Eq.-Eq. conformational preference is likely due to a weak hydrogen bond interaction between the nitrogen lone pair at the N-methylpyrroline and the closest hydrogen in pyridine. Supporting quantum-chemical calculations are also provided. Lavrich, R. J.; Suenram, R. D.; Plusquellic, D. F.; Davis, S. 58th International Symposium on Molecular Spectroscopy, Columbus, OH 2003, RH13.

  3. A case of levocetirizine-induced fixed drug eruption and cross-reaction with piperazine derivatives

    Science.gov (United States)

    Kim, Mi-Yeong; Jo, Eun-Jung; Chang, Yoon-Seok; Cho, Sang-Heon; Min, Kyung-Up

    2013-01-01

    Fixed drug eruption is an uncommon adverse drug reaction caused by delayed cell-mediated hypersensitivity. Levocetirizine is an active (R)-enatiomer of cetirizine and there have been a few reports of fixed drug eruption related to these antihistamines. We experienced a case of levocetirizine-induced fixed drug eruption and cross-reaction with other piperazine derivatives confirmed by patch test. A 73-year-old female patient presented with recurrent generalized itching, cutaneous bullae formation, rash and multiple pigmentation at fixed sites after taking drugs for common cold. She took bepotastine besilate (Talion®) and levocetirizine (Xyzal®) as antihistamine. She took acetaminophen, pseudoephedrine 60 mg / triprolidine 2.5 mg (Actifed®), dihydrocodeinebitartrate 5 mg / di-methylephedrine hydrochloride 17.5 mg / chlorpheniramine maleate 1.5 mg / guaifenesin 50 mg (Codening®) and aluminium hydroxide 200 mg / magnesium carbonate 120 mg (Antad®) at the same time. Patch test was done with suspected drugs and the result was positive with levocetirizine. We additionally performed patch test for other antihistamines such as cetirizine, hydroxyzine, fexofenadine and loratadine. Piperazine derivatives (cetirizine and hydroxyzine) were positive, but piperidine derivatives (fexofenadine and loratadine) were negative to patch test. There was no adverse drug reaction when she was challenged with fexofenadine. We report a case of levocetirizine-induced fixed drug eruption confirmed by patch test. Cross-reactions were only observed in the piperazine derivatives and piperidine antihistamine was tolerant to the patient. PMID:24260733

  4. High morpholine degradation rates and formation of cytochrome P450 during growth on different cyclic amines by newly isolated Mycobacterium sp. strain HE5.

    Science.gov (United States)

    Schräder, T; Schuffenhauer, G; Sielaff, B; Andreesen, J R

    2000-05-01

    Using morpholine as sole source of carbon, nitrogen and energy, strain HE5 (DSM 44238) was isolated from forest soil. The isolated strain was identified as a member of the subgroup of fast-growing Mycobacterium species as revealed by 16S rDNA analysis. An identity of 99.4% was obtained to Mycobacterium gilvum; however, the type strain was unable to utilize morpholine. A maximal growth rate of 0.17 h(-1) was observed at a morpholine concentration of 30 mM, 30 degrees C and pH 7.2. The substrate was tolerated at concentrations up to 100 mM. Besides morpholine, the strain utilized pyrrolidine, piperidine and proposed intermediates in morpholine metabolism such as glycolate, glyoxylate and ethanolamine. Degradation of morpholine, piperidine and pyrrolidine by resting or permeabilized cells was strictly dependent on the presence of oxygen. Addition of the cytochrome-P450-specific inhibitor metyrapone to the growth medium resulted in a significantly decreased growth rate if these cyclic amines were used as a substrate. Carbon monoxide difference spectra of crude extracts from cells grown on these substrates compared to spectra obtained for extracts of succinate-grown cells indicated that cytochrome P450 is specifically expressed during growth on the cyclic amines. These data indicated that a cytochrome-P450-dependent monooxygenase is involved in the degradation of the three cyclic amines.

  5. Geometry and bond-length alternation in nonlinear optical materials. II. Effects of donor strength in two push-pull molecules.

    Science.gov (United States)

    Gainsford, Graeme J; Bhuiyan, M Delower H; Kay, Andrew J

    2008-04-01

    The compounds N-[2-(4-cyano-5-dicyanomethylene-2,2-dimethyl-2,5-dihydrofuran-3-yl)vinyl]-N-phenylacetamide, C(20)H(16)N(4)O(2), (I), and 2-{3-cyano-5,5-dimethyl-4-[2-(piperidin-1-yl)vinyl]-2,5-dihydrofuran-2-ylidene}malononitrile 0.376-hydrate, C(17)H(18)N(4)O x 0.376 H(2)O, (II), are novel push-pull molecules. The significant bonding changes in the polyene chain compared with the parent molecule 2-dicyanomethylene-4,5,5-trimethyl-2,5-dihyrofuran-3-carbonitrile are consistent with the relative electron-donating properties of the acetanilido and piperidine groups. The packing of (I) utilizes one phenyl-cyano C-H...N and two phenyl-carbonyl C-H...O hydrogen bonds. Compound (II) crystallizes with a partial water molecule (0.376H(2)O), consistent with cell packing that is dominated by attractive C-H...N(cyano) interactions. These compounds are precursors to novel nonlinear optical chromophores, studied to assess the impact of donor strength and the extent of conjugation on bond-length alternation, crystal packing and aggregation.

  6. Profiling two indole-2-carboxamides for allosteric modulation of the CB1 receptor.

    Science.gov (United States)

    Ahn, Kwang H; Mahmoud, Mariam M; Samala, Sushma; Lu, Dai; Kendall, Debra A

    2013-03-01

    Allosteric modulation of G-protein coupled receptors (GPCRs) represents a novel approach for fine-tuning GPCR functions. The cannabinoid CB1 receptor, a GPCR associated with the CNS, has been implicated in the treatment of drug addiction, pain, and appetite disorders. We report here the synthesis and pharmacological characterization of two indole-2-carboxamides:5-chloro-3-ethyl-1-methyl-N-(4-(piperidin-1-yl)phenethyl)-1H-indole-2-carboxamide (ICAM-a) and 5-chloro-3-pentyl-N-(4-(piperidin-1-yl)phenethyl)-1H-indole-2-carboxamide (ICAM-b). Although both ICAM-a and ICAM-b enhanced CP55, 940 binding, ICAM-b exhibited the strongest positive cooperativity thus far demonstrated for enhancing agonist binding to the CB1 receptor. Although it displayed negative modulatory effects on G-protein coupling to CB1, ICAM-b induced β-arrestin-mediated downstream activation of extracellular signal-regulated kinase (ERK) signaling. These results indicate that this compound represents a novel class of CB1 ligands that produce biased signaling via CB1.

  7. A novel UV degradation product of Ebastine: isolation and characterization using Q-TOF, NMR, IR and computational chemistry.

    Science.gov (United States)

    Rapolu, Ravi; Pandey, Avadhesh Kumar; Raju, Ch Krishnam; Ghosh, Kaushik; Srinivas, Kolupula; Awasthi, Atul; Navalgund, Sameer G; Surendranath, Koduru V

    2015-03-25

    Forced degradation of Ebastine (1-(4-(1,1-dimethylethyl)phenyl)-4-(4-(diphenylmethoxy) piperidin-1-yl)butan-1-one) drug substance in ultraviolet light condition resulted into an unknown significant degradation product. This degradation product was analyzed using a newly developed reverse-phase HPLC, where it was eluted at 2.73 relative retention time to Ebastine peak. UV degradation product was isolated from reaction mass using preparative HPLC and its structure was elucidated using high resolution MS, multidimensional NMR and FTIR spectroscopic techniques. UV degradation product has been characterized as 2-(4-(benzhydryloxy)piperidin-1-yl)-1-(4-(tert-butyl)phenyl)-2-methylcyclopropanol. (1)H and (13)C NMR chemical shift values were generated using computational chemistry for possible two diastereomers (7R10S and 7R10R) and later 7R10R was confirmed (and its enantiomer) as final structure given it showed close agreement with experimental NMR data. Formation of UV degradation product as a recemic mixture was further verified by computational chemistry evaluation, chiral HPLC and polarimetery. To best of our knowledge, this is a novel degradation product which is not discussed at any form of publication yet.

  8. Identification and quantification of phencyclidine pyrolysis products formed during smoking

    Energy Technology Data Exchange (ETDEWEB)

    Lue, L.P.; Scimeca, J.A.; Thomas, B.F.; Martin, B.R.

    As a result of frequent phencyclidine (PCP) abuse, pyrolysis studies were conducted to further investigate its fate during smoking. Marijuana placebo cigarettes were impregnated with /sup 3/H-PCP HCl and burned under conditions simulating smoking. Mainstream smoke was passed through glass wool filters as well as acidic and basic traps. Approximately 90% of the starting material could be accounted for in the first glass wool trap and cigarette holder. HPLC and GC/MS analysis of methanol extracts of these glass wool traps revealed the presence of 1-phenyl-1-cyclohexene (47% of the starting material) > PCP (40%) > piperidine (15%) > N-acetylpiperidine (9%). It was not possible to fully account for the remainder of the piperidine moiety. It has been reported that at high temperatures PCP is converted to numerous polynuclear aromatic compounds which include styrene, ..cap alpha..-methylstyrene, naphthalene, 2-methyl-naphthalene, 1-methylnaphthalene, biphenyl, cyclohexylbenzene, acenaphthene, phenanthrene, and anthracene. These compounds were not formed from PCP under smoking conditions.

  9. The ketamine analogue methoxetamine and 3- and 4-methoxy analogues of phencyclidine are high affinity and selective ligands for the glutamate NMDA receptor.

    Directory of Open Access Journals (Sweden)

    Bryan L Roth

    Full Text Available In this paper we determined the pharmacological profiles of novel ketamine and phencyclidine analogues currently used as 'designer drugs' and compared them to the parent substances via the resources of the National Institute of Mental Health Psychoactive Drug Screening Program. The ketamine analogues methoxetamine ((RS-2-(ethylamino-2-(3-methoxyphenylcyclohexanone and 3-MeO-PCE (N-ethyl-1-(3-methoxyphenylcyclohexanamine and the 3- and 4-methoxy analogues of phencyclidine, (1-[1-(3-methoxyphenylcyclohexyl]piperidine and 1-[1-(4-methoxyphenylcyclohexyl]piperidine, were all high affinity ligands for the PCP-site on the glutamate NMDA receptor. In addition methoxetamine and PCP and its analogues displayed appreciable affinities for the serotonin transporter, whilst the PCP analogues exhibited high affinities for sigma receptors. Antagonism of the NMDA receptor is thought to be the key pharmacological feature underlying the actions of dissociative anaesthetics. The novel ketamine and PCP analogues had significant affinities for the NMDA receptor in radioligand binding assays, which may explain their psychotomimetic effects in human users. Additional actions on other targets could be important for delineating side-effects.

  10. Modeling anti-HIV compounds: the role of analogue-based approaches.

    Science.gov (United States)

    Srivastava, Hemant Kumar; Bohari, Mohammed H; Sastry, G Narahari

    2012-09-01

    There has been a tremendous progress in the development of anti-HIV therapies since the discovery of the HIV virus. Computer aided drug design in general and analogue-based approaches in particular have played an important role in the process of HIV drug discovery. Structure-based approaches also have played a vital role in this process. There are a large number of studies reported in the literature where QSAR methodology was employed to study the structural requirements for inhibition against various HIV targets like reverse transcriptase, protease, entry and integrase. The current review focuses on those studies and provides a detailed description on the QSAR methodology, descriptors, statistical significance and important findings. This review categorizes the reported QSAR studies on the basis of chemical scaffolds against a particular target. In reverse transcriptase category, QSAR studies on HEPT, TIBO, DABO, DAPY, DATA, AASBN, pyridone and DATZD derivatives have been reviewed. Cyclic urea, fullerene, AHPBA and dihydropyrone derivatives were considered in protease inhibitors category. In addition, QSAR studies on styrylquinoline, carboxylic acid, MBSA and chalcone derivatives were reviewed in integrase inhibitors category. QSAR studies on entry inhibitors like piperidine, benzyl piperidine, benzyl pyrazole, pyrrole and diazepane urea have also been reviewed.

  11. Cis-2,6-bis(2-klorofenil-3,3-dimetilpiperidin-4-one bileşiği üzerine yapısal, spektroskopik, elektronik ve doğrusal olmayan optiksel araştırmalar

    Directory of Open Access Journals (Sweden)

    Ömer Tamer

    2016-12-01

    Full Text Available Piperidin, heterosiklik moleküller arasında en iyi bilinen yapılardan biridir. Güncel çalışmalar bu tür bileşiklerin yapı-doğrusal olmayan optiksel performans ilişkisine odaklanmaktadır. Doğrusal olmayan optik malzemelerin fiber optik iletişim ve optik sinyal işlemlerinde hayati öneme sahip oldukları bilinmektedir. Bu çalışmada, bir piperidin türevi olan cis-2,6-bis(2-klorofenil-3,3-dimetilpiperidin-4-one (2C3DMPO bileşiğinin yapısal, spektroskopik, elektronik ve doğrusal olmayan optik özellikleri analiz edilmiştir. 2C3DMPO için elde edilen teorik sonuçlar deneysel değerler ile iyi bir uyum içindedirler. NMR spektrumunda, elektronegatif O atomundan dolayı, C4 atomu aşağı alanda sinyal vermiştir. HOMO ve LUMO arasındaki küçük enerji aralığı, bağ ve antibağ yörüngeleri arasındaki yoğun etkileşmeler yüksek doğrusal olmayan optik özelliklerin göstergesidir.

  12. Investigation of the histamine H3 receptor binding site. Design and synthesis of hybrid agonists with a lipophilic side chain.

    Science.gov (United States)

    Ishikawa, Makoto; Watanabe, Takashi; Kudo, Toshiaki; Yokoyama, Fumikazu; Yamauchi, Miki; Kato, Kazuhiko; Kakui, Nobukazu; Sato, Yasuo

    2010-09-09

    As a part of our search for novel histamine H3 receptor agonists, we designed and synthesized hybrid compounds in which the lipophilic (4'-alkylphenylthio)ethyl moiety of a novel H3 receptor agonist, 4-(2-(4'-tert-butylphenylthio)ethyl)-1H-imidazole (1), was incorporated into N(alpha)-methylhistamine, immepip, and immethridine derivatives. These hybrid compounds were expected to interact concurrently with the histamine-binding site and a putative hydrophobic region in the H3 receptor. Among them, piperidine- and pyridine-type derivatives displayed partial agonist activity, and (S)-4-(1-(1H-imidazol-4-yl)-2-(4-(trifluoromethyl)phenylthio)ethyl)piperidine (36) was identified as a potent H3 agonist. We performed computational docking studies to examine the binding mode of the agonists. The results indicated that immepip interacts with the key residues, Asp114 and Glu206, in a different manner from histamine. The binding mode of 36 to these residues is similar to that of immepip, and the lipophilic tail of 36 has an additional interaction with a hydrophobic region in transmembrane helix 6 of the receptor. These results indicated that 36 served as a useful tool for studies on receptor-agonist interactions and drug design.

  13. Alkaloid venom weaponry of three Megalomyrmex thief ants and the behavioral response of Cyphomyrmex costatus host ants.

    Science.gov (United States)

    Adams, Rachelle M M; Jones, Tappey H; Longino, John T; Weatherford, Robert G; Mueller, Ulrich G

    2015-04-01

    Social parasites exploit other societies by invading and stealing resources. Some enter protected nests using offensive chemical weaponry made from alkaloid-based venom. We characterized the venoms of three Megalomyrmex thief ant species (M. mondabora, M. mondaboroides, and M. silvestrii) that parasitize the fungus-growing ants, and developed an ethogram to describe host ant reactions to raiding M. mondaboroides and M. silvestrii parasites. We compared piperidine, pyrrolidine, and pyrolizidine venom alkaloid structures with synthetic samples from previous studies, and describe the novel stereochemistry of trans 2-hexyl-5-[8-oxononyl]-pyrrolidine (3) from M. mondabora. We showed that workers of Cyphomyrmex costatus, the host of M. mondaboroides and M. silvestrii, react to a sting by Megalomyrmex parasites mainly with submissive behavior, playing dead or retreating. Host submission also followed brief antennal contact. The behavior of C. costatus ants observed in this study was similar to that of Cyphomyrmex cornutus, host of M. mondabora, suggesting that the alkaloidal venoms with pyrrolidines from M. mondabora, piperidines from M. mondaboroides, and pyrolizidines from M. silvestrii may function similarly as appeasement and repellent allomones against host ants, despite their different chemical structure. With the use of these chemical weapons, the Megalomyrmex thief ants are met with little host resistance and easily exploit host colony resources.

  14. A rapid and robust assay for the determination of the amino acid hypusine as a possible biomarker for a high-throughput screening of antimalarials and for the diagnosis and therapy of different diseases.

    Science.gov (United States)

    Kaiser, Annette; Khomutov, Alex R; Simonian, Alina; Agostinelli, Enzo

    2012-05-01

    Eukaryotic initiation factor 5A (eIF5A) has recently been identified as a biomarker of prognostic significance and therapeutic potential for the treatment in hepatocellular carcinoma. This prompted us to establish a rapid and robust assay to determine deoxyhypusine and hypusine formed with the purified enzymes deoxyhypusine synthase (DHS) and deoxyhypusine hydroxylase (DOHH) from Plasmodium to develop a rapid screening assay for antimalarial drugs. The peptide hydrolysate obtained from hypusinylated eIF5A was analyzed by ultra performance liquid chromatography (UPLC) with retention times for deoxyhypusine of 7.44 min and for hypusine of 7.30 min, respectively. The limit of detection for both compounds was 0.144 ng/μl. Determination of the specific activity of Plasmodium DOHH resulted in a twofold higher specific activity than its human counterpart. Following the iron-complexing strategy of the ferrous iron which is present in the active site of Plasmodium DOHH, a series of iron chelating compounds was tested. 2,2'-Dipyridyl and mimosine abolished DOHH activity completely while 4-oxo-piperidine-carboxylates i.e. the nitrophenylether JK8-2 and EHW 437, the oxime ether of the piperidine aldehyde, showed no inhibition although they were highly active in in vitro cultures of Plasmodium and in vivo in a rodent mouse model. The method allows a high-throughput screening (HPTS) of antimalarial drugs and the evaluation of eIF5A as a biomarker.

  15. Reversible and covalent binding of 5-(hydroxymethyl)-2-furaldehyde (HMF) with lysine and selected amino acids.

    Science.gov (United States)

    Nikolov, Plamen Y; Yaylayan, Varoujan A

    2011-06-08

    The chemical reactivity of 5-(hydroxymethyl)-2-furaldehyde (HMF) with lysine, glycine, and proline was studied using isotope labeling technique. To confirm the formation of HMF adducts in glucose amino acid model systems, a useful strategy was developed in which products simultaneously possessing six glucose (HMF moiety) and any number of amino acid carbon atoms in addition to nitrogen were targeted using specifically labeled precursors such as [(15)N(α)]lysine·2HCl, [(15)N(ε)]lysine·2HCl, [U-(13)C(6)]lysine·2HCl, [(13)C(6)]lysine·2HCl, and [U-(13)C(6)]glucose in the case of lysine model system. In addition, model systems containing HMF and amino acids were also studied to confirm specific adduct formation. Complete labeling studies along with structural analysis using appropriate synthetic precursors such as HMF Schiff base adducts of piperidine and glycine have indicated that HMF generated in the glucose/amino acid model systems initially forms a Schiff base adduct that can undergo decarboxylation through an oxazolidin-5-one intermediate and form two isomeric decarboxylated Schiff bases. Unlike the Schiff bases resulting from primary amines or amino acids such as glycine or lysine, those resulting from secondary amino acids such as proline or secondary amines such as piperidine can further undergo vinylogous Amadori rearrangement, forming N-substituted 5-(aminomethyl)furan-2-carbaldehyde derivatives.

  16. Substituent Effects on Cytotoxic Activity, Spectroscopic Property, and DNA Binding Property of Naphthalimide Derivatives.

    Science.gov (United States)

    Wang, Ke-Rang; Qian, Feng; Sun, Qian; Ma, Cui-Lan; Rong, Rui-Xue; Cao, Zhi-Ran; Wang, Xiao-Man; Li, Xiao-Liu

    2016-05-01

    A series of novel naphthalimide derivatives NI1-5 containing piperazine moieties (N-(2-hydroxyethyl)piperazine and 1-piperazinepropanol) and piperidine moieties (4-piperidinemethanol, 4-hydroxypiperidine and 4-piperidineethanol) have been synthesized and evaluated for their cytotoxic activity, spectroscopic property, and DNA binding behaviors. It was found that substituents at the 4-position remarkably influence the various activities of this series of compound. Compounds NI3-5 modified with piperidines exhibited potent cytotoxic activities against Hela, SGC-7901, and A549 cells with the IC50 values from 0.73 μm to 6.80 μm, which are better than NI1-2 functionalized with piperazines. Compounds NI1-2 showed higher binding capacity with Ct-DNA than compounds NI3-5 based on studies of UV-vis, fluorescence and CD spectra. Furthermore, compounds NI3-5, as DNA intercalators, showed fluorescence enhancement upon binding with Ct-DNA. More interestingly, fluorescence imaging studies of compound NI4 with A549 cells showed that the fluorescence predominantly appeared in the cytoplasm. These results provided a potential application of NI3-5 as anticancer therapeutic and cancer cell imaging agents.

  17. Synthesis and non linear optical properties of new inorganic-organic hybrid material: 4-Benzylpiperidinium sulfate monohydrate

    Science.gov (United States)

    Kessentini, Yassmin; Ahmed, Ali Ben; Al-Juaid, Salih S.; Mhiri, Tahar; Elaoud, Zakaria

    2016-03-01

    Single crystals of 4-benzyl-piperidine sulfate monohydrate were grown by slow evaporation method at room temperature. The synthesized compound was characterized by means of single-crystal X-ray diffraction, FT-IR and Raman spectroscopy, UV-visible and photoluminescence studies. The title compound crystallises at room temperature in the non centrosymmetric space group P212121.The recorded UV-visible spectrum show good transparency in the visible region and indicates a non-zero value of the first Hyperpolarizability. Photoluminescence spectrum shows a broad and intense band at 440 nm and indicates that the crystal emits blue fluorescence. We also report DFT calculations of the electric dipole moments (μ), Polarizability (α), the static first Hyperpolarizability (β) and HOMO-LUMO analysis of the title compound was theoretically investigated by GAUSSIAN 03 package. The calculated static first Hyperpolarizability is equal to 6.4022 × 10-31 esu. The results show that 4-benzyl-piperidine sulfate monohydrate crystal might have important non linear optical behavior and can be a potential non linear optical material of interest.

  18. The effect of heterocyclic S,S’-ligands on the electrochemical properties of some cobalt(III complexes in acid

    Directory of Open Access Journals (Sweden)

    V. M. JOVANOVIC

    2005-02-01

    Full Text Available Eight mixed-ligand cobalt(III complexes with the macrocyclic amine 1,4,8,11-tetraazacyclotetradecane (cyclam and a heterocyclic dithiocarbamate (Rdtc- i.e., morpholine- (Morphdtc, thiomorpholine- (Timdtc, piperazine- (Pzdtc, N-methylpiperazine-(Mepzdtc, piperidine- (Pipdtc, 2-, 3- or 4-methylpiperidine- (2-, 3- and 4-Mepipdtc carbodithionato-S,S ions, of the general formula [Co(cyclamRdtc](ClO42, were investigated in deoxygenated 0.1MHClO4 solutions. Cyclic voltammetry data at a glassy carbon (GC electrode demonstrate a redox reaction of cobalt(III from the complexes at potentials strongly influenced by the presence of different heterocyclic Rdtc- ligands. In this respect, the complexes were separated into two groups: the first, with a heteroatom O, S or N in the heterocyclic ring, and the second, with a methyl group on the piperidine ring of the Rdtc- ligand. Anodic polarization of an Fe electrode in the presence of the complexes shows their influence not only on the dissolution of iron but also on the hydrogen evolution reactions and on this basis complexes the complexes could be divided into the same two groups. It was found that the weaker the inhibiting effect of the free heterocyclic amines is, the significantly higher is the efficiency of the corresponding complexes.

  19. Synthesis, pharmacological activity and structure affinity relationships of spirocyclic σ(1) receptor ligands with a (2-fluoroethyl) residue in 3-position.

    Science.gov (United States)

    Maestrup, Eva Grosse; Wiese, Christian; Schepmann, Dirk; Brust, Peter; Wünsch, Bernhard

    2011-01-01

    In order to develop a fluorinated radiotracer for imaging of σ(1) receptors in the central nervous system a series of (2-fluoroethyl) substituted spirocyclic piperidines 3 has been prepared. In the key step of the synthesis 2-bromocinnamaldehyde acetal 5 was added to piperidones 6 with various substituents at the N-atom. Unexpectedly, this reaction led to 2-benzoxepines 8, which were contracted with acid to afford the spirocyclic 2-benzofuranacetaldehydes 9. The best yields were obtained, when the transformations up to the alcohols 10 were performed without isolation of intermediates. Generally the (2-fluoroethyl) derivatives 3 have higher σ(1) affinity and σ(1)/σ(2) selectivity than the corresponding (3-fluoropropyl) derivatives 2. The most promising candidate for the development as radiotracer is the (2-fluoroethyl) derivative 3a (WMS-1828, fluspidine, 1'-benzyl-3-(2-fluoroethyl)-3H-spiro[[2]benzofuran-1,4'-piperidine]), which shows subnanomolar σ(1) affinity (K(i)=0.59nM) and excellent selectivity over the σ(2) subtype (1331-fold) as well as some other receptor systems. The novel synthetic strategy also allows the systematic pharmacological evaluation of intermediate alcohols 10. Despite their high σ(1) affinity (K(i)=6-32nM) and selectivity the alcohols 10 are 10-30-fold less potent than the bioisosteric fluoro derivatives 3. Copyright © 2010. Published by Elsevier Ltd.

  20. A novel urotensin II receptor antagonist, KR-36996, improved cardiac function and attenuated cardiac hypertrophy in experimental heart failure.

    Science.gov (United States)

    Oh, Kwang-Seok; Lee, Jeong Hyun; Yi, Kyu Yang; Lim, Chae Jo; Park, Byung Kil; Seo, Ho Won; Lee, Byung Ho

    2017-03-15

    Urotensin II and its receptor are thought to be involved in various cardiovascular diseases such as heart failure, pulmonary hypertension and atherosclerosis. Since the regulation of the urotensin II/urotensin II receptor offers a great potential for therapeutic strategies related to the treatment of cardiovascular diseases, the study of selective and potent antagonists for urotensin II receptor is more fascinating. This study was designed to determine the potential therapeutic effects of a newly developed novel urotensin II receptor antagonist, N-(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)benzo[b]thiophene-3-carboxamide (KR-36996), in experimental models of heart failure. KR-36996 displayed a high binding affinity (Ki=4.44±0.67nM) and selectivity for urotensin II receptor. In cell-based study, KR-36996 significantly inhibited urotensin II-induced stress fiber formation and cellular hypertrophy in H9c2UT cells. In transverse aortic constriction-induced cardiac hypertrophy model in mice, the daily oral administration of KR-36996 (30mg/kg) for 14 days significantly decreased left ventricular weight by 40% (Preceptor antagonist could efficiently attenuate both cardiac hypertrophy and dysfunction in experimental heart failure. KR-36996 may be useful as an effective urotensin II receptor antagonist for pharmaceutical or clinical applications.

  1. Structural and sensory characterization of key pungent and tingling compounds from black pepper (Piper nigrum L.).

    Science.gov (United States)

    Dawid, Corinna; Henze, Andrea; Frank, Oliver; Glabasnia, Anneke; Rupp, Mathias; Büning, Kirsten; Orlikowski, Diana; Bader, Matthias; Hofmann, Thomas

    2012-03-21

    To gain a more comprehensive knowledge on whether, besides the well-known piperine, other compounds are responsible for the pungent and tingling oral impression imparted by black pepper, an ethanol extract prepared from black pepper (Piper nigrum L.) was screened for its key sensory-active nonvolatiles by application of taste dilution analysis (TDA). Purification of the compounds perceived with the highest sensory impact, followed by LC-MS and 1D/2D NMR experiments as well as synthesis, led to the structure determination of 25 key pungent and tingling phytochemicals, among which the eight amides 1-(octadeca-2E,4E,13Z-trienyl)piperidine, 1-(octadeca-2E,4E,13Z-trienyl)pyrrolidine, (2E,4E,13Z)-N-isobutyl-octadeca-2,4,13-trienamide, 1-(octadeca-2E,4E,12Z-trienoyl)-pyrrolidine, 1-(eicosa-2E,4E,15Z-trienyl)piperidine, 1-(eicosa-2E,4E,15Z-trienyl)pyrrolidine, (2E,4E,15Z)-N-isobutyl-eicosa-2,4,15-trienamide, and 1-(eicosa-2E,4E,14Z-trienoyl)-pyrrolidine were not yet reported in literature. Sensory studies by means of a modified half-tongue test revealed recognition thresholds ranging from 3.0 to 1150.2 nmol/cm² for pungency and from 520.6 to 2162.1 nmol/cm² for the tingling orosensation depending on their chemical structure.

  2. Structural and medium effects on the reactions of the cumyloxyl radical with intramolecular hydrogen bonded phenols. The interplay between hydrogen-bonding and acid-base interactions on the hydrogen atom transfer reactivity and selectivity.

    Science.gov (United States)

    Salamone, Michela; Amorati, Riccardo; Menichetti, Stefano; Viglianisi, Caterina; Bietti, Massimo

    2014-07-03

    A time-resolved kinetic study on the reactions of the cumyloxyl radical (CumO(•)) with intramolecularly hydrogen bonded 2-(1-piperidinylmethyl)phenol (1) and 4-methoxy-2-(1-piperidinylmethyl)phenol (2) and with 4-methoxy-3-(1-piperidinylmethyl)phenol (3) has been carried out. In acetonitrile, intramolecular hydrogen bonding protects the phenolic O-H of 1 and 2 from attack by CumO(•) and hydrogen atom transfer (HAT) exclusively occurs from the C-H bonds that are α to the piperidine nitrogen (α-C-H bonds). With 3 HAT from both the phenolic O-H and the α-C-H bonds is observed. In the presence of TFA or Mg(ClO4)2, protonation or Mg(2+) complexation of the piperidine nitrogen removes the intramolecular hydrogen bond in 1 and 2 and strongly deactivates the α-C-H bonds of the three substrates. Under these conditions, HAT to CumO(•) exclusively occurs from the phenolic O-H group of 1-3. These results clearly show that in these systems the interplay between intramolecular hydrogen bonding and Brønsted and Lewis acid-base interactions can drastically influence both the HAT reactivity and selectivity. The possible implications of these findings are discussed in the framework of the important role played by tyrosyl radicals in biological systems.

  3. Phenyl ring-substituted lobelane analogs: inhibition of [³H]dopamine uptake at the vesicular monoamine transporter-2.

    Science.gov (United States)

    Nickell, Justin R; Zheng, Guangrong; Deaciuc, Agripina G; Crooks, Peter A; Dwoskin, Linda P

    2011-03-01

    Lobeline attenuates the behavioral effects of methamphetamine via inhibition of the vesicular monoamine transporter (VMAT2). To increase selectivity for VMAT2, chemically defunctionalized lobeline analogs, including lobelane, were designed to eliminate nicotinic acetylcholine receptor affinity. The current study evaluated the ability of lobelane analogs to inhibit [³H]dihydrotetrabenazine (DTBZ) binding to VMAT2 and [³H]dopamine (DA) uptake into isolated synaptic vesicles and determined the mechanism of inhibition. Introduction of aromatic substituents in lobelane maintained analog affinity for the [³H]DTBZ binding site on VMAT2 and inhibitory potency in the [³H]DA uptake assay assessing VMAT2 function. The most potent (K(i) = 13-16 nM) analogs in the series included para-methoxyphenyl nor-lobelane (GZ-252B), para-methoxyphenyl lobelane (GZ-252C), and 2,4-dichlorphenyl lobelane (GZ-260C). Affinity of the analogs for the [³H]DTBZ binding site did not correlate with inhibitory potency in the [³H]DA uptake assay. It is noteworthy that the N-benzylindole-, biphenyl-, and indole-bearing meso-analogs 2,6-bis[2-(1-benzyl-1H-indole-3-yl)ethyl]-1-methylpiperidine hemifumarate (AV-1-292C), 2,6-bis(2-(biphenyl-4-yl)ethyl)piperidine hydrochloride (GZ-272B), and 2,6-bis[2-(1H-indole-3-yl)ethyl]-1-methylpiperidine monofumarate (AV-1-294), respectively] inhibited VMAT2 function (K(i) = 73, 127, and 2130 nM, respectively), yet had little to no affinity for the [³H]DTBZ binding site. These results suggest that the analogs interact at an alternate site to DTBZ on VMAT2. Kinetic analyses of [³H]DA uptake revealed a competitive mechanism for 2,6-bis(2-(4-methoxyphenyl)ethyl)piperidine hydrochloride (GZ-252B), 2,6-bis(2-(4-methoxyphenyl)ethyl)-1-methylpiperidine hydrochloride (GZ-252C), 2,6-bis(2-(2,4-dichlorophenyl)ethyl)piperidine hydrochloride (GZ-260C), and GZ-272B. Similar to methamphetamine, these analogs released [³H]DA from the vesicles, but with higher potency. In

  4. Phenyl Ring-Substituted Lobelane Analogs: Inhibition of [3H]Dopamine Uptake at the Vesicular Monoamine Transporter-2

    Science.gov (United States)

    Nickell, Justin R.; Zheng, Guangrong; Deaciuc, Agripina G.; Crooks, Peter A.

    2011-01-01

    Lobeline attenuates the behavioral effects of methamphetamine via inhibition of the vesicular monoamine transporter (VMAT2). To increase selectivity for VMAT2, chemically defunctionalized lobeline analogs, including lobelane, were designed to eliminate nicotinic acetylcholine receptor affinity. The current study evaluated the ability of lobelane analogs to inhibit [3H]dihydrotetrabenazine (DTBZ) binding to VMAT2 and [3H]dopamine (DA) uptake into isolated synaptic vesicles and determined the mechanism of inhibition. Introduction of aromatic substituents in lobelane maintained analog affinity for the [3H]DTBZ binding site on VMAT2 and inhibitory potency in the [3H]DA uptake assay assessing VMAT2 function. The most potent (Ki = 13–16 nM) analogs in the series included para-methoxyphenyl nor-lobelane (GZ-252B), para-methoxyphenyl lobelane (GZ-252C), and 2,4-dichlorphenyl lobelane (GZ-260C). Affinity of the analogs for the [3H]DTBZ binding site did not correlate with inhibitory potency in the [3H]DA uptake assay. It is noteworthy that the N-benzylindole-, biphenyl-, and indole-bearing meso-analogs 2,6-bis[2-(1-benzyl-1H-indole-3-yl)ethyl]-1-methylpiperidine hemifumarate (AV-1-292C), 2,6-bis(2-(biphenyl-4-yl)ethyl)piperidine hydrochloride (GZ-272B), and 2,6-bis[2-(1H-indole-3-yl)ethyl]-1-methylpiperidine monofumarate (AV-1-294), respectively] inhibited VMAT2 function (Ki = 73, 127, and 2130 nM, respectively), yet had little to no affinity for the [3H]DTBZ binding site. These results suggest that the analogs interact at an alternate site to DTBZ on VMAT2. Kinetic analyses of [3H]DA uptake revealed a competitive mechanism for 2,6-bis(2-(4-methoxyphenyl)ethyl)piperidine hydrochloride (GZ-252B), 2,6-bis(2-(4-methoxyphenyl)ethyl)-1-methylpiperidine hydrochloride (GZ-252C), 2,6-bis(2-(2,4-dichlorophenyl)ethyl)piperidine hydrochloride (GZ-260C), and GZ-272B. Similar to methamphetamine, these analogs released [3H]DA from the vesicles, but with higher potency. In contrast to

  5. Library screening by means of mass spectrometry (MS) binding assays-exemplarily demonstrated for a pseudostatic library addressing γ-aminobutyric acid (GABA) transporter 1 (GAT1).

    Science.gov (United States)

    Sindelar, Miriam; Wanner, Klaus T

    2012-09-01

    In the present study, the application of mass spectrometry (MS) binding assays as a tool for library screening is reported. For library generation, dynamic combinatorial chemistry (DCC) was used. These libraries can be screened by means of MS binding assays when appropriate measures are taken to render the libraries pseudostatic. That way, the efficiency of MS binding assays to determine ligand binding in compound screening with the ease of library generation by DCC is combined. The feasibility of this approach is shown for γ-aminobutyric acid (GABA) transporter 1 (GAT1) as a target, representing the most important subtype of the GABA transporters. For the screening, hydrazone libraries were employed that were generated in the presence of the target by reacting various sets of aldehydes with a hydrazine derivative that is delineated from piperidine-3-carboxylic acid (nipecotic acid), a common fragment of known GAT1 inhibitors. To ensure that the library generated is pseudostatic, a large excess of the nipecotic acid derivative is employed. As the library is generated in a buffer system suitable for binding and the target is already present, the mixtures can be directly analyzed by MS binding assays-the process of library generation and screening thus becoming simple to perform. The binding affinities of the hits identified by deconvolution were confirmed in conventional competitive MS binding assays performed with single compounds obtained by separate synthesis. In this way, two nipecotic acid derivatives exhibiting a biaryl moiety, 1-{2-[2'-(1,1'-biphenyl-2-ylmethylidene)hydrazine]ethyl}piperidine-3-carboxylic acid and 1-(2-{2'-[1-(2-thiophenylphenyl)methylidene]hydrazine}ethyl)piperidine-3-carboxylic acid, were found to be potent GAT1 ligands exhibiting pK(i) values of 6.186 ± 0.028 and 6.229 ± 0.039, respectively. This method enables screening of libraries, whether generated by conventional chemistry or DCC, and is applicable to all kinds of targets including

  6. Anticonvulsant effects of isomeric nonimidazole histamine H3 receptor antagonists.

    Science.gov (United States)

    Sadek, Bassem; Saad, Ali; Schwed, Johannes Stephan; Weizel, Lilia; Walter, Miriam; Stark, Holger

    2016-01-01

    Phenytoin (PHT), valproic acid, and modern antiepileptic drugs (AEDs), eg, remacemide, loreclezole, and safinamide, are only effective within a maximum of 70%-80% of epileptic patients, and in many cases the clinical use of AEDs is restricted by their side effects. Therefore, a continuous need remains to discover innovative chemical entities for the development of active and safer AEDs. Ligands targeting central histamine H3 receptors (H3Rs) for epilepsy might be a promising therapeutic approach. To determine the potential of H3Rs ligands as new AEDs, we recently reported that no anticonvulsant effects were observed for the (S)-2-(4-(3-(piperidin-1-yl)propoxy)benzylamino)propanamide (1). In continuation of our research, we asked whether anticonvulsant differences in activities will be observed for its R-enantiomer, namely, (R)-2-(4-(3-(piperidin-1-yl)propoxy)benzylamino)propaneamide (2) and analogs thereof, in maximum electroshock (MES)-, pentylenetetrazole (PTZ)-, and strychnine (STR)-induced convulsion models in rats having PHT and valproic acid (VPA) as reference AEDs. Unlike the S-enantiomer (1), the results show that animals pretreated intraperitoneally (ip) with the R-enantiomer 2 (10 mg/kg) were moderately protected in MES and STR induced models, whereas proconvulsant effect was observed for the same ligand in PTZ-induced convulsion models. However, animals pretreated with intraperitoneal doses of 5, 10, or 15 mg/kg of structurally bulkier (R)-enantiomer (3), in which 3-piperidinopropan-1-ol in ligand 2 was replaced by (4-(3-(piperidin-1-yl)propoxy)phenyl)methanol, and its (S)-enantiomer (4) significantly and in a dose-dependent manner reduced convulsions or exhibited full protection in MES and PTZ convulsions model, respectively. Interestingly, the protective effects observed for the (R)-enantiomer (3) in MES model were significantly greater than those of the standard H3R inverse agonist/antagonist pitolisant, comparable with those observed for PHT, and

  7. 组胺H3受体拮抗剂/反向激动剂pitolisant的合成%Synthesis of pitolisant as a histamine H3 receptor antagonist/inverse agonist

    Institute of Scientific and Technical Information of China (English)

    曲畅; 梁闯; 吕英翔; 杨桂秋; 宫平

    2013-01-01

    Pitolisant,discovered by Bioprojet,is an orally bioavailable histamine H3 receptor competitive antagonist and inverse agonist in phase IE clinical studies for the oral treatment of excessive daytime sleepiness in parkinson's disease patients. It will probably be the first histamine H3 receptor antagonist/inverse agonist on sale in the future. According to the synthetic method of pitolisant in patent, its synthetic route was established, and the synthetic process was investigated and optimized thoroughly. Starting from 4-chlorobenzyl chloride and diethyl malonate.the key intermediate 3-(4-chlorophenyl) propyl methanesulfonate was obtained by the steps of condensation, hydrolization, decarbolization, reduction and esterification. Another key intermediate 3-(piperidin-1-yl) propan-1-ol was prepared from methyl 3-chloropropanoate via reduction and condensation. Then 3-(4-chlorophenyl) propyl methanesulfonate was condensated with 3-(piperidin-1-yl) propan-1-ol to give pitolisant and the overall yield was 31.4% (calculated by 4-chlorobenzyl chloride). Its structure and some intermediates were confirmed by 1H-NMR and MS. In this procedure, the yield of intermediate 3-(4-chlorophenyl) propanoic acid,was increased by 15% .intermediate 3-(piperidin-1-yl)propan-1-ol, was obtained in a shortened reaction time by adding a catalytic amount of PEG 400. The improved synthetic process is more convenient for industrial application.%目的 对组胺H3受体拮抗剂/反向激动剂pitolisant进行合成工艺研究.方法 以对氯氯苄、丙二酸二乙酯为起始原料,经过缩合、水解、脱羧、还原、酯化、取代反应制得pitolisant.结果与结论 经过6步反应合成目标化合物pitolisant,其结构经1H-NMR及MS确证.对其中多步反应条件进行了工艺考察及优化,总收率为31.4%(以对氯氯苄计).

  8. The chemistry of escapin: identification and quantification of the components in the complex mixture generated by an L-amino acid oxidase in the defensive secretion of the sea snail Aplysia californica.

    Science.gov (United States)

    Kamio, Michiya; Ko, Ko-Chun; Zheng, Shilong; Wang, Binghe; Collins, Stacy L; Gadda, Giovanni; Tai, Phang C; Derby, Charles D

    2009-01-01

    Escapin is an L-amino acid oxidase in the ink of a marine snail, the sea hare Aplysia californica, which oxidizes L-lysine (1) to produce a mixture of chemicals which is antipredatory and antimicrobial. The goal of our study was to determine the identity and relative abundance of the constituents of this mixture, using molecules generated enzymatically with escapin and also using products of organic syntheses. We examined this mixture under the natural range of pH values for ink-from approximately 5 at full strength to approximately 8 when fully diluted in sea water. The enzymatic reaction likely forms an equilibrium mixture containing the linear form alpha-keto-epsilon-aminocaproic acid (2), the cyclic imine Delta(1)-piperidine-2-carboxylic acid (3), the cyclic enamine Delta(2)-piperidine-2-carboxylic acid (4), possibly the linear enol 6-amino-2-hydroxy-hex-2-enoic acid (7), the alpha-dihydroxy acid 6-amino-2,2-dihydroxy-hexanoic acid (8), and the cyclic aminol 2-hydroxy-piperidine-2-carboxylic acid (9). Using NMR and mass spectroscopy, we show that 3 is the major component of this enzymatic product at any pH, but at more basic conditions, the equilibrium shifts to produce relatively more 4, and at acidic conditions, the equilibrium shifts to produce relatively more 2, 7, and/or 9. Studies of escapin's enzyme kinetics demonstrate that because of the high concentrations of escapin and L-lysine in the ink secretion, millimolar concentrations of 3, H(2)O(2), and ammonia are produced, and also lower concentrations of 2, 4, 7, and 9 as a result. We also show that reactions of this mixture with H(2)O(2) produce delta-aminovaleric acid (5) and delta-valerolactam (6), with 6 being the dominant component under the naturally acidic conditions of ink. Thus, the product of escapin's action on L-lysine contains an equilibrium mixture that is more complex than previously known for any L-amino acid oxidase.

  9. Curcumin and synthetic analogs induce reactive oxygen species and decreases specificity protein (Sp transcription factors by targeting microRNAs

    Directory of Open Access Journals (Sweden)

    Gandhy Shruti U

    2012-11-01

    Full Text Available Abstract Background Curcumin inhibits growth of several cancer cell lines, and studies in this laboratory in bladder and pancreatic cancer cells show that curcumin downregulates specificity protein (Sp transcription factors Sp1, Sp3 and Sp4 and pro-oncogenic Sp-regulated genes. In this study, we investigated the anticancer activity of curcumin and several synthetic cyclohexanone and piperidine analogs in colon cancer cells. Methods The effects of curcumin and synthetic analogs on colon cancer cell proliferation and apoptosis were determined using standardized assays. The changes in Sp proteins and Sp-regulated gene products were analysed by western blots, and real time PCR was used to determine microRNA-27a (miR-27a, miR-20a, miR-17-5p and ZBTB10 and ZBTB4 mRNA expression. Results The IC50 (half-maximal values for growth inhibition (24 hr of colon cancer cells by curcumin and synthetic cyclohexanone and piperidine analogs of curcumin varied from 10 μM for curcumin to 0.7 μM for the most active synthetic piperidine analog RL197, which was used along with curcumin as model agents in this study. Curcumin and RL197 inhibited RKO and SW480 colon cancer cell growth and induced apoptosis, and this was accompanied by downregulation of specificity protein (Sp transcription factors Sp1, Sp3 and Sp4 and Sp-regulated genes including the epidermal growth factor receptor (EGFR, hepatocyte growth factor receptor (c-MET, survivin, bcl-2, cyclin D1 and NFκB (p65 and p50. Curcumin and RL197 also induced reactive oxygen species (ROS, and cotreatment with the antioxidant glutathione significantly attenuated curcumin- and RL197-induced growth inhibition and downregulation of Sp1, Sp3, Sp4 and Sp-regulated genes. The mechanism of curcumin-/RL197-induced repression of Sp transcription factors was ROS-dependent and due to induction of the Sp repressors ZBTB10 and ZBTB4 and downregulation of microRNAs (miR-27a, miR-20a and miR-17-5p that regulate these repressors

  10. 含有一个非平面杂环胺配体的新型反铂抗癌药物的水解机理%Hydrolysis Mechanism of New Anticancer Drug Transplatin Analogues Containing One Nonplanar Heterocyclic Amine Ligand

    Institute of Scientific and Technical Information of China (English)

    赵亚华

    2009-01-01

    Hydrolysis processes of novel anticancer transplatin analogues, trans-[PtCl_2(NH_3)(Am)](Am: nonplanar heterocycle piperidine or piperazine), were explored using the B3LYP hybrid functional and isoclectric focusing polarized continuum model (IEF-PCM). Stationary points on the potential energy surfaces for the first and second hydrolysis steps that proceed via a general S_N2 pathway were fully optimized and characterized. The most remarkable structural variations in the hydrolysis process were found to occur in the equatorial plane of five-coordinate trigonal-bipyramidal (TBP) like structures of the intermediates and transition states. We obtained lower activation energies for trans-[PtCl_2(NH_3)(piperazine)] and a slightly higher activation energy for the first step and a slightly lower activation energy for the second step during the hydrolysis of trans-[PtCl_2(NH_3)(piperidine)] by comparison to previous work on the hydrolysis reactions of cisplatin. Our calculations suggest that this class of non-classical transplatin analogues with one nonplanar heterocyclic amine decreases the equatorial steric effect and the hydrolysis reaction barriers.%用B3LYP杂化泛函和等电子聚焦极化连续模型(IEF-PCM)研究了trans-[P[Cl_2(NH_3)(Am)](Am:非平面哌啶或哌嗪)新型反铂抗癌药物的水解反应机理.对经由一般的S_N2机理的第一步和第二步水解反应势能而上的稳定点进行了全优化和表征.在水解中,最显著的结构变化发生在反应过渡态和中间体的五配位三角双锥的赤道面上.与经典顺铂(cisplatin)比较,反式[PtCl_2(NH_3)(piperazine)]的第一步和第二步水解活化能均低于顺铂,而反式[PtCl_2(NH_3)(piperidine)]的第一步水解活化能稍高于顺铂,第二步水解活化能稍低于顺铂.计算表明,这些含有非平面杂环胺反铂的配合物减小了赤道面上的立体效应和水解势垒.

  11. Evaluation of New Dihydrophthalazine-Appended 2,4-Diaminopyrimidines against Bacillus anthracis: Improved Syntheses Using a New Pincer Complex

    Directory of Open Access Journals (Sweden)

    Nagendra Prasad Muddala

    2015-04-01

    Full Text Available The synthesis and evaluation of ten new dihydrophthalazine-appended 2,4-diaminopyrimidines as potential drugs to treat Bacillus anthracis is reported. An improved synthesis utilizing a new pincer catalyst, dichlorobis[1-(dicyclohexylphosphanyl-piperidine]palladium(II, allows the final Heck coupling to be performed at 90 °C using triethylamine as the base. These milder conditions have been used to achieve improved yields for new and previously reported substrates with functional groups that degrade or react at the normal 140 °C reaction temperature. An analytical protocol for separating the S and R enantiomers of two of the most active compounds is also disclosed. Finally, the X-ray structure for the most active enantiomer of the lead compound, (S-RAB1, is given.

  12. A phenomenological relationship between molecular geometry change and conformational energy change

    Science.gov (United States)

    Bodi, Andras; Bjornsson, Ragnar; Arnason, Ingvar

    2010-08-01

    A linear correlation is established between the change in the axial/equatorial conformational energy difference and the change in the molecular geometry transformation during conformational inversion in substituted six-membered ring systems, namely in the 1-substituted cyclohexane/silacyclohexane, cyclohexane/ N-substituted piperidine and 1-substituted silacyclohexane/ P-substituted phosphorinane compound families, and for the analogous gauche/anti conformational isomerism in 1-substituted propanes/1-silapropanes. The nuclear repulsion energy parameterizes the molecular geometry, and changes in the conformational energy between the related compound families are linearly correlated with the changes in the nuclear repulsion energy difference based on DFT (B3LYP, M06-2X), G3B3, and CBS-QB3 calculations. This correlation reproduces the sometimes remarkable contrast between the conformational behavior of analogous compounds, e.g., the lack of a general equatorial preference in silacyclohexanes.

  13. Effect of phosphate activating group on oligonucleotide formation on montmorillonite: the regioselective formation of 3',5'-linked oligoadenylates

    Science.gov (United States)

    Prabahar, K. J.; Cole, T. D.; Ferris, J. P.

    1994-01-01

    The effects of amine structure on the montmorillonite-catalyzed oligomerization of the 5'-phosphoramidates of adenosine are investigated. 4-Aminopyridine derivatives yielded oligoadenylates as long as dodecamers with a regioselectivity for 3',5'-phosphodiester bond formation averaging 88%. Linear and cyclic oligomers are obtained and no A5'ppA-containing products are detected. Oligomers as long as the hexanucleotide are obtained using 2-aminobenzimidazole as the activating group. A predominance of pA2'pA is detected in the dimer fraction along with cyclic 3',5'-trimer; no A5'ppA-containing oligomers were detected. Little or no oligomer formation was observed when morpholine, piperidine, pyrazole, 1,2,4-triazole, and 2-pyridone are used as phosphate-activating groups. The effects of the structure of the phosphate activating group on the oligomer structure and chain lengths are discussed.

  14. SYNTHESIS OF SOME CINNAMIC ACID DERIVATIVES: EFFECT OF GROUPS ATTACHED ON AROMATIC RING TO THE REACTIVITY OF BENZALDEHYDE

    Directory of Open Access Journals (Sweden)

    Marcellino Rudyanto

    2010-06-01

    Full Text Available Synthesis of cinnamic acid and its six derivatives has been done by employing Knoevenagel reaction. Benzaldehyde, 4-butylbenzaldehyde, 4-t-butylbenzaldehyde, 4-butoxybenzaldehyde, 4-phenylbenzaldehyde, 5-bromo-2,4-dimethoxybenzaldehyde, and 5-bromo-2,3-dimethoxybenzaldehyde were reacted with malonic acid in pyridine – piperidine to give cinnamic acid (85,3%, 4-butylcinnamic acid (69,3%, 4-t-butylcinnamic acid (77,7%, 4-butoxycinnamic acid (64,5%, 4-phenylcinnamic acid (65,5%, 5-bromo-2,4-dimethoxycinnamic acid (53,2% and 5-bromo-2,4-dimethoxycinnamic acid (57,2%, respectively. It was disclosed that 4-alkyl, 4-alkoxy, 4-aryl, dan 2-alkoxy groups decrease the reactivity of carbonyl carbon of benzaldehyde.   Keywords: cinnamic acid, cinnamic acid derivatives, Knoevenagel reaction

  15. Crystal structure of (E-4-(acetoxyimino-N-allyl-3-isopropyl-2,6-diphenylpiperidine-1-carbothioamide

    Directory of Open Access Journals (Sweden)

    T. Mohandas

    2015-08-01

    Full Text Available The title compound, C26H31N3O2S, crystallizes with two molecules (A and B in the asymmetric unit. In each case, the piperidine ring exists in a twist-boat conformation. The dihedral angle between the phenyl rings is 46.16 (12° in molecule A and 44.95 (12° in molecule B. In both molecules, the allyl side chain is disordered over two orientations in a 0.649 (9:0.351 (9 ratio for molecule A and 0.826 (10:0.174 (10 ratio for molecule B. In the crystal, neither molecule forms a hydrogen bond from its N—H group, presumably due to steric hindrance. A+A and B+B inversion dimers are formed, linked by pairs of weak C—H...O hydrogen bonds enclosing R22(22 ring motifs.

  16. Synthesis of New Substituted Chromen[4,3-c]pyrazol-4-ones and Their Antioxidant Activities

    Directory of Open Access Journals (Sweden)

    Abdullah Sulaiman Al-Ayed

    2011-12-01

    Full Text Available A series of new coumarin derivatives 4 containing a 4-arylbut-3-en-2-one moiety were synthesized by condensation of 3-acetylcoumarin 1 with aryl aldehydes 2 in chloroform in the presence of piperidine. The interactions of 3-formyl-4-chlorocoumarin (3 with nitrogen-containg nucleophiles leading to the corresponding substituted chromen-[4,3-c]pyrazol-4-ones 5 are described. The structures of the obtained compounds were established on the basis of 1D NMR, 2D NMR and IR and further the compounds were evaluated for possible antioxidant activities. The coumarinic chalcone 4a has been found to be the most active (IC50 = 2.07 μM in this study.

  17. 5-[(E-4-Fluorobenzylidene]-8-(4-fluorophenyl-2-hydroxy-9-phenyl-3,10-diazahexacyclo[10.7.1.13,7.02,11.07,11.016,20]henicosa-1(20,12,14,16,18-pentaen-6-one

    Directory of Open Access Journals (Sweden)

    Raju Suresh Kumar

    2011-11-01

    Full Text Available In the title compound, C38H28F2N2O2, the piperidine ring adopts a chair conformation and the pyrrolidine ring adopts an envelope conformation with the spiro C atom as the flap atom. The naphthalene ring system makes dihedral angles of 39.89 (8, 35.33 (8 and 46.45 (8° with the two fluoro-substituted benzene rings and the phenyl ring, respectively, while the dihedral angle between the two fluoro-substituted benzene rings is 75.21 (10°. An intramolecular O—H...N hydrogen bond generates an S(5 ring. In the crystal, molecules are connected by C—H...O hydrogen bonds, forming supramolecular chains propagating along the c-axis direction. Weak C—H...π interactions further consolidate the structure.

  18. Monoamine oxidase and transaminase screening: biotransformation of 2-methyl-6-alkylpiperidines by Neopestalotiopsis sp. CBMAI 2030.

    Science.gov (United States)

    Costa, Jonas Henrique; da Costa, Bruna Zucoloto; de Angelis, Derlene Attili; Marsaioli, Anita Jocelyne

    2017-08-01

    High-throughput screening detected transaminases (TAs) and monoamine oxidases (MAOs) in fungi by applying a fluorogenic probe. Strains F026, F037, F041, F053, and F057 showed the highest enzymatic conversions (31, 60, 30, 40, and 32%, respectively) and where evaluated for their ability to transform piperidines. Strain F053 (Neopestalotiopsis sp. CBMAI 2030) revealed unusual enzymatic activity to deracemize 2-methyl-6-alkylpiperidines. Neopestalotiopsis sp. CBMAI 2030 was capable to convert 2-methyl-6-propylpiperidine, 2-methyl-6-butylpiperidine, and 2-methyl-6-pentylpiperidine in piperideine with 11, 14, and 24% conversion, respectively. The activity was enhanced by cultivating the fungus with 2-methyl-6-pentylpiperidine (38% conversion and 73% ee).

  19. New potential AChE inhibitor candidates.

    Science.gov (United States)

    de Paula, A A N; Martins, J B L; dos Santos, M L; Nascente, L de C; Romeiro, L A S; Areas, T F M A; Vieira, K S T; Gambôa, N F; Castro, N G; Gargano, R

    2009-09-01

    We have theoretically studied new potential candidates of acetylcholinesterase (AChE) inhibitors designed from cardanol, a non-isoprenoid phenolic lipid of cashew Anacardium occidentale nut-shell liquid. The electronic structure calculations of fifteen molecule derivatives from cardanol were performed using B3LYP level with 6-31G, 6-31G(d), and 6-311+G(2d,p) basis functions. For this study we used the following groups: methyl, acetyl, N,N-dimethylcarbamoyl, N,N-dimethylamine, N,N-diethylamine, piperidine, pyrrolidine, and N,N-methylbenzylamine. Among the proposed compounds we identified that the structures with substitution by N,N-dimethycarbamoyl, N,N-dimethylamine, and pyrrolidine groups were better correlated to rivastigmine, and represent possible AChE inhibitors against Alzheimer disease.

  20. Electronic structure calculations toward new potentially AChE inhibitors

    Science.gov (United States)

    de Paula, A. A. N.; Martins, J. B. L.; Gargano, R.; dos Santos, M. L.; Romeiro, L. A. S.

    2007-10-01

    The main purpose of this study was the use of natural non-isoprenoid phenolic lipid of cashew nut shell liquid from Anacardium occidentale as lead material for generating new potentially candidates of acetylcholinesterase inhibitors. Therefore, we studied the electronic structure of 15 molecules derivatives from the cardanol using the following groups: methyl, acetyl, N, N-dimethylcarbamoyl, N, N-dimethylamine, N, N-diethylamine, piperidine, pyrrolidine, and N-benzylamine. The calculations were performed at RHF level using 6-31G, 6-31G(d), 6-31+G(d) and 6-311G(d,p) basis functions. Among the proposed compounds we found that the structures with substitution by acetyl, N, N-dimethylcarbamoyl, N, N-dimethylamine, and pyrrolidine groups were better correlated to rivastigmine indicating possible activity.

  1. Biarylpyrazole inverse agonists at the cannabinoid CB1 receptor: importance of the C-3 carboxamide oxygen/lysine3.28(192) interaction.

    Science.gov (United States)

    Hurst, Dow; Umejiego, Uju; Lynch, Diane; Seltzman, Herbert; Hyatt, Steven; Roche, Michael; McAllister, Sean; Fleischer, Daniel; Kapur, Ankur; Abood, Mary; Shi, Shanping; Jones, Jannie; Lewis, Deborah; Reggio, Patricia

    2006-10-05

    The biarylpyrazole, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716; 1) has been shown to act as an inverse agonist/antagonist at the cannabinoid CB1 receptor. Our previous mutant cycle study suggested that K3.28(192) is involved in a direct interaction with the C-3 substituent of 1 in wild-type (WT) CB1.(1) However, these results did not establish what part of the C-3 substituent of 1 is involved in the K3.28(192) hydrogen bond, the carboxamide oxygen or the piperidine nitrogen. Furthermore, our previous calcium channel assay results for 5-(4- chlorophenyl)-3-[(E)-2-cyclohexylethenyl]-1-(2,4-dichlorophenyl)-4- methyl-1H-pyrazole (VCHSR; 2) (an analogue of 1 that lacks hydrogen-bonding capability in its C-3 substituent) showed that this compound acts as a neutral antagonist, a result that is in contrast to 1, which acts as an inverse agonist in this same assay.(1) These results suggested a relationship between biarylpyrazole interaction with K3.28(192) at CB1 and inverse agonism, but these results were for a single pair of compounds (1 and 2). The work presented here was designed to test two hypotheses derived from our modeling and mutant cycle results. The hypotheses are as follows: (1) it is the carboxamide oxygen of the C-3 substituent of 1 that interacts directly with K3.28(192) and (2) the interaction with K3.28(192) is crucial for the production of inverse agonism for biarylpyrazoles such as 1. To determine whether the carboxamide oxygen or the piperidine nitrogen of the C-3 substituent may be the interaction site for K3.28(192), we designed, synthesized, and evaluated a new set of analogues of 1 (3-6, Chart 1) in which modifications only to the C-3 substituent of 1 have been made. In each case, the modifications that were made preserved the geometry of this substituent in 1. The absence of the piperidine nitrogen was not found to affect affinity, whereas the absence of the carboxamide oxygen resulted

  2. An aryloxypropanolamine hβ3-adrenoceptor agonist as bladder smooth muscle relaxant.

    Science.gov (United States)

    Tasler, Stefan; Baumgartner, Roland; Behr-Roussel, Delphine; Oger-Roussel, Stephanie; Gorny, Diane; Giuliano, Francois; Ney, Peter

    2012-08-15

    The relaxant effect of an aryloxypropanolamine β3-adrenoceptor agonist on carbachol pre-contracted human detrusor muscle strips was evaluated and compared with literature results from reference compounds of similar mode of action, including mirabegron. A significant relaxation was observed for rac-4-{2-hydroxy-3-[1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino]propoxy}-2-(hydroxymethyl)phenol which was similar to that exerted by mirabegron. In order to allow for a thorough discussion of results in comparison to reference compounds, their affinity, selectivity and efficacy as hβ3-AR agonists have been evaluated and discussed thoroughly. A ranking of hβ3-AR agonists by relative efficacy resulted in the closest analogy to the order of relaxation potential, with only the relaxant effect of mirabegron not reflecting its excellent relative efficacy as such.

  3. Solvent control of intramolecular proton transfer

    DEFF Research Database (Denmark)

    Manolova, Y.; Marciniak, Heinz; Tschierlei, S.

    2017-01-01

    The solvent dependent excited state dynamics of 4-hydroxy-3-(piperidin-1-ylmethyl)-1-naphthaldehyde (compound 2), a candidate for a molecular switch based on intramolecular proton transfer, was investigated by ultrafast spectroscopy and quantum-chemical calculations. In acetonitrile a mixture...... of molecules in the enol and zwitterionic proton transfer (PT) form exists in the ground state. However, the zwitterion is the energetically favored one in the electronically excited state. Optical excitation of the enol form results in intramolecular proton transfer and formation of the PT form within 1.4 ps....... In addition we observe the appearance of a long living species with a rate of 1/(330 ps) which returns to the original ground state on time scales beyond 2 ns and which is attributed to the triplet state. In toluene the enol form is the only observed ground state tautomer, but no light induced proton transfer...

  4. Synthesis of Schiff and Mannich Bases of Isatin Derivatives with 4-Amino-4,5-Dihydro-1H-1,2,4-Triazole-5-Ones

    Directory of Open Access Journals (Sweden)

    Hakan Bektas

    2008-09-01

    Full Text Available Ethyl imidate hydrochlorides 1 were prepared by passing HCl gas through solutions of substituted benzyl cyanides and absolute ethanol. Ethoxycarbonylhydrazones 2 were synthesized from the reaction of compounds 1 with ethyl carbazate. Treatment of 2 with hydrazine hydrate leads to the formation of substituted 4-amino-4,5-dihydro-1H-1,2,4-triazole-5-ones 3. Isatin and 5-chloroisatin were added to 3 to form Schiff bases 4 and N-Mannich bases 5 of these compounds were synthesized by reacting with formaldehyde and piperidine. Their chemical structures were confirmed by means of IR, 1H- and 13C-NMR data and by elemental analysis.

  5. Effect of gamma irradiation on mechanical and thermal properties of DGEBA/cycloaliphatic amine networks with potential for medical applications; Efeito da irradiacao gama nas propriedades mecanicas e termicas de redes DGEBA/amina cicloalifatica com potencial para aplicacoes medicas

    Energy Technology Data Exchange (ETDEWEB)

    Neves, Juliana C.; Silva, Glaura G., E-mail: glaura@qui.ufmg.br [Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG (Brazil); Mendes, Marcio W. Duarte; Bressiani, Ana H.; Bressiani, Jose C. [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil); Garcia, Filiberto Gonzalez [Universidade Federal de Itajuba (UNIFEI), MG (Brazil)

    2013-07-01

    Two epoxy polymers based on diglycidyl ether of bisphenol A (DGEBA), cured with piperidine (Pip) and 4,4'-diamino-3,3'-dimethyldicyclohexylmethane (3DCM), were characterized before and after treatment with γ irradiation. The changes in the mechanical and thermal properties were studied by elastic modulus, glass transition temperature and degradation temperature measurements. A dose of 50 kGy of irradiation caused subtle variations in properties such as rigidity and stability, which are relevant from the fundamental point of view. The variations do not imply on negative impact when considering the stage of sterilization during the use of these systems as a biomaterial in the medical area. (author)

  6. Antiprotozoal activity of Senna racemosa.

    Science.gov (United States)

    Moo-Puc, Rosa E; Mena-Rejon, Gonzalo J; Quijano, Leovigildo; Cedillo-Rivera, Roberto

    2007-06-13

    Methanol extracts of leaves, roots and bark of Senna racemosa (Mill.) H.S. Irwin & Barneby (syn. Cassia racemosa Mill.) were tested for antiprotozooal activity against Giardia intestinalis and Entamoeba histolytica. All of the tested extracts showed good activity against both protozoa species. Extracts from stem bark and leaves were most active, with an IC(50) of 2.10 microg/mL for Giardia intestinalis and 3.87 microg/mL for Entamoeba histolytica. Of the previously isolated compounds from Senna racemosa, the piperidine alkaloid cassine had greater activity against Giardia intestinalis with an IC(50) of 3.28 microg/mL and chrysophanol, a 1,8-dihydroxy-anthraquinone, was the most active agent against Entamoeba histolytica, with an IC(50) of 6.21 microg/mL.

  7. Thermodynamics and binding mode of novel structurally related 1,2,4-thiadiazole derivatives with native and modified cyclodextrins

    Science.gov (United States)

    Terekhova, Irina V.; Chislov, Mikhail V.; Brusnikina, Maria A.; Chibunova, Ekaterina S.; Volkova, Tatyana V.; Zvereva, Irina A.; Proshin, Alexey N.

    2017-03-01

    Study of complex formation of cyclodextrins with 1,2,4-thiadiazole derivatives intended for Alzheimer's disease treatment was carried out using 1H NMR, ITC and phase solubility methods. Structure of cyclodextrins and thiadiazoles affects the binding mode and thermodynamics of complexation. The larger cavity of β- and γ-cyclodextrins is more appropriate for deeper insertion of 1,2,4-thiadiazole derivatives which is accompanied by intensive dehydration and solvent reorganization. Benzene ring of the thiadiazoles is located inside macrocyclic cavity while piperidine ring is placed outside the cavity and can form H-bonds with cyclodextrin exterior. Complexation with cyclodextrins induces the enhancement of aqueous solubility of 1,2,4-thiadiazole derivatives.

  8. (4E-N-[(2-Bromophenylmethoxy]-1,3-dimethyl-2,6-diphenylpiperidin-4-imine

    Directory of Open Access Journals (Sweden)

    Chennan Ramalingan

    2012-07-01

    Full Text Available In the title compound, C26H27BrN2O, the piperidine ring has a chair conformation and all ring substituents occupy equatorial positions, apart from the double-bonded N atom, which occupies a bisectional position. The dihedral angle formed between the phenyl rings is 61.18 (19°, and the phenyl rings form dihedral angles of 49.78 (19 and 69.2 (18° with the bromobenzene ring. The latter is coplanar with the methoxy(methylideneamine fragment [N—O—C—C torsion angle = −171.7 (2°]. Linear supramolecular chains, approximately along [112], sustained by C—H...π interactions, feature in the crystal packing.

  9. Different antagonist binding properties of rat pancreatic and cardiac muscarinic receptors

    Energy Technology Data Exchange (ETDEWEB)

    Waelbroeck, M.; Camus, J.; Winand, J.; Christophe, J.

    1987-11-09

    The antagonist binding properties of rat pancreatic and cardiac muscarinic receptors were compared. In both tissues pirenzepine (PZ) had a low affinity for muscarinic receptors labelled by (/sup 3/H)N-methylscopolamine ((/sup 3/)NMS) (K/sub D/ values of 140 and 280nM, respectively, in pancreatic and cardiac homogenates). The binding properties of pancreatic and cardiac receptors were, however, markedly different. This was indicated by different affinities for dicyclomine, (11-(/(2-((diethylamino)-methyl)-1-piperidinyl/acetyl)-5, 11-dihydro-6H-pyrido(2,3-b)(1,4) benzodiazepin-6-on)(AFDX-116), 4-diphenylacetoxy-N-methyl-piperidine methobromide (4-DAMP) and hexahydrosiladifenidol (HHSiD). Pancreatic and cardiac muscarinic receptros also showed different (/sup 3/H)NMS association and dissociation rates. These results support the concept of M2 receptor subtypes have different binding kinetic properties. 20 references, 3 figures, 1 table.

  10. Nitroxide-Mediated Radical Polymerization of Styrene Initiated from the Surface of Titanium Oxide Nanoparticles

    Directory of Open Access Journals (Sweden)

    M. Abbasian

    2016-01-01

    Full Text Available Titanium dioxide (TiO2 nanoparticles, with an average size of about 45 nm, were encapsulated by polystyrene using in situ nitroxide mediated radical polymerization   in the presence of 3-aminopropyl triethoxy silane (APTES as a coupling agent and 2, 2, 6, 6-tetramethylpiperidinyl-1-oxy  as a initiator. First, the initiator for NMRP was covalently bonded onto the surface of Titanium dioxide nanoparticles through our novel method. For this purpose, the surface of TiO2 nanoparticle was treated with 3-aminopropyl triethoxy silane, a silane coupling agent, and then these functionalized nanoparticles was reacted with ±-chloro phenyl acetyl chloride. The chlorine groups were converted to nitroxide mediated groups by coupling with 1-hydroxy-2, 2, 6, 6-tetramethyl piperidine. These modified TiO2 nanoparticles were then dispersed in styrene (St monomers to carry out the in situ free radical polymerization.

  11. Effect of piperidones on hydrogen permeation and corrosion inhibition of mild steel in acidic solutions

    Indian Academy of Sciences (India)

    S Muralidharan; R Chandrasekar; S V K Iyer

    2000-04-01

    The influence of 3-methyl-2,6-diphenyl piperidin-4-one (MDPO) and 2-phenyl decahydroquinoline-4-one (PDQO) synthesised in the laboratory on hydrogen permeation and corrosion inhibition of mild steel in 1N H2SO4 has been studied using weight loss and various electrochemical AC and DC corrosion-monitoring techniques. Both the compounds inhibit the corrosion of mild steel in H2SO4 Potentiodynamic polarisation studies clearly reveal that they behave predominantly as cathodic inhibitors. The extent of decrease in hydrogen permeation current through steel surfaces has been studied by the hydrogen electropermeation technique. Double layer capacitance () and charge transfer resistance () values are derived from Nyquist plots obtained from AC impedance studies. The adsorption of these compounds on mild steel surfaces from H2SO4 obeys Temkin’s adsorption isotherm.

  12. Azido-iodo-N-benzyl derivatives of threo-methylphenidate (Ritalin, Concerta): Rational design, synthesis, pharmacological evaluation, and dopamine transporter photoaffinity labeling.

    Science.gov (United States)

    Lapinsky, David J; Velagaleti, Ranganadh; Yarravarapu, Nageswari; Liu, Yi; Huang, Yurong; Surratt, Christopher K; Lever, John R; Foster, James D; Acharya, Rejwi; Vaughan, Roxanne A; Deutsch, Howard M

    2011-01-01

    In contrast to tropane-based compounds such as benztropine and cocaine, non-tropane-based photoaffinity ligands for the dopamine transporter (DAT) are relatively unexplored. Towards addressing this knowledge gap, ligands were synthesized in which the piperidine nitrogen of 3- and 4-iodomethylphenidate was substituted with a benzyl group bearing a photoreactive azide. Analog (±)-3a demonstrated modest DAT affinity and a radioiodinated version was shown to bind covalently to rat striatal DAT and hDAT expressed in cultured cells. Co-incubation of (±)-3a with nonradioactive d-(+)-methylphenidate or (-)-2-β-carbomethoxy-3-β-(4-fluorophenyl)tropane (β-CFT, WIN-35,428, a cocaine analog) blocked DAT labeling. Compound (±)-3a represents the first successful example of a DAT photoaffinity ligand based on the methylphenidate scaffold. Such ligands are expected to assist in mapping non-tropane ligand-binding pockets within plasma membrane monoamine transporters.

  13. Toxicosis by Plant Alkaloids in Humans and Animals in Colombia

    Directory of Open Access Journals (Sweden)

    Gonzalo J. Diaz

    2015-12-01

    Full Text Available Due to its tropical location, chains of mountains, inter-Andean valleys, Amazon basin area, eastern plains and shores on both the Atlantic and Pacific Oceans, Colombia has many ecosystems and the second largest plant biodiversity in the world. Many plant species, both native and naturalized, are currently recognized as toxic for both animals and humans, and some of them are known to cause their toxic effects due to their alkaloid content. Among these, there are plants containing the hepatotoxic pyrrolizidine alkaloids, neurotoxins such as the indolizidine alkaloid swainsonine and the piperidine alkaloids coniine and γ-coniceine and tropane alkaloids. Unfortunately, the research in toxic plants in Colombia is not nearly proportional to its plant biodiversity and the scientific information available is only very scarce. The present review aims at summarizing the scarce information about plant alkaloid toxicosis in animals and humans in Colombia.

  14. Toxicosis by Plant Alkaloids in Humans and Animals in Colombia

    Science.gov (United States)

    Diaz, Gonzalo J.

    2015-01-01

    Due to its tropical location, chains of mountains, inter-Andean valleys, Amazon basin area, eastern plains and shores on both the Atlantic and Pacific Oceans, Colombia has many ecosystems and the second largest plant biodiversity in the world. Many plant species, both native and naturalized, are currently recognized as toxic for both animals and humans, and some of them are known to cause their toxic effects due to their alkaloid content. Among these, there are plants containing the hepatotoxic pyrrolizidine alkaloids, neurotoxins such as the indolizidine alkaloid swainsonine and the piperidine alkaloids coniine and γ-coniceine and tropane alkaloids. Unfortunately, the research in toxic plants in Colombia is not nearly proportional to its plant biodiversity and the scientific information available is only very scarce. The present review aims at summarizing the scarce information about plant alkaloid toxicosis in animals and humans in Colombia. PMID:26690479

  15. Synthesis and Biological Evaluation of Some Novel Dithiocarbamate Derivatives

    Directory of Open Access Journals (Sweden)

    Begüm Nurpelin Sağlık

    2014-01-01

    Full Text Available 18 novel dithiocarbamate derivatives were synthesized in order to investigate their inhibitory potency on acetylcholinesterase enzyme and antimicrobial activity. Structures of the synthesized compounds were elucidated by spectral data and elemental analyses. The synthesized compounds showed low enzyme inhibitory activity. However, they displayed good antimicrobial activity profile. Antibacterial activity of compounds 4a, 4e, and 4p (MIC = 25 μg/mL was equal to that of chloramphenicol against Klebsiella pneumoniae (ATCC 700603 and Escherichia coli (ATCC 35218. Most of the compounds exhibited notable antifungal activity against Candida albicans (ATCC 10231, Candida glabrata (ATCC 90030, Candida krusei (ATCC 6258, and Candida parapsilosis (ATCC 7330. Moreover, compound 4a, which carries piperidin-1-yl substituent and dimethylthiocarbamoyl side chain as variable group, showed twofold better anticandidal effect against all Candida species than reference drug ketoconazole.

  16. 1-Formyl-r-2,c-6-bis(4-methoxyphenyl-t-3-methylpiperidin-4-one

    Directory of Open Access Journals (Sweden)

    P. Gayathri

    2009-11-01

    Full Text Available The asymmetric unit of the title compound, C21H23NO4, contains two crystallographically independent molecules A and B. In both molecules, the piperidine-4-one rings adopt a distorted twist-boat conformation. The formyl group at position 1, the methoxyphenyl ring at position 2 and the methyl group at position 3 are attached equatorially. The methoxy phenyl ring at position 6 has an axial orientation. The dihedral angle between the two benzene rings is 55.27 (8° in molecule A, and 55.29 (8° in molecule B. In the crystal, the molecules are linked by weak C—H...O intermolecular hydrogen-bond interactions. In addition, weak C—H...π intermolecular interactions involving the benzene rings at positions 6 and 2 of molecule B are also found in the crystal structure.

  17. Identification of a new tadalafil analogue in an adulterated dietary supplement: trans-Bisprehomotadalafil.

    Science.gov (United States)

    Lee, Ji Hyun; Kim, Hyung Joo; Mandava, Suresh; Hwang, Jungjoong; Park, Hyoung Joon; Cho, Sooyeul; Baek, Sun Young; Lee, Jongkook

    2015-11-10

    A new tadalafil analogue was identified along with homotadalafil during routine screening of an adulterated dietary supplement using HPLC-DAD. The UV spectrum of this analogue was almost identical with that of tadalafil. This compound was isolated from the supplement by using semi-preparative HPLC and its structure was subsequently elucidated by performing Q-TOF/MS/MS and NMR spectroscopic experiments. The spectral data indicate that this tadalafil analogue is a dimeric compound that consists of an ethylamino group and two pretadalafil moieties. NOE experiments and comparison with (1)H NMR spectra of tadalafil and trans-tadalafil suggested the trans-relationship between the substituents on piperidine rings in the pretadalafil moieties.

  18. 3-Ethyl-3-hy-droxy-8-meth-oxy-quinoline-2,4(1H,3H)-dione monohydrate.

    Science.gov (United States)

    Kafka, Stanislav; Pevec, Andrej; Proisl, Karel; Kimmel, Roman; Košmrlj, Janez

    2012-11-01

    In the title hydrate, C(12)H(13)NO(4)·H(2)O, the piperidine ring that is fused to the benzene ring is in a sofa conformation with the chiral C atom lying 0.4084 (18) Å out of the plane of the nine fused-ring atoms. In the crystal, O-H⋯O and N-H⋯O hydrogen bonds link the organic mol-ecules and water mol-ecules into chains running along the b-axis direction. The chains are further connected into layers parallel to the bc plane by π-π inter-actions between inversion-related benzene rings [centroid-centroid distance = 3.8846 (9) Å].

  19. Cellulose nanocrystals prepared via formic acid hydrolysis followed by TEMPO-mediated oxidation.

    Science.gov (United States)

    Li, Bin; Xu, Wenyang; Kronlund, Dennis; Määttänen, Anni; Liu, Jun; Smått, Jan-Henrik; Peltonen, Jouko; Willför, Stefan; Mu, Xindong; Xu, Chunlin

    2015-11-20

    Cellulose nanocrystals (CNCs) as a renewable and biodegradable nanomaterial have wide application value. In this work, CNCs were extracted from bleached chemical pulp using two stages of isolation (i.e. formic acid (FA) hydrolysis and 2,2,6,6-tetramethyl-piperidine-1-oxyl (TEMPO) mediated oxidation) under mild conditions. In the first stage, FA was used to remove hemicellulose, swell cellulose fibers, and release CNCs. The FA could be readily recovered and reused. In the second stage, the CNCs isolated by FA were further modified by TEMPO-mediated oxidation to increase the surface charge of CNCs. It was found that the modified CNCs with more ordered crystal structure and higher surface charge had better redispersibility and higher viscosity in aqueous phase. Therefore, the modified CNCs could be more effective when used as rheology modifier in the fields of water based coating, paint, food etc. Copyright © 2015 Elsevier Ltd. All rights reserved.

  20. Photochemical cleavage of DNA by nitrobenzamides linked to 9-aminoacridine

    Energy Technology Data Exchange (ETDEWEB)

    Nielsen, P.E.; Jeppesen, C.; Egholm, M.; Buchardt, O.

    1988-08-23

    Nitrobenzamido ligands linked to the DNA intercalator 9-aminoacridine via poly(methylene) chains induce single-strand nicks in DNA upon irradiation with long-wavelength ultraviolet light (lambda greater than or equal to 300 nm). Optimal photocleavage activity was found for the reagent 9-((6-(4-nitrobenzamido)hexyl)amino)-acridine. Removal of the acridinyl ligand or changing the position of the nitro group from the 4- to the 2-position caused a 10-fold decrease in photocleavage efficiency, whereas a change to the 3-position caused a 30-fold reduction. The DNA cleavage was 5-fold enhanced by subsequent piperidine treatment and showed some sequence dependency with predominant cleavage at G and T residues. Furthermore, significant differences in cleavage preference were observed when the poly(methylene) linker length was changed.

  1. Design, Synthesis, Antibacterial and Antifungal Activity of Novel 2-[(E-2-aryl-1-ethenyl]-3-(2-sulfanyl-1H-benzo[d]imidazole-5-yl-3,4- dihydro-4-quinolinones

    Directory of Open Access Journals (Sweden)

    Anisetti Ravinder Nath

    2012-01-01

    Full Text Available The novel 2-[(E-2-aryl-1-ethenyl]-3-(2-sulfanyl-1H-benzo[d]imidazole-5-yl-3,4- dihydro-4-quinolinones (4a-j analogs were synthesized by Knoevenagel condensation of a solution of 2-methyl-3-(2-sulfanyl-1H-benzo[d]imidazole-5-yl-3,4-dihydro-4-quinazolinone (3 with aromatic aldehyde in presence of catalytic amount of piperidine. Compounds (4a-j showed significant biological activity against all the standard strains. All the synthesized compounds were characterized on the basis of their IR, 1H NMR, MASS spectroscopic data and elemental analyses. All the compounds have been tested for antimicrobial and antifungal activity by the cup-plate method.

  2. Synthesis, characterisation, stereochemistry and biological activity of N-formylpiperidin-4-ones

    Science.gov (United States)

    Sakthivel, P.; Ponnuswamy, S.

    2014-09-01

    A new series of N-formyl-2,6-bis(4-methoxyphenyl)piperidin-4-ones 5-8 has been synthesized and characterised using IR, mass and 1H, 13C, DEPT and 2D (COSY and HSQC) NMR spectral techniques. The NMR spectral data indicated that the N-formylpiperidin-4-ones 5-8 prefer to exist in a conformational equilibrium between a syn rotamer with a twist boat conformation (TB1) and an anti rotamer with a twist boat conformation (TB2) in solution. The stereodynamics of these systems have been studied by recording the dynamic 1H NMR spectra of compound 5, and the energy barrier for the N-CO rotation was determined to be 64.3 kJ/mol. All of the synthesized compounds (5-8) were screened for their biological activity.

  3. Synthesis, stereochemical and biological studies of some N-cyclohexylcarbamoyl -2,6-diarylpiperidin-4-ones

    Science.gov (United States)

    Sethukumar, A.; Anand, P. Surendar; Kumar, C. Udhaya; Prakasam, B. Arul

    2017-02-01

    A series of N-cyclohexylcarbamoylpiperidin-4-ones were synthesized by the addition reaction of corresponding piperidin-4-ones with cyclohexylisocyanate in benzene. The structure and stereochemistry of the synthesized N-cyclohexylcarbamoyl -2, 6-diarylpiperidin-4-ones, were established on the basis of their analytical and spectral data (IR, 1H and 13C NMR). 2D NMR spectra (HOMOCOSY, HSQC, HMBC and NOESY) were also recorded to analyze the stereochemistry. In the IR spectra of synthesized compounds, the characteristic absorptions due to ring and amide carbonyl functionalities were observed which evidences the formation of N-cyclohexylcarbamoyl-2, 6-diarylpiperidin-4-ones. NMR spectral results are in line with the proposed structure of the compounds synthesized. Conformational analysis was carried out from the extracted coupling constants and NOESY spectral results. The synthesized compounds were evaluated for their antibacterial and antifungal activities.

  4. GC-MS, GC-MS/MS and GC-IR differentiation of desoxy cathinone derivatives: Cyclic tertiary amines related to MDPV.

    Science.gov (United States)

    Abiedalla, Younis; DeRuiter, Jack; Clark, C Randall

    2017-03-24

    The desoxy phenethylamine analogues in this study represent a combination of alkyl side-chain and cyclic amines (azetidine, pyrrolidine, piperidine and azepane) to yield a set of molecules of identical elemental composition as well as major mass spectral fragment ions (base peaks) of identical elemental composition. These desoxy phenethylamine analogues of the aminoketone designer drug, 3,4-methylenedioxy-pyrrovalerone (MDPV) related to the natural product cathinone were prepared from piperonal (3,4-methylenedioxybenzaldehyde) via the intermediate precursor ketones. The aminoketones and the desoxy phenethylamine regioisomers were each separated in capillary gas chromatography experiments using an Rxi(®)-17Sil MS stationary phase with the aminoketones showing greater retention than the corresponding desoxyamines. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Bodilisant-a novel fluorescent, highly affine histamine h3 receptor ligand.

    Science.gov (United States)

    Tomasch, Miriam; Schwed, J Stephan; Paulke, Alexander; Stark, Holger

    2013-02-14

    A piperidine-based lead structure for the human histamine H3 receptor (hH3R) was coupled with the BODIPY fluorophore and resulted in a strong green fluorescent (quantum yield, 0.92) hH3R ligand with affinity in the nanomolar concentration range (K i hH3R = 6.51 ± 3.31 nM), named Bodilisant. Screening for affinities at histamine and dopamine receptor subtypes showed high hH3R preference. Bodilisant was used for visualization of hH3R in hH3R overexpressing HEK-293 cells with fluorescence confocal laser scanning microscopy. In addition, in native human brain tissues, Bodilisant showed clear and displaceable images of labeled hH3R.

  6. (±)-Homocrepidine A, a Pair of Anti-inflammatory Enantiomeric Octahydroindolizine Alkaloid Dimers from Dendrobium crepidatum.

    Science.gov (United States)

    Hu, Yang; Zhang, Chaofeng; Zhao, Xin; Wang, Yue; Feng, Deqiang; Zhang, Mian; Xie, Haifeng

    2016-01-22

    A pair of racemic indolizidine enantiomers, (±)-homocrepidine A (1), and a piperidine derivative, homocrepidine B (2), were isolated from Dendrobium crepidatum along with the known alkaloid crepidine (3). The racemic mixture of 1 was separated into a pair of enantiomers, (+)-1 and (-)-1, by HPLC using a chiral chromatographic substrate, which represents the first successful example of resolving indolizidine racemic mixtures. The absolute configurations of (+)-1 and (-)-1 were assigned from single-crystal X-ray diffraction data. The evaluation of anti-inflammatory activity with LPS-induced RAW 264.7 macrophages revealed that (+)-1 strongly inhibited the production of nitric oxide (IC50, 3.6 μM) and significantly decreased the expression of inducible nitric oxide synthase, while (-)-1 and (±)-1 only had moderate inhibitory effects (IC50, 22.8 and 14.7 μM). Compound 2 showed moderate anti-inflammatory activity (IC50, 27.6 μM).

  7. Chemically robust fluoroalkyl phthalocyanine-oligonucleotide bioconjugates and their GRP78 oncogene photocleavage activity.

    Science.gov (United States)

    Patel, Pradeepkumar; Patel, Hemantbhai H; Borland, Emily; Gorun, Sergiu M; Sabatino, David

    2014-06-18

    The first representative of functionalized fluoroalkyl phthalocyanines, F48H7(COOH)PcZn, is reported. The complex generates (1)O2 affording long-lasting photooxidation of an external substrate without self-decomposition. The carboxylic group couples with an antisense oligonucleotide targeting GRP78 oncogenes, resulting in the F48H7PcZn-cancer targeting oligonucleotide (CTO). The bioconjugated fluorophthalocyanine effectively hybridizes complementary GRP78 DNA and mRNA sequences. Piperidine cleavage assays reveal desired photochemical oligonucleotide oxidative degradation for both F48H7PcZn-CTO:DNA and F48H7PcZn-CTO:mRNA hybrids. This new materials strategy could be extended to other functional fluorinated phthalocyanines-antisense oligonucleotide combinations for long-lasting oncogene-targeting photodynamic therapy.

  8. Oxidation and N-alkylation of galactomannan extracted from Caesalpinia ferrea var. ferrea seeds;Oxidacao e N-alquilacao de galactomanana de sementes de Caesalpina ferrea var. ferrea

    Energy Technology Data Exchange (ETDEWEB)

    Souza, Clayton F. de; Lucyszyn, Neoli; Ferraz, Fernando A.; Sierakowski, Maria Rita, E-mail: clayton@quimica.ufpr.b [Universidade Federal do Parana (UFPR), Curitiba, PR (Brazil). Dept. de Quimica

    2009-07-01

    The objective of this work was the synthesis and characterization of carboxyl (polyelectrolyte, GMPFOXT) and amino alkylate (amphiphilic, GMPFOXD) derivatives of the galactomannan extracted from the seeds of native specie Pau-ferro (Caesalpinia ferrea - GMPF). The derivatives were obtained by selective modification of GMPF at C-6 in the presence of TEMPO reagent (N-oxil-2,2,6,6-tetramethyl-piperidine) and dodecylamine showed high yields (approx 77 and 94% for GMPFOXT and GMPFOXD, respectively). The characteristics of the derivatives were confirmed by spectroscopic techniques of FTIR and {sup 13}C-NMR. By gel permeation chromatography (GPC), was observed a decrease of molar mass values and increase in polydispersity after derivatization, indicating change in the aggregation state in solution, caused by modification on the superficial structure. The development of these products can expand the use of them in different areas such as cosmetics and pharmaceutics, among others. (author)

  9. Low inversion energy barrier of cytisine NH group—an explanation for the FT-IR bands splitting

    Science.gov (United States)

    Rode, Joanna E.; Raczyńska, Ewa D.; Górnicka, Elżbieta; Dobrowolski, Jan Cz.

    2005-07-01

    The DFT calculations using B3PW91 hybrid functional and 6-311++G** basis set were performed for the two most stable isomers of cytisine ( 1a and 1b). The conformation 1a differs from 1b by the orientation ( equatorial and axial, respectively) of the hydrogen atom at the piperidine nitrogen atom. In terms of the Gibbs free energy, the conformation 1a is less stable than 1b by 0.25 kcal mol -1, only. The isomers are separated by 3.6 kcal mol -1—an activation energy barrier, which is higher in energy than the vibrational modes inverting one isomer into another. Presence of such a barrier explains the existence of the two isomers ( equatorial and axial) observed previously in apolar solvents.

  10. FT-IR spectroscopic, AM1 and PM3 computational studies of conformation of natural products: cytisine.

    Science.gov (United States)

    Górnicka, Elzbieta; Raczyńska, Ewa D

    2002-06-10

    Infrared spectra were recorded for cytisine (1) and its model compounds: N-methyl-2-pyridone (2) and piperidine (3) in solution. Eight solvents of different polarity, polarizability and acid-base properties: CCl(4), CS(2), CHCl(3), CDCl(3) (for comparison with the NMR spectra), CH(2)Cl(2), MeOH, Et(2)O and Et(3)N were chosen. Experimental FT-IR spectra were analysed with the help of those calculated for isolated derivatives at the AM1 and PM3 levels. Influence of environment on the conformational preferences in solvated cytisine was discussed and compared with those in the solid state (X-ray measurements) and in the gas phase (quantum-mechanical calculations).

  11. Synthesis, spectroscopy and thermal study of some nickel(II) complexes containing tridentate Schiff bases and substituted amine ligands, X-ray crystal structure of nickel(II) complex.

    Science.gov (United States)

    Kianfar, Ali Hossein; Bahramian, Masomeh; Khavasi, Hamid Reza

    2012-08-01

    Some new tridentate ONO and ONS Schiff base complexes of [NiL(amine)] (L=Salicylidene2-aminophenol and Salicylidene2-aminothiophenol, amine=benzylamine, morpholine, pyrrolidine and piperidine) were synthesized and characterized by IR, UV-vis, (1)H NMR spectroscopy and elemental analysis. The geometry of [NiL(2)(bzlan)] determined by X-ray crystallography indicates that the complex has planar structure and has four coordinate in the solid state. The thermogravimmetry (TG) and differential thermoanalysis (DTA) of the synthesized complexes were carried out in the range of 20-700°C, leading to decomposition of ONO type in two stages and of ONS type in three stages. The ONO and ONS complexes were decomposed to NiO and NiS respectively. Thermal decomposition of the complexes is closely the depends upon nature of the Schiff base ligands and proceeds via first order kinetics.

  12. An Improved Strategy for the Synthesis of Ethylene Glycol by Oxamate-Mediated Catalytic Hydrogenation.

    Science.gov (United States)

    Satapathy, Anilkumar; Gadge, Sandip T; Bhanage, Bhalchandra M

    2017-04-10

    The present study reports an improved approach for the preparation of ethylene glycol (EG) by using carbon monoxide as C1 chemical by a two-step oxidative carbonylation and hydrogenation sequence. In the first step, oxamates are synthesized through oxidative cross double carbonylation of piperidine and ethanol by using Pd/C catalyst under phosphine ligand-free conditions and subsequently hydrogenated by Milstein's catalyst (carbonylhydrido[6-(di-t-butylphosphinomethylene)-2-(N,N-diethylaminomethyl)-1,6-dihydropyridine]ruthenium(II)). The presented stepwise oxamate-mediated coupling provides the basis for a new strategy for the synthesis of EG by selective upgrading of C1 chemicals. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  13. Palladium-Catalyzed Directed C(sp(3))-H Arylation of Saturated Heterocycles at C-3 Using a Concise Optimization Approach.

    Science.gov (United States)

    Affron, Dominic P; Bull, James A

    2016-01-01

    Saturated heterocycles, such as THFs, pyrrolidines, piperidines and THPs, are essential components of many biologically active compounds. Examples of C-H functionalization on these important ring systems remain scarce, especially at unactivated positions. Here we report the development of conditions for the palladium-catalyzed stereoselective C(sp(3))-H arylation at unactivated 3-positions of 5- and 6-membered N- and O-heterocycles with aminoquinoline directing groups. Subtle differences in substrate structures altered their reactivity significantly; and different conditions were required to achieve high yields in each case. Successful conditions were developed using a short empirical optimization approach to cover reaction space with a limited set of variables. Excellent cis-selectivity was achieved in all cases, except for the THP substrate where minor trans-products were formed through a different palladacyclic intermediate. Here, differences in reactivity and selectivity with other directing groups were examined.

  14. Development of new brain imaging agents based upon nocaine-modafinil hybrid monoamine transporter inhibitors.

    Science.gov (United States)

    Musachio, John L; Hong, Jinsoo; Ichise, Masanori; Seneca, Nicholas; Brown, Amira K; Liow, Jeih-San; Halldin, Christer; Innis, Robert B; Pike, Victor W; He, Rong; Zhou, Jia; Kozikowski, Alan P

    2006-06-15

    11C-labeled (+)-trans-2-[[(3R,4S)-4-(4-chlorophenyl)-1-methylpiperidin-3-yl]methylsulfanyl]ethanol ([11C]5) and (+)-trans-2-[[(3R,4S)-4-(4-chlorophenyl)-1-methylpiperidin-3-yl]methylsulfanyl]-1-(piperidin-1-yl)ethanone ([11C]6) were synthesized and evaluated as new imaging agents for the norepinephrine transporter (NET). [11C]5 and [11C]6 display high affinity for the NET in vitro (Ki = 0.94 and 0.68 nM, respectively) and significant selectivity over the dopamine (DAT) and serotonin transporters (SERT). Because of their high affinity and favorable transporter selectivities we speculated that these ligands might serve as useful PET agents for imaging NET in vivo. Contrary to our expectations, both of these ligands provided brain images that were more typical of those shown by agents binding to the DAT.

  15. Aspectos químicos, biológicos e etnofarmacológicos do gênero Cassia

    Directory of Open Access Journals (Sweden)

    Cláudio Viegas Junior

    2006-12-01

    Full Text Available Species of Cassia are widely distributed in tropical and subtropical regions throughout the world, and have been extensively investigated chemically and pharmacologically.They are known to be a rich source of phenolic derivatives, most of them with important biological and pharmacological properties. Some Asian, African and Indian tribes use these species as a laxative, purgative, antimicrobial, antipyretic, antiviral and anti-inflammatory agent. Among a number of other classes of secondary metabolites, such as anthracene derivatives, antraquinones, steroids and stilbenoids, biologically active piperidine alkaloids are an especially important bioactive class of compounds that showed to be restricted to a small group of Cassia species. In this paper we present an overview of the chemical, biological and ethnopharmacological data on Cassia piblished in the literature.

  16. Design, synthesis and antifungal activity of novel triazole derivatives containing substituted 1,2,3-triazole-piperdine side chains.

    Science.gov (United States)

    Jiang, Zhigan; Gu, Julin; Wang, Chen; Wang, Shengzheng; Liu, Na; Jiang, Yan; Dong, Guoqiang; Wang, Yan; Liu, Yang; Yao, Jianzhong; Miao, Zhenyuan; Zhang, Wannian; Sheng, Chunquan

    2014-07-23

    Due to increasing incidence of invasive fungal infections and severe drug resistance to triazole antifungal agents, a series of novel antifungal triazoles with substituted triazole-piperidine side chains were designed and synthesized. Most of the target compounds showed good inhibitory activity against a variety of clinically important fungal pathogens. In particular, compounds 8t and 8v were highly active against Candida albicans and Cryptococcus neoformans with MIC values in the range of 0.125 μg/mL to 0.0125 μg/mL. They represent promising leads for the development of new generation of triazole antifungal agents. Molecular docking studies revealed that the target compounds interacted with CACYP51 mainly through hydrophobic and Van der Waals interactions.

  17. Synthesis and Antimicrobial Activity of Some [1,2,4]-Triazole Derivatives

    Directory of Open Access Journals (Sweden)

    Bhimagouda S. Patil

    2013-01-01

    Full Text Available A series of novel [1,2,4]-triazolo piperidine (8, [1,2,4]-triazolo piperazine (9a-c, [1,2,4]-triazolo phenylether (10a-e, and [1,2,4]-triazolo aniline (11a-c derivatives have been synthesized. The chemical structures of the newly synthesized compounds were characterized by IR, 1H NMR, 13C NMR, and LCMS. The newly synthesized compounds were screened for antimicrobial activity. Among all the compounds tested, 11b (R4=4-MeO– showed the highest activity against Staphylococcus aureus and Escherichia coli, and 9a (R1 and R2=Cl showed the highest activity against Pseudomonas aeruginosa.

  18. Crystal structure of (3S*,4R*-4-fluoro-3-(4-methoxyphenyl-1-oxo-2-phenyl-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid

    Directory of Open Access Journals (Sweden)

    Anna Lehmann

    2017-06-01

    Full Text Available The title compound, C23H18FNO4, crystallized as a racemate. It exhibits a cis conformation with respect to the F atom and the methine H atom. The piperidine ring has a screw-boat conformation. The methoxyphenyl ring and the phenyl ring are inclined to the mean plane of the isoquinoline ring system by 89.85 (4 and 46.62 (5°, respectively, and by 78.15 (5° to one another. In the crystal, molecules are linked by an O—H...O hydrogen bond forming chains propagating along the a-axis direction. The chains are linked by C—H...F hydrogen bonds, forming layers lying parallel to the ab plane.

  19. Structural combination of established 5-HT(2A) receptor ligands: new aspects of the binding mode

    DEFF Research Database (Denmark)

    Kramer, Vasko; Herth, Matthias M; Santini, Martin A;

    2010-01-01

    MH.MZ, MDL 100907, and altanserin are structurally similar 4-benzoyl-piperidine derivatives and are well accommodated to receptor interaction models. We combined structural elements of different high-affinity and selective 5-HT(2A) antagonists, as MH.MZ, altanserin, and SR 46349B, to improve......) with a moderate affinity toward the 5-HT(2A) receptor (K(i) = 57 nm). The remarkably reduced affinity of other compounds (4a), (4b), and (4c) (K(i) = 411, 360 and 356 nm respectively) indicates that MH.MZ can only bind to the 5-HT(2A) receptor with the p-fluorophenylethyl residue in a sterically restricted...

  20. Rhodium-catalyzed cyclohydrocarbonylation approach to the syntheses of enantiopure homokainoids.

    Science.gov (United States)

    Chiou, Wen-Hua; Schoenfelder, Angèle; Sun, Liang; Mann, André; Ojima, Iwao

    2007-12-07

    Homologues of kainic acid, a naturally occurring potent glutamate receptor agonist, were designed based on a rigidified pipecolinoglutamic acid structure and can be regarded as homokainoids for their potential activities in the central nervous system. These novel homokainoids in an enantiomerically pure form were synthesized from enantiopure (R)- and (S)-Garner's aldehyde, featuring (i) the highly diastereoselective addition of alkenylcuprates to the acrylate intermediates and (ii) the Rh-catalyzed cyclohydrocarbonylation of homoallylic amine intermediates to construct the functionalized piperidine moiety in the key steps. For the introduction of a substituent at the 4- or 5-position of pipecolinoglutamic acid, a few different strategies were used, which successfully led to the formation of enantiopure homokainoids.

  1. Paliperidone: 3-{2-[4-(6-fluoro-1,2-benzoxazol-3-ylpiperidin-1-yl]ethyl}-9-hydroxy-2-methyl-1,6,7,8,9,9a-hexahydropyrido[1,2-a]pyrimidin-4-one

    Directory of Open Access Journals (Sweden)

    Richard Betz

    2011-11-01

    Full Text Available The title compound (also known as 9-hydroxyrisperidone, C23H27FN4O3, is a heterocyclic compound with manifold pharmacological properties. The hydroxy group shows disorder over two positions, with site-occupancy factors of 0.856 (2 and 0.144 (2. The piperidine ring adopts a chair conformation, while the annulated ring bearing the hydroxy group is present in a half-chair conformation. Classical O—H...O hydrogen bonds as well as C—H...N contacts connect the molecules into undulating sheets lying perpendicular to the crystallographic b axis. The shortest centroid–centroid distance between two centers of gravity is 3.5867 (8 Å and is apparent between the benzoxazole moiety and the six-membered ring bearing the keto substituent.

  2. Gibberellin-induced inhibition and promotion of sprouting in aerial tubers of Begonia evansiana Andr. in relation to photoperiodic treatment and tuber stage.

    Science.gov (United States)

    Okagami, N; Esashi, Y; Nagao, M

    1977-01-01

    Gibberellic-acid (GA3) treatment, when applied within a period ranging from the start of short-day (SD) treatment until about 10 SD, GA3 strongly inhibited formation of aerial tubers in response to SD and brought about sprouting of developing aerial tubers. In contrast, when applied after about 10 SD or more, GA3 hastened the completion of the dormant state in the tubers and prolonged their dormancy. The dormancy-promoting effect of GA3 on detached tubers increased with their degree of maturation. Application of growth retardants N-dimethylaminosuccinamic acid (B-9), 2-isopropyl-4-dimethylamino-5-methylphenyl-1-piperidine carboxylate methyl chloride (AMO-1618) and 2-chloroethyltrimethylammonium chloride (CCC) to the cuttings delayed the onset of dormancy in the aerial tuber. When the retardants were applied to detached aerial tubers, however, such a delay of dormancy was not observed, and GA3 application did not inhibit sprouting in aerial tubers detached from CCC-treated cuttings.

  3. Investigation of the binding of roxatidine acetate hydrochloride with cyclomaltoheptaose (β-cyclodextrin) using IR and NMR spectroscopy.

    Science.gov (United States)

    Maheshwari, Arti; Sharma, Manisha; Sharma, Deepak

    2011-09-27

    NMR chemical shift changes of the cyclomaltoheptaose (β-cyclodextrin, β-CD) cavity protons as well as roxatidine acetate hydrochloride aromatic ring protons revealed the formation of a RAH-β-CD inclusion complex. Detailed FTIR and NMR spectroscopic ((1)H NMR, COSY, NOESY, ROESY) studies have been done. The stoichiometry of the complex was determined to be 1:1, and the overall binding constant was also determined by Scott's method. The NOESY spectrum confirmed the selective penetration of the aromatic ring of RAH into the β-CD cavity in comparison to that of the piperidine ring. The mode of penetration of the guest into the CD cavity and structure of the complex has been established.

  4. H/D isotope effect of {sup 1}H MAS NMR spectra and {sup 79}Br NQR frequencies of piperidinium p-bromobenzoate and pyrrolidinium p-bromobenzoate

    Energy Technology Data Exchange (ETDEWEB)

    Honda, Hisashi, E-mail: hhonda@yokohama-cu.ac.jp [Yokohama City University, Graduate School of Nanobioscience (Japan); Kyo, Shinshin [Yokohama City University, Faculty of Sciences (Japan); Akaho, Yousuke [Yokohama City University, Faculty of International College of Arts and Sciences (Japan); Takamizawa, Satoshi [Yokohama City University, Graduate School of Nanobioscience (Japan); Terao, Hiromitsu [Tokushima University, Faculty of Integrated Arts and Sciences (Japan)

    2010-04-15

    H/D isotope effects onto {sup 79}Br NQR frequencies of piperidinium p-bromobenzoate were studied by deuterium substitution of hydrogen atoms which form two kinds of N-H Midline-Horizontal-Ellipsis O type hydrogen bonds, and the isotope shift of ca. 100 kHz were detected for a whole observed temperature range. In addition, {sup 1}H MAS NMR spectra measurements of piperidinium and pyrrolidinium p-bromobenzoate were carried out and little isotope changes of NMR line shape were detected. In order to reveal effects of molecular arrangements into the obtained isotope shift of NQR frequencies, single-crystal X-ray measurement of piperidinium p-bromobenzoate-d2 and density-functional-theory calculation were carried out. Our estimation showed the dihedral-angle change between piperidine and benzene ring contributes to isotope shift rather than those of N-H lengths by deuterium substitution.

  5. Toxicosis by Plant Alkaloids in Humans and Animals in Colombia.

    Science.gov (United States)

    Diaz, Gonzalo J

    2015-12-11

    Due to its tropical location, chains of mountains, inter-Andean valleys, Amazon basin area, eastern plains and shores on both the Atlantic and Pacific Oceans, Colombia has many ecosystems and the second largest plant biodiversity in the world. Many plant species, both native and naturalized, are currently recognized as toxic for both animals and humans, and some of them are known to cause their toxic effects due to their alkaloid content. Among these, there are plants containing the hepatotoxic pyrrolizidine alkaloids, neurotoxins such as the indolizidine alkaloid swainsonine and the piperidine alkaloids coniine and γ-coniceine and tropane alkaloids. Unfortunately, the research in toxic plants in Colombia is not nearly proportional to its plant biodiversity and the scientific information available is only very scarce. The present review aims at summarizing the scarce information about plant alkaloid toxicosis in animals and humans in Colombia.

  6. Crystal structure of (3S*,4R*)-4-fluoro-3-(4-meth-oxy-phen-yl)-1-oxo-2-phenyl-1,2,3,4-tetra-hydro-iso-quinoline-4-carb-oxy-lic acid.

    Science.gov (United States)

    Lehmann, Anna; Lechner, Lisa; Radacki, Krzysztof; Braunschweig, Holger; Holzgrabe, Ulrike

    2017-06-01

    The title compound, C23H18FNO4, crystallized as a racemate. It exhibits a cis conformation with respect to the F atom and the methine H atom. The piperidine ring has a screw-boat conformation. The meth-oxy-phenyl ring and the phenyl ring are inclined to the mean plane of the iso-quinoline ring system by 89.85 (4) and 46.62 (5)°, respectively, and by 78.15 (5)° to one another. In the crystal, mol-ecules are linked by an O-H⋯O hydrogen bond forming chains propagating along the a-axis direction. The chains are linked by C-H⋯F hydrogen bonds, forming layers lying parallel to the ab plane.

  7. Coulometric titrations of bases in propylene carbonate and g-butyrolactone using hydroquinone as the depolarizer and a quinhydrone indicator electrode

    Directory of Open Access Journals (Sweden)

    Z. D. STANIC

    2000-08-01

    Full Text Available The application of hydroquinone for the coulometric generation of hydrogen ions in propylene carbonate (PC and g-butyrolactone (GBL is described. The current-potential curves recorded for theid sepolarizer, titrated bases, indicator and the solvents used showed that the investigated depolarizer is oxidized at lower potentials than the oxidation potentials of other components in the solution. the hydrogen ions generated by the oxidation of hydroquinone were used for the titration of organic bases (triethylamine, n-butylamine, pyridine, quinoline, aniline, N,N’-diphenylguanidine, piperidine, and 2,2’-bipiridine in PC and GBL with visual (Crystal Violet as indicator and potentiometric end-point detection using a quinhydrone electrode as the indicator electrode. The quinhydrone added to the to be analyzed solution served both as a source of hydrogen ions and, together with the immersed platinum electrode, as a quinhydrone electrode. The relative error of the determination of the bases was about 1 %.

  8. A facile synthesis of ω-aminoalkyl ammonium hydrogen phosphates

    Institute of Scientific and Technical Information of China (English)

    Wei Bo Kong; Xiao Yong Zhou; Yang Yang; Xing Yi Xie

    2012-01-01

    A series of ω-aminoalkyl ammonium hydrogen phosphates were synthesized through a simple and efficient three-step method.The starting materials,ω-aminoalkyl alcohols (AC-n,with carbon number n =3,4,5,6),were amino-protected with 9-fluorenylmethyl chloroformate (Fmoc-Cl),followed by phosphorylation with POCl3 and deprotection in piperidine/DMF The structures of each intermediate and final product were confirmed by 1H NMR,FTIR and mass spectrum.The yield of each step was about 77-92%,with a total yield higher than 56%.This new method was superior in low-cost raw materials,mild reaction temperatures (0-25 ℃) and easy purification methods.

  9. Comparison of the electronic properties, and thermodynamic and kinetic parameters of the aquation of selected platinum(II) derivatives with their anticancer IC50 indexes.

    Science.gov (United States)

    Bradác, Ondrej; Zimmermann, Tomás; Burda, Jaroslav V

    2008-08-01

    Three potential anticancer agents {trans-[PtCl(2)(NH(3))(thiazole)], cis-[PtCl(2)(NH(3))(piperidine)], and PtCl(2)(NH(3))(cyclohexylamine) (JM118)} were explored and compared with cisplatin and the inactive [PtCl(dien)](+) complex. Basic electronic properties, bonding and stabilization energies were determined, and thermodynamic and kinetic parameters for the aquation reaction were estimated at the B3LYP/6-311++G(2df,2pd) level of theory. Since the aquation process represents activation of these agents, the obtained rate constants were compared with the experimental IC(50) values for several tumor cells. Despite the fact that the processes in which these drugs are involved and the way in which they affect cells are very complex, some correlations can be deduced.

  10. Design and synthesis of N-substituted indazole-3-carboxamides as poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors(†).

    Science.gov (United States)

    Patel, Maulik R; Pandya, Kashyap G; Lau-Cam, Cesar A; Singh, Satyakam; Pino, Maria A; Billack, Blase; Degenhardt, Kurt; Talele, Tanaji T

    2012-04-01

    A group of novel N-1-substituted indazole-3-carboxamide derivatives were synthesized and evaluated as inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1). A structure-based design strategy was applied to a weakly active unsubstituted 1H-indazole-3-carboxamide 2, by introducing a three carbon linker between 1H-indazole-3-carboxamide and different heterocycles, and led to compounds 4 [1-(3-(piperidine-1-yl)propyl)-1H-indazole-3-carboxamide, IC(50) =36μm] and 5 [1-(3-(2,3-dioxoindolin-1-yl)propyl)-1H-indazole-3-carboxamide, IC(50) = 6.8μm]. Compound 5 was evaluated in rats for its protective action against diabetes induced by a treatment with streptozotocin, a known diabetogenic agent. In addition to preserving the ability of the pancreas to secrete insulin, compound 5 was also able to attenuate the ensuing hyperglycemic response to a significant extent.

  11. Capturing a photoexcited molecular structure through time-domain x-ray absorption fine structure.

    Energy Technology Data Exchange (ETDEWEB)

    Chen, L. X.; Jaeger, W. J. H.; Jennings, G.; Gosztola, D. J.; Munkholm, A.; Hessler, J. P.

    2001-04-13

    The determination of the structure of transient molecules, such as photoexcited states, in disordered media (such as in solution) usually requires methods with high temporal resolution. The transient molecular structure of a reaction intermediate produced by photoexcitation of NiTPP-L{sub 2} (NiTPP, nickeltetraphenylporphyrin; L, piperidine) in solution was determined by x-ray absorption fine structure (XAFS) data obtained on a 14-nanosecond time scale from a third-generation synchrotron source. The XAFS measurements confirm that photoexcitation leads to the rapid removal of both axial ligands to produce a transient square-planar intermediate, NiTPP, with a lifetime of 28 nanoseconds. The transient structure of the photodissociated intermediate is nearly identical to that of the ground state NiTPP, suggesting that the intermediate adopts the same structure as the ground state in a noncoordinating solvent before it recombines with two ligands to form the more stable octahedrally coordinated NiTPP-L{sub 2}.

  12. Anomalous H/D isotope effect on {sup 35}Cl NQR frequencies in piperidinium p-chlorobenzoate

    Energy Technology Data Exchange (ETDEWEB)

    Nakano, Ryo; Honda, Hisashi, E-mail: hhonda@yokohama-cu.ac.jp [Yokohama City University, Graduate School of Integrated Science (Japan); Kimura, Taiki [Yokohama City University, Faculty of Science (Japan); Nakata, Eiichi; Takamizawa, Satoshi; Noro, Sumiko [Yokohama City University, Graduate School of Integrated Science (Japan); Ishimaru, Shin' ichi [Tokyo Denki University, Department of Green and Sustainable Chemistry (Japan)

    2008-01-15

    Anomalous isotope effects were detected in the {sup 35}Cl nuclear quadrupole resonance (NQR) frequency of piperidinium p-chlrobenzoate (C{sub 5}H{sub 10}NH. ClC{sub 6}H{sub 4}COOH) by deuteration of hydrogen atoms. The atoms were determined to form two kinds of N-H...O type H-bonds in the crystal structure. Large frequency shifts of the {sup 35}Cl resonance lines reaching 288 kHz at 77 K and 278 kHz at room temperature were caused upon deuteration, in spite of the fact that the Cl atoms in the molecule do not form hydrogen bonds in the crystal. Results of single crystal X-ray diffraction measurements and density-functional-theorem calculations suggest that a dihedral-angle change of 1.8{sup o} between benzene and the piperidine ring contributes to {sup 35}Cl NQR anomalous frequency shifts.

  13. Catalytic Dehydration of 4-Hydroxy-3-hexanone to 4-Hexen-3-one over HZSM-5 Zeolite

    Institute of Scientific and Technical Information of China (English)

    Huang Kai; Zheng Haitao; Tao Keyi

    2013-01-01

    A study on catalytic dehydration of 4-hydroxy-3-hexanone (HH) to 4-hexen-3-one (HO) was carried out through conversion of HH over HZSM-5 zeolite catalyst in a ifxed-bed reactor (FBR) operating under atmospheric pressure. The test indicated a relatively high activity of the HZSM-5 zeolite capable of achieving a HH conversion of 99.2% and a HO yield of 83.5%. Catalyst deactivation could be prevented by increasing the reaction temperature by 10℃ for every 20 h and adding 2.0% of piperidine in the feed. A catalyst stability test (for 100 h) in FBR showed that the catalyst was active even after 100 h of time-on-stream with HH conversion remaining at 99.2% and HO yield still reaching over 83.5%. Regenera-tion experiment showed that the regenerated catalyst demonstrated a catalytic performance comparable to the fresh one.

  14. Insecticidal activity of isobutylamides derived from Piper nigrum against adult of two mosquito species, Culex pipiens pallens and Aedes aegypti.

    Science.gov (United States)

    Park, Il-Kwon

    2012-01-01

    The insecticidal activity of Piper nigrum fruit-derived piperidine alkaloid (piperine) and N-isobutylamide alkaloids (pellitorine, guineensine, pipercide and retrofractamide A) against female adults of Culex pipiens pallens and Aedes aegypti was examined. On the basis of 24-h LD(50) values, the compound most toxic to female C. pipiens pallens was pellitorine (0.4 µg/♀) followed by guineensine (1.9 µg/♀), retrofractamide A (2.4 µg/♀) and pipercide (3.2 µg/♀). LD(50) value of chlorpyrifos was 0.03 µg/♀. Against female A. aegypti, the insecticidal activity was more pronounced in pellitorine (0.17 µg/♀) than in retrofractamide A (1.5 µg/♀), guineensine (1.7 µg/♀), and pipercide (2.0 µg/♀). LD(50) value of chlorpyrifos was 0.0014 µg/♀.

  15. Alkamides from the fruits of Piper longum and Piper nigrum displaying potent cell adhesion inhibition.

    Science.gov (United States)

    Lee, Seung Woong; Kim, Young Kook; Kim, Koanhoi; Lee, Hyun Sun; Choi, Jung Ho; Lee, Woo Song; Jun, Chang-Duk; Park, Jee Hun; Lee, Jeong Min; Rho, Mun-Chual

    2008-08-15

    Eight alkamides 1-8 were isolated by bioassay-guided isolation of EtOH extracts of the fruits of Piper longum and Piper nigum (Piperaceae). Their structures were elucidated by spectroscopic analysis ((1)H, (13)C NMR, and ESI-MS) as follows: guineensine (1), retrofracamide C (2), (2E,4Z,8E)-N-[9-(3,4-methylenedioxyphenyl)-2,4,8-nonatrienoyl]piperidine (3), pipernonaline (4), piperrolein B (5), piperchabamide D (6), pellitorin (7), and dehydropipernonaline (8). Their compounds 3-5, 7, and 8 inhibited potently the direct binding between sICAM-1 and LFA-1 of THP-1 cells in a dose-dependent manner, with IC(50) values of 10.7, 8.8, 13.4, 13.5, and 6.0 microg/mL, respectively.

  16. Antimycobacterial and cytotoxicity activity of synthetic and natural compounds

    Energy Technology Data Exchange (ETDEWEB)

    Souza, Ana O. de [Instituto Butantan, Sao Paulo, SP (Brazil). Lab. de Bioquimica e Biofisica]. E-mail: olivia@butantan.gov.br; Galetti, Fabio C.S.; Silva, Celio L. [Universidade de Sao Paulo (USP), Ribeirao Preto, SP (Brazil). Faculdade de Medicina. Dept. de Bioquimica e Imunologia] (and others)

    2007-07-01

    Antimycobacterial and cytotoxicity activity of synthetic and natural compounds. Secondary metabolites from Curvularia eragrostidis and Drechslera dematioidea, Clusia sp. floral resin, alkaloids from Pilocarpus alatus, salicylideneanilines, piperidine amides, the amine 1-cinnamylpiperazine and chiral pyridinium salts were assayed on Mycobacterium tuberculosis H37Rv. N-(salicylidene)-2-hydroxyaniline was the most effective compound with a minimal inhibitory concentration (MIC) of 8 {mu}mol/L. Dihydrocurvularin was moderately effective with a MIC of 40 {mu}mol/L. Clusia sp. floral resin and a gallocatechin-epigallocatechin mixture showed MIC of 0.02 g/L and 38 {mu}mol/L, respectively. The cytotoxicity was evaluated for N-(salicylidene)-2-hydroxyaniline, curvularin, dihydrocurvularin and Clusia sp. floral resin, and the selectivity indexes were > 125, 0.47, 0.75 and 5, respectively. (author)

  17. Effect of leaving group on the oligomerization of 5'-AMP on montmorillonite. [Abstract only

    Science.gov (United States)

    Prabahar, K. Joseph; Ferris, James P.

    1994-01-01

    The oligomerization of imidazole derivative of 5'-AMP (ImpA) in the presence of montmorillonite clay yields oligomers containing up to 10 monomer units. In these reactions, the heterocyclic base, imidazole is the leaving group. In our present study, we synthesized a series of activated nucleotides of 5'AMP using other leaving groups such as pyrazole, 1,2,4-triazole, piperidine, morpholine, 4-aminopyridine, 4-methylaminopyridine, 4-dimethylaminopyridine, 2-aminobenzimidazole etc. to determine the effect of amine leaving group on the products of the oligomerization reaction. Earlier results from our laboratory showed that the presence AppA in the clay reaction of ImpA enhances the oligomerization reaction to yield higher oligomers. We also studied the effect of AppA in the clay mediated oligomerization reaction of the activated nucleotides. Oligomerization of 2-amino-benzimidazole derivative of 5'-AMP gave higher oligomers containing up to nine monomer units in the presence of AppA.

  18. A universal, photocleavable DNA base: nitropiperonyl 2'-deoxyriboside.

    Science.gov (United States)

    Pirrung, M C; Zhao, X; Harris, S V

    2001-03-23

    A universal, photochemically cleavable DNA base analogue would add desirable versatility to a number of methods in molecular biology. A novel C-nucleoside, nitropiperonyl deoxyriboside (NPdR, P), has been investigated for this purpose. NPdR can be converted to its 5'-DMTr-3'-CE-phosphoramidite and was incorporated into pentacosanucleotides by conventional synthesis techniques. The destabilizing effect on hybrid formation with a complementary strand when this P base opposes A, T, and G was found to be 3-5 kcal/mol, but 9 kcal/mol when it opposes C. Brief irradiation (lambda > 360 nm, 20 min) of DNA containing the P base and piperidine treatment causes strand cleavage giving the 3'- and 5'-phosphates. Two significant recent interests, universal/non-hydrogen-bonding base analogues and photochemical backbone cleavage, have thus been combined in a single molecule that serves as a light-based DNA scissors.

  19. Polarographic determination of loratadine in pharmaceutical preparations.

    Science.gov (United States)

    Squella, J A; Sturm, J C; Diaz, M A; Pessoa, H; Nuñez-Vergara, L J

    1996-12-01

    Loratadine, a potent antihistamine drug, is not directly electroreducible at a dropping mercury electrode; however, by means of a nitration procedure it is possible to obtain a nitro-loratadine derivative which has been identified as 4-(8-chloro-7-nitro-5,6-dihydro-11 H-benzo-[5,6]-cyclohepta-[l,2-b]-pyridin-l l-ylidene)-1-piperidine carboxylic acid ethyl ester. The electrochemical reduction of this derivative at different pHs and concentrations using polarography and cyclic voltammetry was studied. The derivative exhibits a differential pulse polarographic peak due to the reduction of the nitro group. This peak was used in order to develop an analytical procedure for determining loratadine in pharmaceutical dosage forms. The recovery study shows adequate accuracy and precision for the developed assay and the excipients do not interfere in the determination.

  20. Synthesis of New Fluorine Substituted Heterocyclic Nitrogen Systems Derived from p-Aminosalicylic Acid as Antimycobacterial Agents

    Directory of Open Access Journals (Sweden)

    Mohammed Saleh I. T. Makki

    2013-01-01

    Full Text Available Some new fluorine substituted heterocyclic nitrogen systems 2–17 have been synthesized from ring closure reactions of substituted p-amino salicylic acids (PAS. The Schiffs base of PAS was cyclized with chloroacetyl chloride and mercaptoacetic acid to give azetidinone 2, thiazolidinone 3, and spiro-fluoroindolothiazoline-dione 10. However, PAS when reacted directly with 4-fluorobenzoyl chloride and 5-oxazolinone yielded derivatives 4, 5, and 7. Aminomethylation of PAS using formaldehyde and piperidine or piperazine formed N-alkyl and N,N′-dialkyl derivatives (11 and 12 respectively upon fluorinated benzoylation gave compounds 13 and 14. Similarly, treatment of PAS with thiosemicarbazide 15 and subsequent cyclization with diethyl oxalate yielded the fluorinated heterocycle 17. The structures of the fluorinated heterocyclic systems have been established on the basis of elemental analysis, 1H NMR, 13C NMR, and MS spectral data. Some of the targets exhibited a high inhibition towards Mycobacterium strain with favorable log P values.

  1. SYNTHESIS, CHARACTERIZATION OF SOME NOVEL PYRAZOLES AND THEIR GROWTH PROMOTING ACTIVITY ON SOME FLOWERING PLANTS

    Directory of Open Access Journals (Sweden)

    Hushare VJ

    2013-01-01

    Full Text Available A series of chlorosubstituted 4-aroylpyrazoles have been synthesized by refluxing of chlorosubstituted-3-aroylflavones and 3-alkoylchromone with phenylhydrazine hydrochloride in dioxane medium with 0.5 ml of piperidine. Chlorosubstituted-3-aroylflavones and chlorosubstituted-3-alkoylchromone were prepared by refluxing them separately with iodine crystal in ethanol. Initially chlorosubstituted-3-aroylflavanones and 3-alkoylchromanone have been prepared separately by the interaction of different aldehydes with 1(2-hydroxy-3,5-dichlorophenyl-3-phenyl-1,3-propanedione. Constitutions of synthesized compounds have been confirmed on the basis of elemental analysis, molecular weight determination, UV-Visible, I.R. and 1H-NMR spectral data. The titled compounds were evaluated for their growth promoting activity on some flowering plants viz. Papaver rhoeas, Dianthus chinensis, Candy tuft, Calendula officinalise, Gladiola tristis, Gaillardia.

  2. Methyl-substitution of an iminohydantoin spiropiperidine β-secretase (BACE-1) inhibitor has a profound effect on its potency.

    Science.gov (United States)

    Egbertson, Melissa; McGaughey, Georgia B; Pitzenberger, Steven M; Stauffer, Shaun R; Coburn, Craig A; Stachel, Shawn J; Yang, Wenjin; Barrow, James C; Neilson, Lou Anne; McWherter, Melody; Perlow, Debra; Fahr, Bruce; Munshi, Sanjeev; Allison, Timothy J; Holloway, Katharine; Selnick, Harold G; Yang, ZhiQiang; Swestock, John; Simon, Adam J; Sankaranarayanan, Sethu; Colussi, Dennis; Tugusheva, Katherine; Lai, Ming-Tain; Pietrak, Beth; Haugabook, Shari; Jin, Lixia; Chen, I-W; Holahan, Marie; Stranieri-Michener, Maria; Cook, Jacquelynn J; Vacca, Joseph; Graham, Samuel L

    2015-11-01

    The IC50 of a beta-secretase (BACE-1) lead compound was improved ∼200-fold from 11 μM to 55 nM through the addition of a single methyl group. Computational chemistry, small molecule NMR, and protein crystallography capabilities were used to compare the solution conformation of the ligand under varying pH conditions to its conformation when bound in the active site. Chemical modification then explored available binding pockets adjacent to the ligand. A strategically placed methyl group not only maintained the required pKa of the piperidine nitrogen and filled a small hydrophobic pocket, but more importantly, stabilized the conformation best suited for optimized binding to the receptor.

  3. Crosslinking in the diglycidyl ether oligoepichlorhydrin-piperazine

    Directory of Open Access Journals (Sweden)

    Konstantyn E. Varlan

    2014-03-01

    Full Text Available The possibility of acquiring film material from a mixture of oligoepichlorhydrin diglycidylether and piperazyne discussed. The process involves elongation of the chain by means of reaction of the oligomer terminal oxyran cycles with piperazine aminogrups, and the subsequent formation of crosslinked by tertiary amine alongthe chainsalkylation whis chlorometyl dand groups of macromolecules. With this purpose, the model system investigated: epichlorohydrin−piperidine, epichlorohydrin−piperazine, oligoetylenglikol glicidyl ether−piperazine. The possibility of regulating the contributions of reactions of epoxy group and alkylation on crosslinking primary stage is disclosed, as well as material properties. Taking into account the found regularities receive elastic film structured materials with quaternary nitrogen atoms in the nodes. The ratio of tertiary and quaternary structure of nitrogen depends on the process conditions. Films swell in polar solvents and has ion-exchange properties.

  4. Hydrolysis mechanisms of trans platinum-based anticancer drug with heterocyclic amine ligands: A comparative DFT study%杂环反铂(Ⅱ)抗癌药物水解反应机理的DFT研究

    Institute of Scientific and Technical Information of China (English)

    李添; 周立新; 李娟

    2012-01-01

    In this work, the hydrolysis processes of the anticancer drugs trans-[PtCl2 (piperi-dine) ( Am)], Am = 2.-pico]ine( 1), 3-picoline(2) , 4-picoiine(3), trans-[PtCl; (piperidine) ( piper-azine)] (4), trans-[PtCl2 ( piperazme )2 ] (5 ) and trans-[ PtCl2 (iminoether )2 ] (6 ) have been studied using hybrid density functional theory (B3LYP) and iso-electnc focusing polarized con-tinuum model CIEF-PCM) solvation models. The hydrolysis reactions leading to the activated drug form a key step for the reaction with the target DNA. The stationary points on the poten-tial energy surfaces for the first and second hydrolysis steps, proceeding via a general SN2 pathway, were fully optimized and characterized. It is found that the processes of the reactions follow the established theory for ligand substitution in square planar complexes,that is, substi-tution reactions usually occur via Pt-Iigand exchange reactions with a trigonal-bipyramidsl transition stale structure; the geometries of the transition states (TS) agree with the previous related work and all of the reactions are endothermic; the barrier height of the second hydroly-sis is always higher than that of the first step for all the systems. In comparison with previous work on cisplatin, a faster rate of hydrolysis is determined for the reaction. We make a com-parison with previous work on the hydrolysis processes of analogous trans platinum-based anti- cancer drugs. The results provide detailed energy profiles for the mechanism of hydrolysis of 1, 2, 3. 4, 5 and 6, which may assist in understanding the reaction mechanism of the drug with the DNA target and in the design of novel Pt-based anticancer drugs with trans geometries.%用DFT-B3LYP方法和IEF-PCM溶剂化模型研究了反铂抗癌药物trans-[PtCl2(piperidine)(Am)](Am=2-picoline(1).3-picoline(2),4 picoline(3)),trans-[PtCl2(piperidine)(piperazine)](4),trans-[PtCl2(piperazine)2](5)and trans-[PtCl2(iminoether)2](6)的水解过程.水解反应是药物与DNA靶

  5. Optimization of amine-terminated polyacrylonitrile synthesis and characterization

    Directory of Open Access Journals (Sweden)

    Mohamed H. El-Newehy

    2014-04-01

    Full Text Available Amine-terminated PANs were prepared in two steps. The first step includes free radical polymerization of acrylonitrile (AN using initiator pair of ammonium persulfate and sodium thiosulfate as redox system. In the second step, the amino groups were introduced through the reaction of polyacrylonitrile with excess of different diamines (10-fold including ethylenediamine (EDA, hexamethylenediamine (HMDA and octamethylenediamine (OMDA, to yield PAN–EDA, PAN–HMDA and PAN–OMDA, respectively. Optimization of the amine-terminated PANs synthesis was carried out at different temperatures (30–90 °C and different time intervals (4–24 h. In addition, the introduction of the amino group was followed by the piperidine test and recording of the FT-IR spectra. All polymers were characterized by, 1H NMR spectra, thermogravimetric analysis (TGA, and FT-IR spectra.

  6. Design, synthesis and docking studies of novel 1,2-dihydro-4-hydroxy-2-oxoquinoline-3-carboxamide derivatives as a potential anti-proliferative agents.

    Science.gov (United States)

    Banu, Saleha; Bollu, Rajitha; Bantu, Rajashaker; Nagarapu, Lingaiah; Polepalli, Sowjanya; Jain, Nishant; Vangala, Radhika; Manga, Vijjulatha

    2017-01-05

    A new series of 4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide hybrids 8a-l have been designed and synthesized using peptide coupling agents with substituted N-phenyl piperazines and piperidines with good to excellent yields. The synthesized compounds were evaluated for their in vitro anti-proliferative activity against PANC 1, HeLa and MDA-MB-231. The compounds 8d, 8e, 8f, 8g, 8h and 8k exhibited considerable anti-proliferative activity with GI50 values ranging from 0.15 to 1.4 μM. The structure and anti-proliferative activity relationship was further supported by in silico molecular docking study of the active compounds against tubulin protein. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  7. A thermal and electrochemical properties research on gel polymer electrolyte membrane of lithium ion battery

    Science.gov (United States)

    Li, Libo; Ma, Yue; Wang, Wentao; Xu, Yanping; You, Jun; Zhang, Yonghong

    2016-12-01

    N-methyl-N-propyl-piperidin-bis(trifluoromethylsulfonyl)imide/bis(trifluoromethylsulfonyl) imide lithium base/polymethyl methacrylate(PP13TFSI/LiTFSI/PMMA) gel polymer electrolyte (GPE) membrane was prepared by in situ polymerization. The physical and chemical properties were comprehensively discussed. The decomposition characteristics were emphasized by thermogravimetric (TG-DTG) method in the nitrogen atmosphere at the different heating rates of 5, 10, 15 and 20 °C min-1, respectively. The activation energy was calculated with the iso-conversional methods of Ozawa and Kissinger, Friedman, respectively, and the Coats-Redfern methods were adopted to employ the detailed mechanism of the electrolyte membrane. The equation f(α)=3/2[(1-α)1/3-1] was quite an appropriate kinetic mechanisms to describe the thermal decomposition process with an activation energy (Eα) of 184 kJ/mol and a pre-exponential factor (A) of 1.894×1011 were obtained.

  8. 11-[(E-Benzylidene]-14-hydroxy-8-phenyl-6-thia-3,13-diazaheptacyclo[13.7.1.19,13.02,9.02,14.03,7.019,23]tetracosa-1(22,15(23,16,18,20-pentaen-10-one

    Directory of Open Access Journals (Sweden)

    Raju Suresh Kumar

    2012-07-01

    Full Text Available In the title compound, C34H28N2O2S, the piperidine ring adopts a chair conformation. One of the pyrrolidine rings adopts an envelope conformation with the methylene C atom at the flap whereas the other pyrrolidine ring and the thiazolidine ring adopt half-chair conformations. The mean plane of the dihydroacenaphthylene ring system [maximum deviation = 0.067 (1 Å] makes dihedral angles of 28.31 (5 and 31.32 (6° with the two terminal benzene rings. An intramolecular O—H...N hydrogen bond forms an S(5 ring motif. In the crystal, molecules are linked by C—H...O and C—H...S hydrogen bonds into layers lying parallel to the ac plane.

  9. 5-[(E-2-Bromobenzylidene]-8-(2-bromophenyl-2-hydroxy-10-methyl-3,10-diazahexacyclo[10.7.1.13,7.02,11.07,11.016,20]henicosa-1(20,12,14,16,18-pentaen-6-one

    Directory of Open Access Journals (Sweden)

    Raju Suresh Kumar

    2010-09-01

    Full Text Available In the title compound, C33H26Br2N2O2, the piperidine group adopts an envelope conformation while the two pyrrolidine groups adopt half-chair and envelope conformations. The dihydroacenaphthylene group is almost planar, with a maximum deviation of 0.105 (1 Å. The dihedral angle between the two bromophenyl rings is 60.19 (8°. An intramolecular O—H...N interaction is observed, generating an S(5 ring motif. The crystal structure is stabilized by intermolecular C—H...O interactions. Short Br...Br [3.461 (1 Å] and Br...C [3.322 (2 Å] intermolecular contacts are observed, as well as π–π interactions [centroid–centroid distance = 3.793 (1 Å].

  10. Synthesis of β-Amino Acid Derivatives

    Institute of Scientific and Technical Information of China (English)

    Zhao Yonghua; Ma Zhihua; Jiang Nan; Wang Jianbo

    2004-01-01

    In recent years, β-amino acids and their derivatives have attracted considerable attention due to their occurrence in biologically active natural products, such as dolastatins,cyclohexylnorstatine and Taxol. β-Amino acids also find application in the synthesis of β-lactams,piperidines, indolizidines. Moreover, the peptides consisting of β-amino acids, the so-called β-peptides, have been extensively studied recently. Consequently, considerable efforts have been directed to the synthesis of β-amino acids and their derivatives1. In particular, stereoselective synthesis of β-amino acids has been a challenging project, and there are only limited methods available. In this presentation, we report our efforts in this area.

  11. Synthesis and pharmacological evaluation of 1-isopropyl-1,2,3,4-tetrahydroisoquinoline derivatives as novel antihypertensive agents.

    Science.gov (United States)

    Watanuki, Susumu; Matsuura, Keisuke; Tomura, Yuichi; Okada, Minoru; Okazaki, Toshio; Ohta, Mitsuaki; Tsukamoto, Shin-Ichi

    2011-01-01

    A series of 1-isopropyl-1,2,3,4-tetrahydroisoquinoline derivatives were synthesized and their bradycardic activities were evaluated in isolated guinea pig right atria. Structure-activity relationship studies revealed that the introduction of an appropriate substituent and its position on the 1,2,3,4-tetrahydroisoquinoline ring are essential for potent in vitro activity. Furthermore, the tether between the piperidyl moiety and the terminal aromatic ring is important for potent antihypertensive activity. Oral administration of 6-fluoro-1-isopropyl-2-{[1-(2-phenylethyl)piperidin-4-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline (3b) to spontaneously hypertensive rats (SHR) elicited antihypertensive effects without inducing reflex tachycardia, which is often caused by traditional L-type Ca²⁺ channel blockers.

  12. Synthesis and insecticidal activity of new deoxypodophyllotoxin derivatives modified in the D-ring.

    Science.gov (United States)

    Wang, Juanjuan; Yu, Xiang; Zhi, Xiaoyan; Xu, Hui

    2014-09-15

    In continuation of our program aimed at the discovery of new natural-product-based insecticidal agents, twenty-six deoxypodophyllotoxin derivatives modified in the D-ring were synthesized and evaluated as insecticidal agents against the pre-third-instar larvae of oriental armyworm, Mythimna separata (Walker) in vivo at 1 mg/mL. The configuration of three compounds 3, 4, and IIIi was unambiguously determined by single-crystal X-ray diffraction. It demonstrated that aminolysis of deoxypodophyllotoxin in the presence of pyrrolidine and piperidine could result in complete inversion of the configuration of the carbonyl group at its C-2 position. Five compounds IIa, IIi-k, and IIIh showed the equal or higher insecticidal activity than toosendanin. Especially IIj displayed the most potent insecticidal activity with the final mortality rate of 65.5%.

  13. Fluorescence Studies of Selected 2-Alkylaminopyrimidines

    Directory of Open Access Journals (Sweden)

    B. K. Low

    2004-06-01

    Full Text Available The reactions of 2-chloropyrimidine with methylamine, ethylamine and piperidine gave the corresponding 2-N-methylamino-, 2-N-ethylamino- and 2N- piperidinopyrimidines, respectively. The fluorescence properties of these alkylamino derivatives in chloroform, ethyl acetate, carbon tetrachloride, acetone, ether, ethanol and methanol were studied. All the alkylamino derivatives showed the highest fluorescence intensity in polar protic solvents; thus 2-N-methylaminopyrimidine (highest fluorescence intensity at 377 nm when excited at 282 nm and 2-N-ethylaminopyrimidine (highest fluorescence intensity at 375 nm, when excited at 286 nm showed the highest fluorescence in methanol. In ethanol, 2-N-piperidinopyrimidine showed a fluorescence peak at 403 nm when excited at 360 nm and in chloroform it fluoresced at 392 nm when excited at 356 nm.

  14. (1R*,21S*,22R*,24S*-Methyl ethyl 2-[23-hydroxy-22,24-diphenyl-8,11,14-trioxa-25-azatetracyclo[19.3.1.02,7.015,20]pentacosa-2,4,6,15(20,16,18-hexaen-25-yl]but-2-enedioate

    Directory of Open Access Journals (Sweden)

    Truong Hong Hieu

    2013-07-01

    Full Text Available The title compound, C40H41NO8, is a product of the reduction of the cyclic carbonyl group of the γ-piperidone subunit of the aza-14-crown-4 ether with subsequent re-esterification of its dimethyl butenoate substituent into a monoethyl monomethyl group. The azacrown macrocycle exhibits a bowl conformation with a dihedral angle of 70.82 (5° between the benzene rings fused to it. The piperidine ring adopts a chair conformation and the methyl ethyl ethylenedicarboxylate fragment has a cis conformation, with a dihedral angle of 66.51 (7° between the two carboxylate groups. The ethyl group is disordered over two sites with occupancies of 0.70 (1:0.30 (1. In the crystal, molecules form inversion dimers, via pairs of O—H...O hydrogen bonds, that stack along the a axis.

  15. Ruthenium(II) complexes containing bidentate Schiff bases and triphenylphosphine or triphenylarsine

    Indian Academy of Sciences (India)

    P Viswanathamurthi; R Karvembu; V Tharaneeswaran; K Natarajan

    2005-05-01

    Reactions of ruthenium(II) complexes [RuHX(CO)(EPh3)2(B)] (X = H or Cl; B = EPh3, pyridine (py) or piperidine (pip); E = P or As) with bidentate Schiff base ligands derived by condensing - hydroxyacetophenone with aniline, - or -methylaniline have been carried out. The products were characterized by analytical, IR, electronic and 1H-NMR spectral studies and are formulated as [Ru(X)(CO) (L)(EPh3)(B)] (L = Schiff base anion; X = H or Cl; B = EPh3, py or pip; E = P or As). An octahedral structure has been tentatively proposed for the new complexes. The new complexes were tested for their catalytic activities in the oxidation of benzyl alcohol to benzaldehyde.

  16. Spectral assignments and structural studies of a warfarin derivative stereoselectively formed by tandem cyclization

    Science.gov (United States)

    Velayutham Pillai, M.; Rajeswari, K.; Vidhyasagar, T.

    2015-11-01

    The structural elucidation of a Mannich condensation product of rac-Warfarin with benzaldehyde and methyl amine was carried out using IR, Mass, 1H NMR, 13C NMR, 1H-1H COSY, 1H-13C COSY, DEPT-135, HMBC, NOESY spectra and single crystal X-ray diffraction. Formation of a new pyran ring via a tandem cyclization in the presence of methyl amine was observed. The optimized geometry and HOMO-LUMO energy gap along with other important physical parameters were found by Gaussian 09 program using HF 6-31G (d, p) and B3YLP/DFT 6-31G (d, p) level of theory. The preferred conformation of the piperidine ring in solution state was found to be chair from the NMR spectra. Single crystal X-ray diffraction and optimized geometry (by theoretical study) also confirms the chair conformation in the solid state.

  17. Methyl trans-(±-1-oxo-2-phenethyl-3-(thiophen-2-yl-1,2,3,4-tetrahydroisoquinoline-4-carboxylate

    Directory of Open Access Journals (Sweden)

    Mehmet Akkurt

    2009-06-01

    Full Text Available In the title compound, C23H21NO3S, the piperidine ring of the tetrahydroisoquinolinone unit adopts a screw-boat conformation. The thiophene ring is disordered in a 0.700 (3:0.300 (3 ratio by an approximate 180° rotation of the ring around the C—C bond linking the ring to the tetrahydroisoquinolinone unit. The benzene ring of the tetrahydroisoquinolinone unit makes dihedral angles of 83.1 (2 and 62.38 (11° with the major occupancy thiophene ring and the phenyl ring, respectively. The dihedral angle between the phenyl ring and the thiophene ring is 71.0 (2°. In the crystal structure, molecules are linked together by intermolecular C—H...O and C—H...π interactions.

  18. Crystal structures of resorcin[4]arene and pyrogallol[4]arene complexes with DL-pipecolinic acid. Model compounds for the recognition of the pipecolinyl ring, a key fragment of FK506, through C-H⋯π interaction

    Science.gov (United States)

    Fujisawa, Ikuhide; Kitamura, Yuji; Kato, Ryo; Murayama, Kazutaka; Aoki, Katsuyuki

    2014-01-01

    Resorcin[4]arene (resorcinol cyclic tetramer, abbreviated as RCT) or pyrogallol[4]arene (pyrogallol cyclic tetramer, PCT) form host-guest 1:1 complexes with DL-pipecolinic acid (DL-pipeH), RCT·DL-pipeH·EtOH·8H2O (1), PCT DL-pipeH·EtOH·4H2O (2), and PCT·DL-pipeH·3H2O (3), whose crystal structures have been determined. In each complex, the pipeH ligand is incorporated into the bowl-shaped cavity of the RCT or PCT host molecules through C-H⋯π interactions between alkyl protons of the piperidine ring of pipeH and π-rings of RCT or PCT, forming an [(RCT/PCT)·pipeH] structural fragment. In 1 and 3, two [(RCT/PCT) pipeH] fragments self-associate across an inversion center to form a guest-mediated, obliquely declined dimeric structure [(RCT/PCT)·L-pipeH·D-pipeH (RCT/PCT)]. In 2, each PCT-capped pipeH ligand bridges to two adjacent PCT molecules to form guest-mediated, optically-discrete helical polymers [PCT·L-pipeH]n or [PCT·D-pipeH]n. An 1H NMR experiment shows that the complexation through C-H⋯π interaction between the piperidine ring of pipeH and π-rings of RCT or PCT occurs also in solution, with the binding constants of 9.7 ± 0.6 M-1 for RCT and 26.5 ± 1.5 M-1 for PCT. These complexes provide a synthetic model for the recognition of the pipecolinyl-ring moiety, a key constituent of immunosuppressant drugs such as FK506, FK520 or rapamycin, by their binding proteins through C-H⋯π interaction.

  19. Remediation of hemorrhagic shock-induced intestinal barrier dysfunction by treatment with diphenyldihaloketones EF24 and CLEFMA.

    Science.gov (United States)

    Yadav, Vivek R; Hussain, Alamdar; Sahoo, Kaustuv; Awasthi, Vibhudutta

    2014-11-01

    Gut is very sensitive to hypoperfusion and hypoxia, and deranged gastrointestinal barrier is implicated in systemic failure of various organs. We recently demonstrated that diphenyldihaloketone EF24 [3,5-bis(2-fluorobenzylidene)piperidin-4-one] improves survival in a rat model of hemorrhagic shock. In this study, we tested EF24 and its other analog CLEFMA (4-[3,5-bis(2-chlorobenzylidene)-4-oxo-piperidine-1-yl]-4-oxo-2-butenoic acid) for their effect on intestinal barrier dysfunction in hypovolemic shock. Hypovolemia was induced in rats by withdrawing 50% of blood. EF24 or CLEFMA (0.4 mg/kg i.p.) treatment was provided, without volume resuscitation, after 1 hour of hemorrhage. Ileum was collected 5 hours after the treatment to investigate the expression of tight junction proteins (zonula occludens, claudin, and occludin) and epithelial injury markers [myeloperoxidase, ileal lipid-binding protein (ILBP), CD163, and plasma citrulline]. The ileal permeability for dextran-fluoroisothiocyanate and Evan's blue dye was determined. EF24 and CLEFMA reduced the hypovolemia-induced plasma citrulline levels and the ileal expression of myeloperoxidase, ILBP, and CD163. The drugs also restored the basal expression levels of zonula occludens, claudin, and occludin, which were substantially deranged by hypovolemia. In ischemic ileum, the expression of phospho(tyrosine)-zonula occludens-1 was reduced, which was reinstated by EF24 and CLEFMA. In contrast, the drug treatments maintained the hypovolemia-induced expression of phospho(threonine)-occludin, but reduced that of phospho(tyrosine)-occludin. Both EF24 and CLEFMA treatments reduced the intestinal permeability enhanced by hypovolemia. EF24 and CLEFMA attenuate hypovolemic gut pathology and protect barrier function by restoring the status of tight junction proteins. These effects were observed in unresuscitated shock, implying the benefit of EF24 and CLEFMA in prehospital care of shock.

  20. Test purchase, synthesis, and characterization of 2-methoxydiphenidine (MXP) and differentiation from its meta- and para-substituted isomers.

    Science.gov (United States)

    McLaughlin, Gavin; Morris, Noreen; Kavanagh, Pierce V; Power, John D; O'Brien, John; Talbot, Brian; Elliott, Simon P; Wallach, Jason; Hoang, Khoa; Morris, Hamilton; Brandt, Simon D

    2016-01-01

    The structurally diverse nature of the 1,2-diphenylethylamine template provides access to a range of substances for drug discovery work but some have attracted attention as 'research chemicals'. The most recent examples include diphenidine, i.e. 1-(1,2-diphenylethyl)piperidine and 2-methoxydiphenidine, i.e. 1-[1-(2-methoxyphenyl)-2-phenylethyl]piperidine (MXP, methoxyphenidine, 2-MXP) that have been associated with uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist activity. Analytical challenges encountered during chemical analysis include the presence of positional isomers. Three powdered samples suspected to contain 2-MXP were obtained from three Internet retailers in the United Kingdom and subjected to analytical characterization by gas chromatography (GC) and high performance liquid chromatography (HPLC) coupled to various forms of mass spectrometry (MS). Nuclear magnetic resonance spectroscopy, infrared spectroscopy and thin layer chromatography were also employed. This was supported by the synthesis of all three isomers (2-, 3- and 4-MXP) by two different synthetic routes. The analytical data obtained for the three purchased samples were consistent with the synthesized 2-MXP standard and the differentiation between the isomers was possible. Distinct stability differences were observed for all three isomers during in-source collision-induced dissociation of the protonated molecule when employing detection under HPLC selected-ion monitoring detection, which added to the ability to differentiate between them. Furthermore, the analysis of a 2-MXP tablet by matrix assisted inlet ionization Orbitrap mass spectrometry confirmed that it was possible to detect the protonated molecule of 2-MXP directly from the tablet surface following addition of 3-nitrobenzonitrile as the matrix.

  1. Studies on molecular properties prediction and histamine H3 receptor affinities of novel ligands with uracil-based motifs.

    Science.gov (United States)

    Lipani, Luca; Odadzic, Dalibor; Weizel, Lilia; Schwed, Johannes-Stephan; Sadek, Bassem; Stark, Holger

    2014-10-30

    The histamine H3 receptor (H3R) plays a role in cognitive and memory processes and is involved in different neurological disorders, including Alzheimer's disease, schizophrenia, and narcolepsy. Therefore, several hH3R antagonists/inverse agonists entered clinical phases for a broad spectrum of mainly centrally occurring diseases. However, many other promising candidates failed due to their pharmacokinetic profile, mostly because of their strong lipophilicity accompanied with low solubility. Analysis of previous potential H3R selective antagonists/inverse agonists, e.g. pitolisant, revealed promising results concerning physicochemical properties and drug-likeness. Herein, a series of new hH3R ligands 8-20 consisting of piperidin-1-yl or piperidin-1-yl-propoxyphenyl coupled to different uracil, thymine, and 5,6-dimethyluracil related moieties, were synthesized, evaluated on their binding properties at the hH3R and the estimation of different physicochemical and drug-likeness properties. Due to the coupling to various positions at pyrimidine-2,4-(1H,3H)-dione, affinity at hH3Rs and drug-likeness parameters have been improved. For instance, compound 9 showed in addition to high affinity at the hH3R (pKi (hH3R) = 8.14) clog S, clog P, LE, LipE, and drug-likeness score values of -4.36, 3.47, 0.34, 4.63, and 1.54, respectively. Also, the methyl substituted analog 17 (pKi (hH3R) = 8.15) revealed LE, LipE and drug-likeness score values of -3.29, 2.47, 0.49, 5.52, and 1.76, respectively.

  2. Profile of pridopidine and its potential in the treatment of Huntington disease: the evidence to date

    Directory of Open Access Journals (Sweden)

    Squitieri F

    2015-10-01

    Full Text Available Ferdinando Squitieri,1 Justo Garcia de Yebenes2 1IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo and Mendel Institute of Human Genetics, Rome, Italy; 2Fundación para Investigaciones Neurológicas, Madrid, Spain Abstract: Huntington disease (HD is a chronic, genetic, neurodegenerative disease for which there is no cure. The main symptoms of HD are abnormal involuntary movements (chorea and dystonia, impaired voluntary movements (ie, incoordination and gait balance, progressive cognitive decline, and psychiatric disturbances. HD is caused by a CAG-repeat expanded mutation in the HTT gene, which encodes the huntingtin protein. The inherited mutation results in the production of an elongated polyQ mutant huntingtin protein (mHtt. The cellular functions of the Htt protein are not yet fully understood, but the functions of its mutant variant are thought to include alteration of gene transcription and energy production, and dysregulation of neurotransmitter metabolism, receptors, and growth factors. The phenylpiperidines pridopidine (4-[3-methanesulfonyl-phenyl]-1-propyl-piperidine; formerly known as ACR16 and OSU6162 ([S]-[-]-3-[3-methane [sulfonyl-phenyl]-1-propyl-piperidine are members of a new class of pharmacologic agents known as “dopamine stabilizers”. Recent clinical trials have highlighted the potential of pridopidine for symptomatic treatment of patients with HD. More recently, the analysis of HD models (ie, in vitro and in mice highlighted previously unknown effects of pridopidine (increase in brain-derived neurotrophic factor, reduction in mHtt levels, and σ-1 receptor binding and modulation. These additional functions of pridopidine suggest it might be a neuroprotective and disease-modifying drug. Data from ongoing clinical trials of pridopidine will help define its place in the treatment of HD. This commentary examines the available preclinical and clinical evidence regarding the use of pridopidine in HD. Keywords

  3. Widespread Chemical Detoxification of Alkaloid Venom by Formicine Ants.

    Science.gov (United States)

    LeBrun, Edward G; Diebold, Peter J; Orr, Matthew R; Gilbert, Lawrence E

    2015-10-01

    The ability to detoxify defensive compounds of competitors provides key ecological advantages that can influence community-level processes. Although common in plants and bacteria, this type of detoxification interaction is extremely rare in animals. Here, using laboratory behavioral assays and analyses of videotaped interactions in South America, we report widespread venom detoxification among ants in the subfamily Formicinae. Across both data sets, nine formicine species, representing all major clades, used a stereotyped grooming behavior to self-apply formic acid (acidopore grooming) in response to fire ant (Solenopsis invicta and S. saevissima) venom exposure. In laboratory assays, this behavior increased the survivorship of species following exposure to S. invicta venom. Species expressed the behavior when exposed to additional alkaloid venoms, including both compositionally similar piperidine venom of an additional fire ant species and the pyrrolidine/pyrroline alkaloid venom of a Monomorium species. In addition, species expressed the behavior following exposure to the uncharacterized venom of a Crematogaster species. However, species did not express acidopore grooming when confronted with protein-based ant venoms or when exposed to monoterpenoid-based venom. This pattern, combined with the specific chemistry of the reaction of formic acid with venom alkaloids, indicates that alkaloid venoms are targets of detoxification grooming. Solenopsis thief ants, and Monomorium species stand out as brood-predators of formicine ants that produce piperidine, pyrrolidine, and pyrroline venom, providing an important ecological context for the use of detoxification behavior. Detoxification behavior also represents a mechanism that can influence the order of assemblage dominance hierarchies surrounding food competition. Thus, this behavior likely influences ant-assemblages through a variety of ecological pathways.

  4. Monoacylglycerol lipase (MAGL inhibition attenuates acute lung injury in mice.

    Directory of Open Access Journals (Sweden)

    Carolina Costola-de-Souza

    Full Text Available Endocannabinoid signaling is terminated by enzymatic hydrolysis, a process that, for 2-Arachidonoylglycerol (2-AG, is mediated by monoacylglycerol lipase (MAGL. The piperidine carbamate, 4-nitrophenyl- 4-(dibenzo[d] [1,3]dioxol-5-yl (hydroxy methyl piperidine- 1-carboxylate (JZL184, is a drug that inhibits MAGL and presents high potency and selectivity. Thus, JZL184 increases the levels of 2-AG, an endocannabinoid that acts on the CB1 and CB2 cannabinoid receptors. Here, we investigated the effects of MAGL inhibition, with a single dose (16 mg/kg, intraperitoneally (i.p. of JZL184, in a murine model of lipopolysaccharide (LPS -induced acute lung injury (ALI 6, 24 and 48 hours after the inflammatory insult. Treatment with JZL184 decreased the leukocyte migration into the lungs as well as the vascular permeability measured through the bronchoalveolar lavage fluid (BAL and histological analysis. JZL184 also reduced the cytokine and chemokine levels in the BAL and adhesion molecule expression in the blood and BAL. The CB1 and CB2 receptors were considered involved in the anti-inflammatory effects of JZL184 because the AM281 selective CB1 receptor antagonist (1-(2,4-dichlorophenyl-5-(4-iodophenyl-4-methyl-N-4-morpholinyl-1H-pyrazole-3-carboxamide and the AM630 selective CB2 receptor antagonist ([6-iodo-2-methyl-1-[2-(4-morpholinylethyl]-1H-indol-3-yl](4-methoxyphenyl-methanone blocked the anti-inflammatory effects previously described for JZL184. It was concluded that MAGL inhibition, and consequently the increase in 2-AG levels, produced anti-inflammatory effects in a murine model of LPS-induced ALI, a finding that was considered a consequence of the activation of the CB1 and CB2 receptors.

  5. Profile of pridopidine and its potential in the treatment of Huntington disease: the evidence to date.

    Science.gov (United States)

    Squitieri, Ferdinando; de Yebenes, Justo Garcia

    2015-01-01

    Huntington disease (HD) is a chronic, genetic, neurodegenerative disease for which there is no cure. The main symptoms of HD are abnormal involuntary movements (chorea and dystonia), impaired voluntary movements (ie, incoordination and gait balance), progressive cognitive decline, and psychiatric disturbances. HD is caused by a CAG-repeat expanded mutation in the HTT gene, which encodes the huntingtin protein. The inherited mutation results in the production of an elongated polyQ mutant huntingtin protein (mHtt). The cellular functions of the Htt protein are not yet fully understood, but the functions of its mutant variant are thought to include alteration of gene transcription and energy production, and dysregulation of neurotransmitter metabolism, receptors, and growth factors. The phenylpiperidines pridopidine (4-[3-methanesulfonyl-phenyl]-1-propyl-piperidine; formerly known as ACR16) and OSU6162 ([S]-[-]-3-[3-methane [sulfonyl-phenyl]-1-propyl-piperidine) are members of a new class of pharmacologic agents known as "dopamine stabilizers". Recent clinical trials have highlighted the potential of pridopidine for symptomatic treatment of patients with HD. More recently, the analysis of HD models (ie, in vitro and in mice) highlighted previously unknown effects of pridopidine (increase in brain-derived neurotrophic factor, reduction in mHtt levels, and σ-1 receptor binding and modulation). These additional functions of pridopidine suggest it might be a neuroprotective and disease-modifying drug. Data from ongoing clinical trials of pridopidine will help define its place in the treatment of HD. This commentary examines the available preclinical and clinical evidence regarding the use of pridopidine in HD.

  6. Design of HIV-1 integrase inhibitors targeting the catalytic domain as well as its interaction with LEDGF/p75: a scaffold hopping approach using salicylate and catechol groups.

    Science.gov (United States)

    Fan, Xing; Zhang, Feng-Hua; Al-Safi, Rasha I; Zeng, Li-Fan; Shabaik, Yumna; Debnath, Bikash; Sanchez, Tino W; Odde, Srinivas; Neamati, Nouri; Long, Ya-Qiu

    2011-08-15

    HIV-1 integrase (IN) is a validated therapeutic target for antiviral drug design. However, the emergence of viral strains resistant to clinically studied IN inhibitors demands the discovery of novel inhibitors that are structurally as well mechanistically different. Herein, we describe the design and discovery of novel IN inhibitors targeting the catalytic domain as well as its interaction with LEDGF/p75, which is essential for the HIV-1 integration as an IN cofactor. By merging the pharmacophores of salicylate and catechol, the 2,3-dihydroxybenzamide (5a) was identified as a new scaffold to inhibit the strand transfer reaction efficiently. Further structural modifications on the 2,3-dihydroxybenzamide scaffold revealed that the heteroaromatic functionality attached on the carboxamide portion and the piperidin-1-ylsulfonyl substituted at the phenyl ring are beneficial for the activity, resulting in a low micromolar IN inhibitor (5p, IC(50)=5 μM) with more than 40-fold selectivity for the strand transfer over the 3'-processing reaction. More significantly, this active scaffold remarkably inhibited the interaction between IN and LEDGF/p75 cofactor. The prototype example, N-(cyclohexylmethyl)-2,3-dihydroxy-5-(piperidin-1-ylsulfonyl) benzamide (5u) inhibited the IN-LEDGF/p75 interaction with an IC(50) value of 8 μM. Using molecular modeling, the mechanism of action was hypothesized to involve the chelation of the divalent metal ions inside the IN active site. Furthermore, the inhibitor of IN-LEDGF/p75 interaction was properly bound to the LEDGF/p75 binding site on IN. This work provides a new and efficient approach to evolve novel HIV-1 IN inhibitors from rational integration and optimization of previously reported inhibitors.

  7. Synthesis and antioxidant evaluation of some new pyrazolopyridine derivatives.

    Science.gov (United States)

    Gouda, Moustafa A

    2012-02-01

    4,6-Dimethyl-1H-pyrazolo[3,4-b]pyridine-3-amine (1) was used as a key intermediate for the synthesis of imidazolopyrazole derivatives 7-11 upon interaction with 3-(2-bromoacetyl)-2H-chromen-2-one (2), 2-(benzothiazol-2-yl)-4-chloro-3-oxobutanenitrile (3), 2,3-dibromonaphthalene-1,4-dione (4), naphtha[2,3-b]oxirene-2,7-dione (5), 2,5-dichloro-3,6-dihydroxyhexa-2,5-diene-1,4-dione (6), respectively. Acetylation of 11 afforded the bis-acetyl 12. Also, the imidazolopyrimidine 15 was prepared via treatment of 1 with sodium 3,4-dioxo-3,4-dihydronaphthalene-1-sulfonate (13) in DMF followed by cyclization of the bis-pyrazolopyrimidine 14 with glacial acetic acid. On the other hand, compound 1 was reacted with (E)-1-(4-methoxyphenyl)-5-(piperidin-1-yl)pent-1-en-3-one hydrochloride (16), 2-hydroxy-3-((piperidin-1-yl)-methyl)-naphthalene-1,4-dione (17), 2-styryl-2H-indene-1,3-dione (18), enaminone 22, chloroquinoline-3-carbaldehyde 27a, chloroquinoline-(6-methyl)-3-carbaldehyde 27b and 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde (28) to afford pyrazolo[3,4-a]pyrimidines 19-21, 23, 29a, 29b and 30, respectively. Also, the pyrazolopyrimidinone 33 was obtained via treatment of 1 with 1-cyanoacetyl-3,5-dimethylpyrazole (31) followed by cyclization of the formed intermediate 32 with glacial acetic acid. Finally, treatment of 1 with o-terephthalaldehyde in glacial acetic acid afforded diazepine 34. The newly synthesized compounds were screened for their antioxidant properties in which some of them exhibited promising activities. Compounds 1, 14, 15, 23, 26, 29a, 30 and 32 have the ability to protect DNA from the damage induced by bleomycin.

  8. Juliprosopine and juliprosine from prosopis juliflora leaves induce mitochondrial damage and cytoplasmic vacuolation on cocultured glial cells and neurons.

    Science.gov (United States)

    Silva, Victor Diogenes A; Pitanga, Bruno P S; Nascimento, Ravena P; Souza, Cleide S; Coelho, Paulo Lucas C; Menezes-Filho, Noélio; Silva, André Mário M; Costa, Maria de Fátima D; El-Bachá, Ramon S; Velozo, Eudes S; Costa, Silvia L

    2013-12-16

    Prosopis juliflora is a shrub largely used for animal and human consumption. However, ingestion has been shown to induce intoxication in animals, which is characterized by neuromuscular alterations induced by mechanisms that are not yet well understood. In this study, we investigated the cytotoxicity of a total alkaloid extract (TAE) and one alkaloid fraction (F32) obtained from P. juliflora leaves to rat cortical neurons and glial cells. Nuclear magnetic resonance characterization of F32 showed that this fraction is composed of a mixture of two piperidine alkaloids, juliprosopine (majority constituent) and juliprosine. TAE and F32 at concentrations between 0.3 and 45 μg/mL were tested for 24 h on neuron/glial cell primary cocultures. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test revealed that TAE and F32 were cytotoxic to cocultures, and their IC50 values were 31.07 and 7.362 μg/mL, respectively. Exposure to a subtoxic concentration of TAE or F32 (0.3-3 μg/mL) induced vacuolation and disruption of the astrocyte monolayer and neurite network, ultrastructural changes, characterized by formation of double-membrane vacuoles, and mitochondrial damage, associated with changes in β-tubulin III and glial fibrillary acidic protein expression. Microglial proliferation was also observed in cultures exposed to TAE or F32, with increasing levels of OX-42-positive cells. Considering that F32 was more cytotoxic than TAE and that F32 reproduced in vitro the main morphologic and ultrastructural changes of "cara torta" disease, we can also suggest that piperidine alkaloids juliprosopine and juliprosine are primarily responsible for the neurotoxic damage observed in animals after they have consumed the plant.

  9. Effects of CP-900691, a novel peroxisome proliferator-activated receptor α, agonist on diabetic nephropathy in the BTBR ob/ob mouse.

    Science.gov (United States)

    Askari, Bardia; Wietecha, Tomasz; Hudkins, Kelly L; Fox, Edward J; O'Brien, Kevin D; Kim, Jinkyu; Nguyen, Tri Q; Alpers, Charles E

    2014-08-01

    Piperidine-based peroxisome proliferator-activated receptor-α agonists are agents that are efficacious in improving lipid, glycemic, and inflammatory indicators in diabetes and obesity. This study sought to determine whether CP-900691 ((S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester; CP), a member of this novel class of agents, by decreasing plasma triglycerides, could prevent diabetic nephropathy in the Black and Tan, BRachyuric (BTBR) ob/ob mouse model of type 2 diabetes mellitus. Four-week old female BTBR WT and BTBR ob/ob mice received either regular chow or one containing CP (3 mg/kg per day) for 14 weeks. CP elevated plasma high-density lipoprotein, albuminuria, and urinary excretion of 8-epi PGF(2α), a product of the nonenzymatic metabolism of arachidonic acid and whose production is elevated in oxidative stress, in BTBR WT mice. In BTBR ob/ob mice, CP reduced plasma triglycerides and non-esterified fatty acids, fasting blood glucose, body weight, and plasma interleukin-6, while concomitantly improving insulin resistance. Despite these beneficial metabolic effects, CP had no effect on elevated plasma insulin, 8-epi PGF(2α) excretion, and albuminuria, and surprisingly, did not ameliorate the development of diabetic nephropathy, having no effect on the accumulation of renal macrophages, glomerular hypertrophy, and increased mesangial matrix expansion. In addition, CP did not increase plasma high-density lipoprotein in BTBR ob/ob mice, while paradoxically increasing total cholesterol levels. These findings indicate that 8-epi PGF(2α), possibly along with hyperinsulinemia and inflammatory and dysfunctional lipoproteins, is integral to the development of diabetic nephropathy and should be considered as a potential target of therapy in the treatment of diabetic nephropathy.

  10. Anticonvulsant effects of isomeric nonimidazole histamine H3 receptor antagonists

    Directory of Open Access Journals (Sweden)

    Sadek B

    2016-11-01

    Full Text Available Bassem Sadek,1 Ali Saad,1 Johannes Stephan Schwed,2,3 Lilia Weizel,2 Miriam Walter,2 Holger Stark2,3 1Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates; 2Biocenter, Institute of Pharmaceutical Chemistry, Goethe University, Frankfurt, Germany; 3Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University, Düsseldorf, Germany Abstract: Phenytoin (PHT, valproic acid, and modern antiepileptic drugs (AEDs, eg, remacemide, loreclezole, and safinamide, are only effective within a maximum of 70%–80% of epileptic patients, and in many cases the clinical use of AEDs is restricted by their side effects. Therefore, a continuous need remains to discover innovative chemical entities for the development of active and safer AEDs. Ligands targeting central histamine H3 receptors (H3Rs for epilepsy might be a promising therapeutic approach. To determine the potential of H3Rs ligands as new AEDs, we recently reported that no anticonvulsant effects were observed for the (S-2-(4-(3-(piperidin-1-ylpropoxybenzylaminopropanamide (1. In continuation of our research, we asked whether anticonvulsant differences in activities will be observed for its R-enantiomer, namely, (R-2-(4-(3-(piperidin-1-ylpropoxybenzylaminopropaneamide (2 and analogs thereof, in maximum electroshock (MES-, pentylenetetrazole (PTZ-, and strychnine (STR-induced convulsion models in rats having PHT and valproic acid (VPA as reference AEDs. Unlike the S-enantiomer (1, the results show that animals pretreated intraperitoneally (ip with the R-enantiomer 2 (10 mg/kg were moderately protected in MES and STR induced models, whereas proconvulsant effect was observed for the same ligand in PTZ-induced convulsion models. However, animals pretreated with intraperitoneal doses of 5, 10, or 15 mg/kg of structurally bulkier (R-enantiomer (3

  11. Molecular interaction of a potent nonpeptide agonist with the chemokine receptor CCR8.

    Science.gov (United States)

    Jensen, Pia C; Nygaard, Rie; Thiele, Stefanie; Elder, Amy; Zhu, Guoming; Kolbeck, Roland; Ghosh, Shomir; Schwartz, Thue W; Rosenkilde, Mette M

    2007-08-01

    Most nonpeptide antagonists for CC-chemokine receptors share a common pharmacophore with a centrally located, positively charged amine that interacts with the highly conserved glutamic acid (Glu) located in position 6 of transmembrane helix VII (VII:06). We present a novel CCR8 nonpeptide agonist, 8-[3-(2-methoxyphenoxy)benzyl]-1-phenethyl-1,3,8-triaza-spiro[4.5]decan-4-one (LMD-009), that also contains a centrally located, positively charged amine. LMD-009 selectively stimulated CCR8 among the 20 identified human chemokine receptors. It mediated chemotaxis, inositol phosphate accumulation, and calcium release with high potencies (EC50 from 11 to 87 nM) and with efficacies similar to that of the endogenous agonist CCL1, and it competed for 125I-CCL1 binding with an affinity of 66 nM. A series of 29 mutations targeting 25 amino acids broadly distributed in the minor and major ligand-binding pockets of CCR8 uncovered that the binding of LMD-009 and of four analogs [2-(1-(3-(2-methoxyphenoxy)benzyl)-4-hydroxypiperidin-4-yl)benzoic acid (LMD-584), N-ethyl-2-4-methoxybenzenesulfonamide (LMD-902), N-(1-(3-(2-methoxyphenoxy)benzyl)piperidin-4-yl)-2-phenyl-4-(pyrrolidin-1yl)butanamide (LMD-268), and N-(1-(3-(2-methoxyphenoxy)benzyl)piperidin-4-yl)-1,2,3,4-tetrahydro-2-oxoquinoline-4-carboxamide (LMD-174)] included several key-residues for nonpeptide antagonists targeting CCR1, -2, and -5. It is noteworthy that a decrease in potency of nearly 1000-fold was observed for all five compounds for the Ala substitution of the anchor-point GluVII:06 (Glu(286)) and a gain-of-function of 19-fold was observed for LMD-009 (but not the four other analogs) for the Ala substitution of PheVI:16 (Phe(254)). These structural hallmarks were particularly important in the generation of a model of the molecular mechanism of action for LMD-009. In conclusion, we present the first molecular mapping of the interaction of a nonpeptide agonist with a chemokine receptor and show that the binding

  12. Drug-likeness approach of 2-aminopyrimidines as histamine H3 receptor ligands

    Directory of Open Access Journals (Sweden)

    Sadek B

    2014-09-01

    Full Text Available Bassem Sadek,1 Annemarie Schreeb,2 Johannes Stephan Schwed,2,3 Lilia Weizel,2 Holger Stark3 1Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates; 2Biocenter, Institute of Pharmaceutical Chemistry, Johann-Wolfgang Goethe University, Frankfurt, Germany; 3Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University, Duesseldorf, Germany Abstract: A small series of compounds containing derivatives of 2,4-diamino- and 2,4,6-triaminopyrimidine (compounds 2–7 was synthesized and tested for binding affinity to human histamine H3 receptors (hH3Rs stably expressed in HEK-293 cells and human H4Rs (hH4Rs co-expressed with Gαi2 and Gβ1γ2 subunits in Sf9 cells. Working in part from the lead compound 6-(4-methylpiperazin-1-yl-N4-(3-(piperidin-1-ylpropylpyrimidine-2,4-diamine (compound 1 with unsatisfactory affinity and selectivity to hH3Rs, our structure-activity relationship studies revealed that replacement of 4-methylpiperazino by N-benzylamine and substitution of an amine group at the 2-position of the 2-aminopyrimidine core structure with 3-piperidinopropoxyphenyl moiety as an hH3R pharmacophore resulted in N4-benzyl-N2-(4-(3-(piperidin-1-ylpropoxyphenylpyrimidine-2,4-diamine (compound 5 with high hH3R affinity (ki =4.49±1.25 nM and H3R receptor subtype selectivity of more than 6,500×. Moreover, initial metric analyses were conducted based on their target-oriented drug-likeness for predictively quantifying lipophilicity, ligand efficiency, lipophilicity-dependent ligand efficiency, molecular size-independent efficiency, and topological molecular polar surface. As to the development of potential H3R ligands, results showed that integration of the hH3R pharmacophore in hH4R-affine structural scaffolds resulted in compounds with high hH3R affinity (4.5–650 nM, moderate to low hH4R affinity (4,500–30,000 nM, receptor subtype selectivity

  13. δ-Opioid Mechanisms for ADL5747 and ADL5859 Effects in Mice: Analgesia, Locomotion, and Receptor Internalization

    Science.gov (United States)

    Nozaki, Chihiro; Le Bourdonnec, Bertrand; Reiss, David; Windh, Rolf T.; Little, Patrick J.; Dolle, Roland E.; Gavériaux-Ruff, Claire

    2012-01-01

    N,N-diethyl-4-(5-hydroxyspiro[chromene-2,4′-piperidine]-4-yl) benzamide (ADL5859) and N,N-diethyl-3-hydroxy-4-(spiro[chromene-2,4′-piperidine]-4-yl)benzamide (ADL5747) are novel δ-opioid agonists that show good oral bioavailability and analgesic and antidepressive effects in the rat and represent potential drugs for chronic pain treatment. Here, we used genetic approaches to investigate molecular mechanisms underlying their analgesic effects in the mouse. We tested analgesic effects of ADL5859 and ADL5747 in mice by using mechanical sensitivity measures in both complete Freund's adjuvant and sciatic nerve ligation pain models. We examined their analgesic effects in δ-opioid receptor constitutive knockout (KO) mice and mice with a conditional deletion of δ-receptor in peripheral voltage-gated sodium channel (Nav)1.8-expressing neurons (cKO mice). Both ADL5859 and ADL5747, and the prototypical δ agonist 4-[(R)-[(2S,5R)-4-allyl-2,5-dimethyl-piperazin-1-yl]-(3-methoxyphenyl)methyl]-N,N-diethyl-benzamide (SNC80) as a control, significantly reduced inflammatory and neuropathic pain. The antiallodynic effects of all three δ-opioid agonists were abolished in constitutive δ-receptor KO mice and strongly diminished in δ-receptor cKO mice. We also measured two other well described effects of δ agonists, increase in locomotor activity and agonist-induced receptor internalization by using knock-in mice expressing enhanced green fluorescence protein-tagged δ receptors. In contrast to SNC80, ADL5859 and ADL5747 did not induce either hyperlocomotion or receptor internalization in vivo. In conclusion, both ADL5859 and ADL5747 showed efficient pain-reducing properties in the two models of chronic pain. Their effects were mediated by δ-opioid receptors, with a main contribution of receptors expressed on peripheral Nav1.8-positive neurons. The lack of in vivo receptor internalization and locomotor activation, typically induced by SNC80, suggests agonist-biased activity

  14. Non-imidazole histamine H3 receptor ligands incorporating antiepileptic moieties.

    Science.gov (United States)

    Sadek, Bassem; Schwed, Johannes Stephan; Subramanian, Dhanasekaran; Weizel, Lilia; Walter, Miriam; Adem, Abdu; Stark, Holger

    2014-04-22

    A small series of histamine H3 receptor (H3R) ligands (1-5) incorporating different antiepileptic structural motifs has been newly synthesized. All compounds exhibited moderate to high in vitro hH3R affinities up to a sub-nanomolar concentration range with pKi values in the range of 6.25-9.62 with varying preferences for this receptor subtype. The compounds (1-5) were further investigated in vivo on anticonvulsant effects against maximum electroshock (MES)-induced and pentylenetetrazole (PTZ)-kindled convulsions in rats having phenytoin (PHT) as the reference antiepileptic drug (AED). Surprisingly, animals pretreated with 1 mg/kg, i.p. of 5,5-diphenyl-3-(3-(piperidin-1-yl)propyl)imidazolidine-2,4-dione (4) were only moderately protected and no protection was observed for compounds 1-3 and 5 in three different doses (1 mg, 5 mg, and 10 mg/kg i.p.). Compound 4 (1 mg/kg, i.p.) failed to modify PTZ-kindled convulsion. However, a dose of 10 mg/kg significantly reduced convulsions in both models. In contrast, 5,5-diphenyl-3-(4-(3-(piperidin-1-yl)propoxy)benzyl)imidazolidine-2,4-dione (5) (1, 5, and 10 mg/kg, i.p.) showed proconvulsant effects in the MES model with further confirmation of these results in the PTZ model as no protection was observed against convulsion in the doses tested (1 and 10 mg/kg). In addition, compound 4 (10 mg/kg, i.p.) significantly prolonged myoclonic latency time and shortened total convulsion duration when compared to control, PHT or standard H3R inverse agonist/antagonist pitolisant (PIT). Our results showed that H3R pharmacophores could successfully be structurally combined to antiepileptic moieties, especially phenytoin partial structures, maintaining the H3R affinity. However, the new derivatives for multiple-target approaches in epilepsy models are complex and show that pharmacophore elements are not easily pharmacologically combinable.

  15. Drug-likeness approach of 2-aminopyrimidines as histamine H3 receptor ligands.

    Science.gov (United States)

    Sadek, Bassem; Schreeb, Annemarie; Schwed, Johannes Stephan; Weizel, Lilia; Stark, Holger

    2014-01-01

    A small series of compounds containing derivatives of 2,4-diamino- and 2,4,6-triaminopyrimidine (compounds 2-7) was synthesized and tested for binding affinity to human histamine H3 receptors (hH3Rs) stably expressed in HEK-293 cells and human H4Rs (hH4Rs) co-expressed with Gαi2 and Gβ1γ2 subunits in Sf9 cells. Working in part from the lead compound 6-(4-methylpiperazin-1-yl)-N (4)-(3-(piperidin-1-yl)propyl)pyrimidine-2,4-diamine (compound 1) with unsatisfactory affinity and selectivity to hH3Rs, our structure-activity relationship studies revealed that replacement of 4-methylpiperazino by N-benzylamine and substitution of an amine group at the 2-position of the 2-aminopyrimidine core structure with 3-piperidinopropoxyphenyl moiety as an hH3R pharmacophore resulted in N (4)-benzyl-N (2)-(4-(3-(piperidin-1-yl)propoxy)phenyl)pyrimidine-2,4-diamine (compound 5) with high hH3R affinity (k(i) =4.49 ± 1.25 nM) and H3R receptor subtype selectivity of more than 6,500×. Moreover, initial metric analyses were conducted based on their target-oriented drug-likeness for predictively quantifying lipophilicity, ligand efficiency, lipophilicity-dependent ligand efficiency, molecular size-independent efficiency, and topological molecular polar surface. As to the development of potential H3R ligands, results showed that integration of the hH3R pharmacophore in hH4R-affine structural scaffolds resulted in compounds with high hH3R affinity (4.5-650 nM), moderate to low hH4R affinity (4,500-30,000 nM), receptor subtype selectivity (ratio hH4R/hH3R; 8-6,500), and promising calculated drug-likeness properties.

  16. The stability of methyl-, ethyl- and fluoroethylesters against carboxylesterases in vitro: there is no difference

    Energy Technology Data Exchange (ETDEWEB)

    Nics, Lukas [Department of Nuclear Medicine, Medical University of Vienna, A-1090 Vienna (Austria); Department of Nutritional Sciences, University of Vienna, A-1090 Vienna (Austria); Haeusler, Daniela [Department of Nuclear Medicine, Medical University of Vienna, A-1090 Vienna (Austria); Department of Pharmaceutical Technology and Biopharmaceutics, University of Vienna, A-1090 Vienna (Austria); Wadsak, Wolfgang [Department of Nuclear Medicine, Medical University of Vienna, A-1090 Vienna (Austria); Department of Inorganic Chemistry, University of Vienna, A-1090 Vienna (Austria); Wagner, Karl-Heinz [Department of Nutritional Sciences, University of Vienna, A-1090 Vienna (Austria); Dudczak, Robert; Kletter, Kurt [Department of Nuclear Medicine, Medical University of Vienna, A-1090 Vienna (Austria); Mitterhauser, Markus, E-mail: markus.mitterhauser@meduniwien.ac.a [Department of Nuclear Medicine, Medical University of Vienna, A-1090 Vienna (Austria); Department of Pharmaceutical Technology and Biopharmaceutics, University of Vienna, A-1090 Vienna (Austria); Hospital Pharmacy of the General Hospital of Vienna, A-1090 Vienna (Austria)

    2011-01-15

    Introduction: Carboxylesterases (CES) play a very important role in the hydrophilic biotransformation of a huge number of structurally diverse drugs and especially play a leading part in the catabolic pathway of carboxylesters or thioesters. Hence, the aim of the present study was the comparison of the in vitro stability of methyl- and ethylesters with fluoroethylesters. Methods: We incubated methyl 3{beta}-(4-iodophenyl)tropane-2{beta}-carboxylate ({beta}-CIT)/2-fluoroethyl 3{beta}-(4-iodophenyl)tropane-2{beta}-carboxylate (FE-CIT), methyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate (MTO)/ethyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate (ETO)/2-fluoroethyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate (FETO), ethyl 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-benzo-[f]imidazo[1,5-a]-[1,4] diazepine-3-carboxylate (FMZ)/2-fluoroethyl 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-benzo-[f]imidazo[1,5-a]-[1,4] diazepine-3-carboxylate (FFMZ), methyl 1-phenylethyl-4-(N-propanoylanilino)piperidine-4-carboxylate (CFN)/2-fluoroethyl 1-phenylethyl-4-(N-propanoylanilino)piperidine-4-carboxylate ((FE-CF)N) and methyl 2,4-diethyl-3-methylsulfanylcarbonyl-6-phenylpyridine-5-carboxylate [(Me){sup 2}-SUPPY]/2-fluorethyl 2,4-diethyl-3-ethylsulfanylcarbonyl-6-phenylpyridine-5-carboxylate (FE-SUPPY) under physiological conditions. The enzymatic reactions were stopped at different time points and analyzed by a standard protocol. Results: The Michaelis-Menten constants (K{sub M}) and limiting velocities (V{sub max}) are comparable. The statistical K{sub M} values were as follows: {beta}-CIT/FE-CIT, P>.05; MTO/FETO, P>.06; ETO/FETO, P>.09; FMZ/FFMZ, P>.05; CFN/ (FE-CFN), P>.9; (Me){sup 2}-SUPPY/FE-SUPPY, P>.07. Conclusion: We found no statistical difference in stability against CES in vitro. These findings support the strategy to translate C-11-methyl-/ethylesters into their longer-lived F-18-fluoroethyl analogues.

  17. Developing new PET tracers to image the growth hormone secretagogue receptor 1a (GHS-R1a).

    Science.gov (United States)

    Kawamura, Kazunori; Fujinaga, Masayuki; Shimoda, Yoko; Yamasaki, Tomoteru; Zhang, Yiding; Hatori, Akiko; Xie, Lin; Wakizaka, Hidekatsu; Kumata, Katsushi; Ohkubo, Takayuki; Kurihara, Yusuke; Ogawa, Masanao; Nengaki, Nobuki; Zhang, Ming-Rong

    2017-09-01

    `The growth hormone secretagogue receptor 1a (GHS-R1a) is the orphan G-protein-coupled receptor, and its endogenous ligand is ghrelin. GHS-R1a contributes to regulation of glucose homeostasis, memory and learning, food addiction, and neuroprotection. Several PET tracers for GHS-R1a have been developed, but none have been reported to be clinically applicable to GHS-R1a imaging. In this study, we developed three new PET tracers for GHS-R1a: (18)F-labeled 6-(4-chlorophenyl)-3-((1-(2-fluoroethyl)piperidin-3-yl)methyl)-2-(o-tolyl)quinazolin-4(3H)-one (1), (11)C-labeled 6-(4-chlorophenyl)-3-((1-(2-methoxyethyl)piperidin-3-yl)methyl)-2-(o-tolyl)quinazolin-4(3H)-one (2), and (11)C-labeled (S)-(4-(1H-indole-6-carbonyl)-3-methylpiperazin-1-yl)(4'-methoxy-[1,1'-biphenyl]-4-yl)methanone (3). [(18)F]1 was synthesized by the (18)F-fluoroethylation; [(11)C]2 or [(11)C]3 was synthesized by the (11)C-methylation. Biodistribution studies and PET studies were conducted in mice. We successfully radiosynthesized [(18)F]1, [(11)C]2, and [(11)C]3 with appropriate radioactivity for the animal study. In the ex vivo biodistribution study, 60min following injection, the radioactivity level of [(18)F]1 was relatively high in the small intestine, that of [(11)C]2 was high in the liver, and that of [(11)C]3 was high in the pancreas. The radioactivity levels of the three PET tracers were relatively low in the brain. Under pretreatment with YIL781 (a selective and high affinity antagonist for GHS-R1a), the pancreas radioactivity level at 30min following [(11)C]3 injection was significantly reduced to 55% of control, but the radioactivity in the brain was not changed. In the PET study under control conditions, high radioactivity levels in the liver and pancreas were observed following [(11)C]3 injection. With YIL781 pretreatment, the accumulated radioactivity in the pancreas 15-60min after [(11)C]3 injection was significantly decreased to 78% of control. [(11)C]3 exhibited relatively high uptake

  18. -Phenoxo--pseudohalide and -pseudohalide dinuclear, tetranuclear and one-dimensional complexes: magneto-structural correlation and interesting type of solid state isomerism

    Indian Academy of Sciences (India)

    Sujit Sasmal; Sasankasekhar Mohanta

    2012-11-01

    Five Schiff base ligands have been utilized to explore metallo-pseudohalide (azide or cyanate) systems. These ligands are the 1:1 condensation products of 3-methoxysalicylaldehyde with ethanolamine (H2L1)/1-(2-aminoethyl)-piperidine (HL2)/ 4-(2-aminoethyl)-morpholine (HL3) or salicylaldehyde with 1-(2-aminoethyl)-piperidine (HL4)/4-(2-aminoethyl)-morpholine (HL5). The derived complexes are as follows: Four heterobridged -phenoxo-1,1-azide/cyanate dinickel(II) compounds of composition [Ni$^{\\text{II}}_{2}$ (HL1)3(1,1-N3)]$\\cdot$3H2O (1), [Ni$^{\\text{II}}_{2}$ (L2)2(1,1-N3)(N3)(H2O)]·CH3CH2OH (2), [Ni$^{\\text{II}}_{2}$ (L3)2-(1,1-N3)(CH3CN)(H2O)](ClO4)·H2O·CH3CN (3) and [Ni$^{\\text{II}}_{2}$ (HL1)3(1,1-NCO)]·2H2O (4); Two 1,3-azide bridged tetranickel(II) compounds [{NiII(L4)(1,3-N3)(H2O)}4] (5) and [{NiII(L5)(1,3-N3)(H2O)}4] (6); Two 1,3-azide/cyanate one-dimensional compounds [CuIIL5(1,3-NCO)]·2H2O (7) and [CuIIL5(1,3-N3)]·2H2O (8). Except compound 5 which shows overall antiferromagnetic coupling, other compounds exhibit overall ferromagnetic interaction. Syntheses, crystal structures, magnetic properties, density functional theoretical (DFT) calculations and experimental/theoretical magneto-structural correlations have been carried out which have revealed some interesting observations on composition/topology, magneto-structural correlations and solid state isomerism. The results have been already published. The present report deals with a review of the salient and interesting features of these works.

  19. Relation between the catalytic efficiency of the synthetic analogues of catechol oxidase with their electrochemical property in the free state and substrate-bound state.

    Science.gov (United States)

    Chakraborty, Prateeti; Adhikary, Jaydeep; Ghosh, Bipinbihari; Sanyal, Ria; Chattopadhyay, Shyamal Kumar; Bauzá, Antonio; Frontera, Antonio; Zangrando, Ennio; Das, Debasis

    2014-08-18

    A library of 15 dicopper complexes as synthetic analogues of catechol oxidase has been synthesized with the aim to determine the relationship between the electrochemical behavior of the dicopper(II) species in the absence as well as in the presence of 3,5-di-tert-butylcatechol (3,5-DTBC) as model substrate and the catalytic activity, kcat, in DMSO medium. The complexes have been characterized by routine physicochemical techniques as well as by X-ray single-crystal structure analysis in some cases. Fifteen "end-off" compartmental ligands have been designed as 1 + 2 Schiff-base condensation product of 2,6-diformyl-4-R-phenol (R = Me, (t)Bu, and Cl) and five different amines, N-(2-aminoethyl)piperazine, N-(2-aminoethyl)pyrrolidine, N-(2-aminoethyl)morpholine, N-(3-aminopropyl)morpholine, and N-(2-aminoethyl)piperidine. Interestingly, in case of the combination of 2,6-diformyl-4-methylphenol and N-(2-aminoethyl)morpholine/N-(3-aminopropyl)morpholine/N-(2-aminoethyl)piperidine 1 + 1 condensation becomes the reality and the ligands are denoted as L2(1-3). On reaction of copper(II) nitrate with L2(1-3) in situ complexes 3, 12, and 13 are formed having general formula Cu2(L2(1-3))2(NO3)2. The remaining 12 ligands obtained as 1 + 2 condensation products are denoted as L1(1-12), which produce complexes having general formula Cu2(L1(1-12))(NO3)2. Catecholase activity of all 15 complexes has been investigated in DMSO medium using 3,5-DTBC as model substrate. Treatment on the basis of Michaelis-Menten model has been applied for kinetic study, and thereby turnover number, kcat, values have been evaluated. Cyclic voltametric (CV) and differential pulse voltametric (DPV) studies of the complexes in the presence as well as in the absence of 3,5-DTBC have been thoroughly investigated in DMSO medium. From those studies it is evident that oxidation of 3,5-DTBC catalyzed by dicopper(II) complexes proceed via two steps: first, semibenzoquinone followed by benzoquinone with concomitant

  20. Syntheses, structures, and magnetic properties of three one-dimensional end-to-end azide/cyanate-bridged copper(II) compounds exhibiting ferromagnetic interaction: new type of solid state isomerism.

    Science.gov (United States)

    Sasmal, Sujit; Sarkar, Sohini; Aliaga-Alcalde, Núria; Mohanta, Sasankasekhar

    2011-06-20

    The work in this paper presents the syntheses, structures, and magnetic properties of three end-to-end (EE) azide/cyanate-bridged copper(II) compounds [Cu(II)L(1)(μ(1,3)-NCO)](n)·2nH(2)O (1), [Cu(II)L(1)(μ(1,3)-N(3))](n)·2nH(2)O (2), and [Cu(II)L(2)(μ(1,3)-N(3))](n) (3), where the ligands used to achieve these species, HL(1) and HL(2), are the tridentate Schiff base ligands obtained from [1 + 1] condensations of salicylaldehyde with 4-(2-aminoethyl)-morpholine and 3-methoxy salicylaldehyde with 1-(2-aminoethyl)-piperidine, respectively. Compounds 1 and 2 crystallize in the monoclinic P2(1)/c space group, while compound 3 crystallizes in the orthorhombic Pbca space group. The metal center in 1-3 is in all cases pentacoordinated. Three coordination positions of the metal center in 1, 2, or 3 are satisfied by the phenoxo oxygen atom, imine nitrogen atom, and morpholine (for 1 and 2) or piperidine (for 3) nitrogen atom of one deprotonated ligand, [L(1)](-) or [L(2)](-). The remaining two coordination positions are satisfied by two nitrogen atoms of two end-to-end bridging azide ligands for 2 and 3 and one nitrogen atom and one oxygen atom of two end-to-end bridging cyanate ligands for 1. The coordination geometry of the metal ion is distorted square pyramidal in which one EE azide/cyanate occupies the apical position. Variable-temperature (2-300 K) magnetic susceptibilities of 1-3 have been measured under magnetic fields of 0.05 (from 2 to 30 K) and 1.0 T (from 30 to 300 K). The simulation reveals a ferromagnetic interaction in all three compounds with J values of +0.19 ± 0.01, +0.79 ± 0.01, and +1.25 ± 0.007 cm(-1) for 1, 2, and 3, respectively. Compound 1 is the sole example of a ferromagnetically coupled EE cyanate-bridged 1-D copper(II) system. In addition, a rare example of supramolecular isomerism and a nice example of magnetic isomerism have been observed and most interestingly a new type of solid state isomerism has emerged as a result of the comparison

  1. A novel radioligand for glycine transporter 1: characterization and use in autoradiographic and in vivo brain occupancy studies

    Energy Technology Data Exchange (ETDEWEB)

    Zeng Zhizhen [Imaging, Merck Research Laboratories, West Point, PA 19486 (United States)], E-mail: zhizhen_zeng@merck.com; O' Brien, Julie A. [Sleep and Psychiatric Disorders, Merck Research Laboratories, West Point, PA 19486 (United States); Lemaire, Wei [Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486 (United States); O' Malley, Stacey S.; Miller, Patricia J. [Imaging, Merck Research Laboratories, West Point, PA 19486 (United States); Zhao Zhijian [Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486 (United States); Wallace, Michael A. [Drug Metabolism, Merck Research Laboratories, Rahway, NJ 07065 (United States); Raab, Conrad [Drug Metabolism, Merck Research Laboratories, West Point, PA 19486 (United States); Lindsley, Craig W. [Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486 (United States); Departments of Pharmacology and Chemistry, Vanderbilt University, Nashville, TN 37232 (United States); Sur, Cyrille; Williams, David L. [Imaging, Merck Research Laboratories, West Point, PA 19486 (United States)

    2008-04-15

    Introduction: In an effort to develop agents to test the NMDA hypofunction hypothesis of schizophrenia, benchmark compounds from a program to discover potent, selective, competitive glycine transporter 1 (GlyT1) inhibitors were radiolabeled in order to further study the detailed pharmacology of these inhibitors and the distribution of GlyT1 in brain. We here report the in vitro characterization of [{sup 35}S](S)-2-amino-4-chloro-N-(1-(4-phenyl-1-(propylsulfonyl)piperidin-4-yl) ethyl)benzamide ([{sup 35}S]ACPPB), a radiotracer developed from a potent and selective non-sarcosine-derived GlyT1 inhibitor, its use in autoradiographic studies to localize (S)-2-amino-6-chloro-N-(1-(4-phenyl-1-(propylsulfonyl)piperidin-4-yl)ethyl) benzamide (ACPPB) binding sites in rat and rhesus brain and for in vivo occupancy assays of competitive GlyT1 inhibitors. Methods: Functional potencies of unlabeled compounds were characterized by [{sup 14}C]glycine uptake into JAR (human placental choriocarcinoma) cells and synaptosomes. Radioligand binding studies were performed with tissue homogenates. Autoradiographic studies were performed on tissue slices. Results: ACPPB is a potent (K{sub d}=1.9 nM), selective, GlyT1 inhibitor that, when radiolabeled with [{sup 35}S], is a well-behaved radioligand with low nondisplaceable binding. Autoradiographic studies of rat and rhesus brain slices with this ligand showed that specific binding sites were plentiful and nonhomogeneously distributed, with high levels of binding in the brainstem, cerebellar white matter, thalamus, cortical white matter and spinal cord gray matter. In vivo studies demonstrate displaceable binding of [{sup 35}S]ACPPB in rat brain tissues following iv administration of this radioligand. Conclusions: This is the first report of detailed anatomical localization of GlyT1 using direct radioligand binding, and the first demonstration that an in vivo occupancy assay is feasible, suggesting that it may also be feasible to develop

  2. Non-competitive Inhibition of Nicotinic Acetylcholine Receptors by Ladybird Beetle Alkaloids.

    Science.gov (United States)

    Leong, Ron L; Xing, Hong; Braekman, Jean-Claude; Kem, William R

    2015-10-01

    Ladybird beetles (Family Coccinellidae) secrete an alkaloid rich venom from their leg joints that protects them from predators. Coccinellines, the major venom constituents, are alkaloids composed of three fused piperidine rings that share a common nitrogen atom. Although many coccinellines have been isolated and chemically characterized, their pharmacological properties are essentially unknown. Using radioligand binding and functional assays we investigated the actions of several coccinellines on skeletal muscle and α7 nicotinic acetylcholine receptors (nAChRs). The alkaloids were shown to displace the specific binding of tritiated piperidyl-N-(1-(2-thienyl)cyclohexyl)-3,4-piperidine ([(3)H]-TCP), which has been shown to bind deep within the ion channel of the electric fish (Torpedo) muscle nAChR. The stereoisomers precoccinelline and hippodamine (whose nitrogens are predicted to be ionized at physiological pH) and their respective analogs N-methyl-precoccinelline and N-methyl-hippodamine (whose quaternary nitrogens are permanently charged) displayed similar IC50s for inhibition of [(3)H]-TCP binding. However, the corresponding precoccinelline and hippodamine N-oxides, coccinelline and convergine (which have an electronegative oxygen bonded to an electropositive nitrogen) displayed significantly higher binding IC50s. Finally, exochomine, a dimeric coccinelline containing the hippodamine structure, displayed the highest IC50 (lowest affinity) for displacing specific [(3)H]-TCP binding. The presence of a desensitizing concentration (10(-3) M) of carbachol (CCh) had little or no effect on the affinity of the Torpedo nAChR for the three coccinellines tested. High concentrations of the coccinellid alkaloids did not affect binding of [(3)H]-cytisine to Torpedo receptor ACh binding sites. Inhibition of the alpha7 nAChR with pre-equilibrated precoccinelline was insurmountable with respect to ACh concentration. We conclude that the coccinellines bind to one or more

  3. Tramadole Withdrawal in a Neonate: A Case Report

    Directory of Open Access Journals (Sweden)

    H Borna

    2012-09-01

    Full Text Available Background: Tramadol is a synthetics 4-phenyl-piperidine analogue of codeine used for treating moderate to severe pain. Tramadol is a FDA pregnancy category C medication which induces release of serotonin and inhibits the reuptake of norepinephrine. Chronic use of this drug during pregnancy may lead to physical dependency and withdrawal syndrome in the neonate.Case presentation: We report the newborn of a woman admitted in the delivery ward of Mostafa Khomeini Hospital in Tehran, Iran in 2011. The mother suffered from chronic low back pain and headache and frequently took tramadol during pregnancy. The infant had a gestational age of 38.5 w, a birth weight of 2950 gr and an Apgar score of 9/10 at 1 and 5 minutes after birth. The first signs of withdrawal syndrome occurred after 24 h with nausea, vomiting, poor feeding, and tremor. Later, agitation, tremor, hyprertonicity, and repeated multifocal myoclonus, and generalized tonic-clonic seizures developed. Clinical signs of withdrawal syndrome waned under phenobarbital therapy.Conclusion: Drug withdrawal syndrome should be considered in the neonates of pregnant mothers who chronically take tramadol. Tramadol administration during pregnancy should be restricted to carefully selected cases.

  4. The monoacylglycerol lipase inhibitor JZL184 decreases inflammatory response in skeletal muscle contusion in rats.

    Science.gov (United States)

    Jiang, Shu-Kun; Zhang, Miao; Tian, Zhi-Ling; Wang, Meng; Zhao, Rui; Wang, Lin-Lin; Li, Shan-Shan; Liu, Min; Li, Jiao-Yong; Zhang, Meng-Zhou; Guan, Da-Wei

    2015-08-15

    Muscle wound healing process is a typical inflammation-evoked event. The monoacylglycerol lipase (MAGL) inhibitor (4-nitrophenyl)4-[bis(1,3-benzodioxol -5-yl)-hydroxymethyl]piperidine-1-carboxylate (JZL184) has been previously reported to reduce inflammation in colitis and acute lung injury in mice, which provide a new strategy for primary care of skeletal muscle injury. We investigated the effect of JZL184 on inflammation in rat muscle contusion model, and found decreased neutrophil and macrophage infiltration and pro-inflammatory cytokine expression. With extension of post-traumatic interval, myofiber regeneration was significantly hindered with increased collagen types I and ІІІ mRNAfibroblast infiltration as well as promoted fibrosis. Furthermore, 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-morpholin-4-ylpyrazole-3-carboxamide (AM281, a selective cannabinoid CB1 receptor antagonist) and [6-iodo-2-methyl-1-(2-morpholin-4-ylethyl)indol-3-yl]-(4-methoxyphenyl)methanone (AM630, a selective cannabinoid CB2 receptor antagonist) treatment alleviated the anti-inflammatory effect of JZL184. Our findings demonstrate that JZL184 is able to inhibit the inflammatory response and interfere with contused muscle healing, in which the anti-inflammatory action may be mediated through cannabinoid CB1 and CB2 receptors.

  5. Alkynyl-naphthalimide Fluorophores: Gold Coordination Chemistry and Cellular Imaging Applications.

    Science.gov (United States)

    Langdon-Jones, Emily E; Lloyd, David; Hayes, Anthony J; Wainwright, Shane D; Mottram, Huw J; Coles, Simon J; Horton, Peter N; Pope, Simon J A

    2015-07-01

    A range of fluorescent alkynyl-naphthalimide fluorophores has been synthesized and their photophysical properties examined. The fluorescent ligands are based upon a 4-substituted 1,8-naphthalimide core and incorporate structural variations (at the 4-position) to tune the amphiphilic character: chloro (L1), 4-[2-(2-aminoethoxy)ethanol] (L2), 4-[2-(2-methoxyethoxy)ethylamino] (L3), piperidine (L4), morpholine (L5), 4-methylpiperidine (L6), and 4-piperidone ethylene ketal (L7) variants. The amino-substituted species (L2-L7) are fluorescent in the visible region at around 517-535 nm through a naphthalimide-localized intramolecular charge transfer (ICT), with appreciable Stokes' shifts of ca. 6500 cm(-1) and lifetimes up to 10.4 ns. Corresponding two-coordinate Au(I) complexes [Au(L)(PPh3)] were isolated, with X-ray structural studies revealing the expected coordination mode via the alkyne donor. The Au(I) complexes retain the visible fluorescence associated with the coordinated alkynyl-naphthalimide ligand. The ligands and complexes were investigated for their cytotoxicity across a range of cell lines (LOVO, MCF-7, A549, PC3, HEK) and their potential as cell imaging agents for HEK (human embryonic kidney) cells and Spironucleus vortens using confocal fluorescence microscopy. The images reveal that these fluorophores are highly compatible with fluorescence microscopy and show some clear intracellular localization patterns that are dependent upon the specific nature of the naphthalimide substituent.

  6. Nuclear magnetic resonance at 310 MHz in a superconducting solenoid; Resonance magnetique nucleaire a 310 MHz dans un solenoide supra-conducteur

    Energy Technology Data Exchange (ETDEWEB)

    Dunand, J.J. [Commissariat a l' Energie Atomique, Grenoble (France). Centre d' Etudes Nucleaires

    1970-07-01

    The realisation of an NMR spectrometer with a superconducting magnet is presented in the first section. The methods to attain the best possible homogeneity of the magnetic field and to minimize the error in the spectrometer are described. The second section is devoted to the study of elastomers and nitr-oxides free radicals. A shift of the transition temperature with the magnetic field appears for the elastomers. The increasing paramagnetic shift has allowed a complete study by NMR of piperidinic and pyrrolidinic nitroxide free radicals. (author) [French] Dans la premiere partie est exposee la realisation d'un spectrometre de RMN utilisant un solenoide supraconducteur. Des solutions sont donnees pour obtenir la meilleure homogeneite possible du champ magnetique et pour minimiser les sources d'erreur apportees par le spectrometre. La deuxieme partie est consacree a l'etude d'elastomeres et de radicaux libres nitroxydes. Une variation de la temperature de transition avec le champ magnetique est mise en evidence pour les elastomeres. L'accroissement du deplacement paramagnetique a permis une etude complete par RMN des radicaux libres nitroxydes piperidiniques et pyrrolidiniques. (auteur)

  7. YQ36: A Novel Bisindolylmaleimide Analogue Induces KB/VCR Cell Death

    Directory of Open Access Journals (Sweden)

    Ji Cao

    2009-01-01

    Full Text Available Overexpression of multidrug resistance proteins P-glycoprotein (P-gp, MDR1 causes resistance of the tumor cells against a variety of chemotherapeutic agents. 3-(1-methyl-1H-indol-3-yl-1-phenyl-4-(1-(3-(piperidin-1-ylpropyl-1H-pyrazolo[3,4-b]pyridine-3-yl-1H-pyrrole-2,5-dione (YQ36 is a novel analogue of bisindolylmaleimide, which has been reported to overcome multidrug resistance. Here, we dedicated to investigate the anticancer activity of YQ36 on KB/VCR cells. The results revealed that YQ36 exhibited great antiproliferative activity on three parental cell lines and MDR1 overexpressed cell lines. Moreover, the hypersensitivity of YQ36 was confirmed on the base of great apoptosis induction and unaltered intracellular drug accumulation in KB/VCR cells. Further results suggested that YQ36 could not be considered as a substrate of P-gp, which contributed to its successfully escaping from the efflux mediated by P-gp. Interestingly, we observed that YQ36 could accumulate in nucleus and induce DNA damage. YQ36 could also induce the activation of caspase-3, imposing effects on the mitochondrial function. Collectively, our data demonstrated that YQ36 exhibited potent activities against MDR cells, inducing DNA damage and triggering subsequent apoptosis via mitochondrial pathway.

  8. SKF 525-A and cytochrome P-450 ligands inhibit with high affinity the binding of ( sup 3 H)dextromethorphan and. sigma. ligands to guinea pig brain

    Energy Technology Data Exchange (ETDEWEB)

    Klein, M.; Canoll, P.D.; Musacchio, J.M. (New York Univ. Medical Center, New York, NY (USA))

    1991-01-01

    The DM{sub 1}/{sigma}{sub 1} site binds dextromethorphan (DM) and {sigma} receptor ligands. The broad binding specificity of this site and its peculiar subcellular distribution prompted us to explore the possibility that this site is a member of the cytochrome P-450 superfamily of enzymes. We tested the effects of the liver microsomal monooxygenase inhibitor SKF 525-A (Proadifen), and other P-450 substrates on the binding of ({sup 3}H)dextromethorphan, ({sup 3}H)3- (3-Hydroxyphenyl) -N- (1-propyl) piperidine and (+)-({sup 3}H)1,3-Di-o-tolyl-guanidine (({sup 3}H)DTG) to the guinea pig brain. SKF 525-A, l-lobeline and GBR-12909 inhibited the binding of the three labeled ligands with nM affinity. Each drug has identical nM K{sub i} values for the high-affinity site labeled by the three ligands. This indicated that they displaced the labeled ligands from the common DM{sub 1}{sigma}{sub 1} site. Debrisoquine and sparteine, prototypical substrates for liver debrisoquine 4-hydroxylase, displayed K{sub i} values of 9-13 and 3-4 {mu}M respectively against the three labeled ligands. These results, the broad specificity of the DM{sub 1}/{sigma}{sub 1} binding site, and its peculiar subcellular distribution, raises the possibility that this binding site is a member of the cytochrome P-450 superfamily of isozymes, rather than a neurotransmitter receptor.

  9. Skimming behaviour and spreading potential of Stenus species and Dianous coerulescens (Coleoptera: Staphylinidae)

    Science.gov (United States)

    Lang, Carolin; Seifert, Karlheinz; Dettner, Konrad

    2012-11-01

    Rove beetles of the genus Stenus Latreille and the genus Dianous Leach possess pygidial glands containing a multifunctional secretion of piperidine and pyridine-derived alkaloids as well as several terpenes. One important character of this secretion is the spreading potential of its different compounds, stenusine, norstenusine, 3-(2-methyl-1-butenyl)pyridine, cicindeloine, α-pinene, 1,8-cineole and 6-methyl-5-heptene-2-one. The individual secretion composition enables the beetles to skim rapidly and far over the water surface, even when just a small amount of secretion is emitted. Ethological investigations of several Stenus species revealed that the skimming ability, skimming velocity and the skimming behaviour differ between the Stenus species. These differences can be linked to varied habitat claims and secretion saving mechanisms. By means of tensiometer measurements using the pendant drop method, the spreading pressure of all secretion constituents as well as some naturally identical beetle secretions on the water surface could be established. The compound 3-(2-methyl-1-butenyl)pyridine excelled stenusine believed to date to be mainly responsible for skimming relating to its surface activity. The naturally identical secretions are not subject to synergistic effects of the single compounds concerning the spreading potential. Furthermore, evolutionary aspects of the Steninae's pygidial gland secretion are discussed.

  10. Copper(I) thiocyanate-amine networks: synthesis, structure, and luminescence behavior.

    Science.gov (United States)

    Miller, Kayla M; McCullough, Shannon M; Lepekhina, Elena A; Thibau, Isabelle J; Pike, Robert D; Li, Xiaobo; Killarney, James P; Patterson, Howard H

    2011-08-01

    A series of metal-organic networks of CuSCN were prepared by direct reactions with substituted pyridine and aliphatic amine ligands, L. Thiocyanate bridging is seen in all but 1 of 11 new X-ray structures. Structures are reported for (CuSCN)L sheets (L = 3-chloro- and 3-bromopyridine, N-methylmorpholine), ladders (L = 2-ethylpyridine, N-methylpiperidine), and chains (L = 2,4,6-collidine). X-ray structures of (CuSCN)L(2) are chains (L = 4-ethyl- and 4-t-butylpyridine, piperidine, and morpholine). A unique N-thiocyanato monomer structure, (CuSCN)(3-ethylpyridine)(3), is also reported. In most cases, amine ligands are thermally released at temperatures temperature is observed for the substituted pyridine complexes. High solid state quantum efficiencies are seen for many of the CuSCN-L complexes. Microsecond phosphorescence lifetimes seen for CuSCN-L are in direct contrast to the nanosecond-lifetime emission of CuSCN. MLCT associated with pyridine π* orbitals is proposed as the excitation mechanism. © 2011 American Chemical Society

  11. Crystallization of a pentapeptide-repeat protein by reductive cyclic pentylation of free amines with glutaraldehyde

    Energy Technology Data Exchange (ETDEWEB)

    Vetting, Matthew W., E-mail: vetting@aecom.yu.edu; Hegde, Subray S.; Blanchard, John S. [Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461 (United States)

    2009-05-01

    A method to modify proteins with glutaraldehyde under reducing conditions is presented. Treatment with glutaraldehyde and dimethylaminoborane was found to result in cyclic pentylation of free amines and facilitated the structural determination of a protein previously recalcitrant to the formation of diffraction quality crystals. The pentapeptide-repeat protein EfsQnr from Enterococcus faecalis protects DNA gyrase from inhibition by fluoroquinolones. EfsQnr was cloned and purified to homogeneity, but failed to produce diffraction-quality crystals in initial crystallization screens. Treatment of EfsQnr with glutaraldehyde and the strong reducing agent borane–dimethylamine resulted in a derivatized protein which produced crystals that diffracted to 1.6 Å resolution; their structure was subsequently determined by single-wavelength anomalous dispersion. Analysis of the derivatized protein using Fourier transform ion cyclotron resonance mass spectrometry indicated a mass increase of 68 Da per free amino group. Electron-density maps about a limited number of structurally ordered lysines indicated that the modification was a cyclic pentylation of free amines, producing piperidine groups.

  12. Identification of small molecules that disrupt signaling between ABL and its positive regulator RIN1.

    Directory of Open Access Journals (Sweden)

    Pamela Y Ting

    Full Text Available Constitutively active BCR-ABL kinase fusions are causative mutations in the pathogenesis of hematopoietic neoplasias including chronic myelogenous leukemia (CML. Although these fusions have been successfully targeted with kinase inhibitors, drug-resistance and relapse continue to limit long-term survival, highlighting the need for continued innovative drug discovery. We developed a time-resolved Förster resonance energy transfer (TR-FRET -based assay to identify compounds that disrupt stimulation of the ABL kinase by blocking its ability to bind the positive regulator RIN1. This assay was used in a high throughput screen (HTS of two small molecule libraries totaling 444,743 compounds. 708 confirmed hits were counter-screened to eliminate off-target inhibitors and reanalyzed to prioritize compounds with IC50 values below 10 μM. The CML cell line K562 was then used to identify five compounds that decrease MAPK1/3 phosphorylation, which we determined to be an indicator of RIN1-dependent ABL signaling. One of these compounds is a thiadiazole, and the other four are structurally related acyl piperidine amides. Notably, these five compounds lower cellular BCR-ABL1 kinase activity by blocking a positive regulatory interaction rather than directly inhibiting ABL catalytic function.

  13. Kilogram-scale synthesis of a second-generation dendrimer based on 1,3,5-triazine using green and industrially compatible methods with a single chromatographic step.

    Science.gov (United States)

    Chouai, Abdellatif; Simanek, Eric E

    2008-03-21

    A kilogram scale, divergent and iterative synthesis of a second generation, triazine dendrimer with 12 protected amines on the periphery using common laboratory equipment is reported. The route benefits from common reaction conditions, inexpensive reagents, and aqueous solvents. From the monomers, the desired product dendrimer--the last uncommitted intermediate that leads to a range of committed, generation three targets--can be obtained in 70% overall yield. Of critical importance in the execution of this divergent synthesis is the differential reactivity of chlorine atoms of trichlorotriazine. The stepwise, nucleophilic aromatic substitution of these atoms with amine nucleophiles is both the basis for the dendrimer growth as well as incorporation of solubilizing piperidine groups. Intermediates are obtained and purified through precipitation and/or extraction protocols with the exception of the final product. Isolation of the target dendrimer requires a single silica gel plug filtration. The purity of this material is assessed at >93%, a level consistent with and/or exceeding other commercially available targets.

  14. Synthesis and biological evaluation of 4-(aminomethyl)-1-hydroxypyrazole analogues of muscimol as γ-aminobutyric acid(a) receptor agonists.

    Science.gov (United States)

    Petersen, Jette G; Bergmann, Rikke; Møller, Henriette A; Jørgensen, Charlotte G; Nielsen, Birgitte; Kehler, Jan; Frydenvang, Karla; Kristensen, Jesper; Balle, Thomas; Jensen, Anders A; Kristiansen, Uffe; Frølund, Bente

    2013-02-14

    A series of bioisosteric 4-(aminomethyl)-1-hydroxypyrazole (4-AHP) analogues of muscimol, a GABA(A) receptor agonist, has been synthesized and pharmacologically characterized at native and selected recombinant GABA(A) receptors. The unsubstituted 4-AHP analogue (2a) (EC(50) 19 μM, R(max) 69%) was a moderately potent agonist at human α(1)β(2)γ(2) GABA(A) receptors, and in SAR studies substitutions in the 3- and/or 5-position were found to be detrimental to binding affinities. Ligand-receptor docking in an α(1)β(2)γ(2) GABA(A) receptor homology model along with the obtained SAR indicate that 2a and muscimol share a common binding mode, which deviates from the binding mode of the structurally related antagonist series based on 4-(piperidin-4-yl)-1-hydroxypyrazole (4-PHP, 1). Selectivity for α(1)β(2)γ(2) over ρ(1) GABA(A) receptors was observed for the 5-chloro, 5-bromo, and 5-methyl substituted analogues of 2a illustrating that even small differences in structure can give rise to subtype selectivity.

  15. 1,4-Diphenalkylpiperidines: A new scaffold for the design of potent inhibitors of the vesicular monoamine transporter-2.

    Science.gov (United States)

    Nickell, Justin R; Culver, John P; Janganati, Venumadhav; Zheng, Guangrong; Dwoskin, Linda P; Crooks, Peter A

    2016-07-01

    A series of 1,4-diphenalkylpiperidine analogs were synthesized and evaluated for their affinity and inhibitory potency at the [(3)H]dihydrotetrabenazine (DTBZ) binding site and [(3)H]dopamine (DA) uptake site on the vesicular monoamine transporter-2 (VMAT2). Results revealed that translocation of the phenethyl side chains of lobelane from C2 and C6 to C1 and C4 around the central piperidine ring slightly reduces affinity and inhibitory potency at VMAT2 with respect to lobelane. However, methoxy and fluoro-substitution of either phenyl ring of these 1,4-diphenethyl analogs afforded VMAT2 inhibition comparable or higher (5-fold) affinity at the DTBZ binding and DA uptake sites relative to lobelane, whereas replacement of the 4-phenethyl moiety in these analogs with a 4-phenmethyl moiety markedly reduced affinity for the DTBZ binding and DA uptake sites by 3- and 5-fold, respectively. Among the twenty five 1,4-diphenethylpiperidine analogs evaluated, compounds containing a 4-(2-methoxyphenethyl) moiety exhibited the most potent inhibition of DTBZ binding and vesicular DA uptake. From this subgroup, analogs 8h, 8j and 8m exhibited Ki values of 9.3nM, 13nM and 13nM, respectively, for inhibition of [(3)H]DA uptake by VMAT2, and represent some of the most potent inhibitors of VMAT2 function reported thus far.

  16. Synthesis, structural and conformational study of some amides derived from 3-methyl-3-azabicyclo[3.2.1]octan-8α(β)-amines

    Science.gov (United States)

    Iriepa, I.; Bellanato, J.; Gálvez, E.; Madrid, A. I.

    2008-08-01

    Some amides ( 1α- 7α and 1β- 7β) derived from 3-methyl-3-azabicyclo[3.2.1]octan-8α(β)-amines were synthesized and studied by IR, 1H and 13C NMR spectroscopies. The assignment of all carbon and protons resonances was achieved through the application of one dimensional selective NOE and two dimensional NMR techniques: homonuclear NOESY and heteronuclear 1H- 13C gHSQC correlated spectroscopies. Total correlation spectroscopy (TOCSY) experiments were also carried out. In CDCl 3 solution, at room temperature, all compounds adopt a chair-envelope conformation with the N-CH 3 group in equatorial disposition. In the α-epimers the piperidine ring is puckered at C8 to relieve the interactions between the amido group and the H6(7)x protons. α- and β-Epimers show a preferred trans disposition for the NH-CO group and free rotation of the NH-CO-R group around the C8-NH bond. Finally, NMR and IR data reveal that compounds 7α and 7β adopt in CDCl 3 solution a preferred s-cis conformation for the O dbnd C-C dbnd C system, the proportion of this conformation increasing when the polarity of the solvent decreases.

  17. The pharmacology of spontaneously open alpha 1 beta 3 epsilon GABA A receptor-ionophores.

    Science.gov (United States)

    Maksay, Gábor; Thompson, Sally A; Wafford, Keith A

    2003-06-01

    Human alpha(1)beta(3) epsilon GABA(A) receptors were expressed in Xenopus oocytes and examined using the conventional two-electrode voltage-clamp technique and compared to alpha(1)beta(3)gamma(2) receptors. The effects of several GABA(A) agonists were studied, and the allosteric modulation of the channel by a number of GABAergic modulators investigated. The presence of the epsilon subunit increased the potency and efficacy of direct activation by partial GABA(A) agonists (piperidine-4-sulphonic acid and thio-4-PIOL), pentobarbital and neuro-steroids. Direct activation by 3-hydroxylated neurosteroids was restricted to 3alpha epimers, while chirality at C5 was indifferent. The 3beta-sulfate esters of pregnenolone and dehydroepiandrosterone inhibited the spontaneous currents with efficacies higher, while bicuculline methiodide and SR 95531 did so lower than picrotoxin and TBPS. Furosemide, fipronil, triphenylcyanoborate and Zn(2+) blocked the spontaneous currents of alpha(1)beta(3) epsilon receptors with different efficacies. Flunitrazepam and 4'-chlorodiazepam inhibited the spontaneous currents with micromolar potencies. In conclusion, spontaneously active alpha(1)beta(3) epsilon GABA(A) receptors can be potentiated and blocked by GABAergic agents within a broad range of efficacy.

  18. Synthesis, Characterization and Photophysical Properties of Pyridine-Carbazole Acrylonitrile Derivatives

    Directory of Open Access Journals (Sweden)

    Gabriel Ramos-Ortiz

    2011-03-01

    Full Text Available We synthesized three novel highly fluorescent compounds, 2-(2’-pyridyl-3-(N-ethyl-(3’-carbazolylacrylonitrile, 2-(3”-pyridyl-3-(N-ethyl-(3’-carbazolylacrylonitrile, and 2-(4-pyridyl-3-(N-ethyl-(3’-carbazolylacrylonitrile by Knoevenagel condensation. The first two were synthesized without solvent in the presence of piperidine as a catalyst; the third was synthesized without a catalyst and with N,N-dimethylformamide as a solvent. In solution, the molar absorption coefficients showed absorptions at 380, 378, and 396 nm, respectively; in solid state, absorptions were at 398, 390, and 442 nm, respectively. The fluorescence emission was at 540, 540 and 604 nm, respectively, the 2-(4-pyridyl-3-(N-ethyl-(3’-carbazolylacrylonitrile showed a red shift in the emission of 64 nm compared to the other two compounds. The fluorescence quantum yield for the compounds in powder form showed values of 0.05, 0.14, and 0.006, respectively; compared with the value measured for the Alq3 reference, 2-(3”-pyridyl-3-(N-ethyl-(3’-carbazolylacrylonitrile had a lightly higher value. The third harmonic generation measurement for 2-(2’-pyridyl-3-(N-ethyl-(3’-carbazolylacrylonitrile yielded a χ(3 value of 5.5 × 10−12 esu, similar to that reported for commercial polymers.

  19. Tetrahydrocannabinol interactions with phencyclidine and methaqualone

    Energy Technology Data Exchange (ETDEWEB)

    Lame, M.W.

    1983-01-01

    To determine the effects of ..delta../sup 9/-tetrahydrocannabinol (THC) on the pharmacokinetics and metabolism of phencyclidine (PCP) or methaqualone (MTQ), both in vivo and in vitro studies were conducted using Sprague Dawley rats. In the in vivo studies, plasma levels of /sup 3/H-PCP.HCl equivalents were significantly altered by the administration of THC, with the test curve elevated and parallel to the control. Tissue data followed the same pattern as plasma. The urinary, fecal, and biliary excretion of /sup 3/H-PCP.HCl equivalents for the most part did not show significant perturbation with the coadministration of THC. With respect of MTQ, plasma studies indicated that THC could significantly elevate /sup 14/C-MTQ equivalents for the first 4.5 hours, reduce these levels from approximately 6.5 to 16.5 hours, and again elevate the levels above controls for the period from 19.5 to 22.5 hours. All significant changes in tissue levels mirrored plasma value differences seen between test and control animals. Biliary excretion data indicated that THC showed a trend towards altering the active excretion of /sup 14/C-MTQ equivalents. In vitro microsomal metabolism studies indicated that THC production of phenylcyclohexylamine, 1-(1-phenyl-4-hydroxycyclohexyl)piperidine, and 1-(1-phenylcyclohexyl)-4-hydroxypiperidine. Similar studies conducted with MTQ revealed that THC at the 0.05, 0.025, and 0.0125 mM levels also inhibited the metabolism of this compound.

  20. Synthesis and evaluation of benzimidazole derivatives as selective COX-2 inhibitors.

    Science.gov (United States)

    Rathore, Ankita; Mujeeb-Ur-Rahman; Siddiqui, Anees A; Ali, Abuzer; Yar, Mohammad Shahar

    2015-01-01

    A new series of 1-{(5-substituted-alkyl/aryl-1,3,4-oxadiazol-2-yl)methyl}-2-(piperidin-1-ylmethyl)-1Hbenzimidazoles (5a-5r) was synthesized and screened for their inhibitory activity against COX (1 and 2). In vivo antiinflammatory activity of potent compounds was done by carrageenan-induced rat paw edema model. In vitro anticancer activity of synthesized compounds was also performed at the National Cancer Institute (NCI) against NCI 60 cell lines panel. Out of the 18 compounds screened, 5h, 5i, 5j and 5l were found to be potent COX-2 inhibitors in the range of IC50 0.06-0.81 μM. In vivo anti-inflammatory screening results revealed that the compounds 5h and 5j manifested profound percent protection of 72.8 and 75.0%, respectively. Compound 5f exhibited moderate cytotoxicity with 58.79% growth inhibition against SNB-75 (CNS Cancer) cell lines and moderate activity against COX-2 (IC50 = 8.0 μM).