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Sample records for quinuclidines

  1. Centrosymmetric dimer of quinuclidine betaine and squaric acid complex

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    Dega-Szafran, Z.; Katrusiak, A.; Szafran, M.

    2012-12-01

    The complex of squaric acid (3,4-dihydroxy-3-cyclobuten-1,2-dion, H2SQ) with quinuclidine betaine (1-carboxymethyl-1-azabicyclo[2.2.2]octane inner salt, QNB), 1, has been characterized by single-crystal X-ray analysis, FTIR and NMR spectroscopies and by DFT calculations. In the crystal of 1, monoclinic space group P21/n, one proton from H2SQ is transferred to QNB. QNBH+ and HSQ- are linked together by a Osbnd H⋯O hydrogen bond of 2.553(2) Å. Two such QNBH+·HSQ- complexes form a centrosymmetric dimer bridged by two Osbnd H⋯O bonds of 2.536(2) Å. The FTIR spectrum is consistent with the X-ray results. The structures of monomer QNBH+·HSQ- (1a) and dimer [QNB·H2SQ]2 (2) have been optimized at the B3LYP/6-311++G(d,p) level of theory. Isolated dimer 2 optimized back to a molecular aggregate of H2SQ and QNB. The calculated frequencies for the optimized structure of dimer 2 have been used to explain the frequencies of the experimental FTIR spectrum. The interpretation of 1H and 13C NMR spectra has been based on the calculated GIAO/B3LYP/6-311++G(d,p) magnetic isotropic shielding constants for monomer 1a.

  2. Preparation of Novel meta- and para-Substituted N-Benzyl Protected Quinuclidine Esters and Their Resolution with Butyrylcholinesterase

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    Srđanka Tomić

    2012-01-01

    Full Text Available Since the optically active quinuclidin-3-ol is an important intermediate in the preparation of physiologically or pharmacologically active compounds, a new biocatalytic method for the production of chiral quinuclidin-3-ols was examined. Butyrylcholinesterase (BChE; EC 3.1.1.8 was chosen as a biocatalyst in a preparative kinetic resolution of enantiomers. A series of racemic, (R- and (S-esters of quinuclidin-3-ol and acetic, benzoic, phthalic and isonicotinic acids were synthesized, as well as their racemic quaternary N-benzyl, meta- and para-N-bromo and N-methylbenzyl derivatives. After the resolution, all N-benzyl protected groups were successfully removed by catalytic transfer hydrogenation with ammonium formate (10% Pd-C. Hydrolyses studies with BChE confirmed that (R-enantiomers of the prepared esters are much better substrates for the enzyme than (S-enantiomers. Introduction of bromine atom or methyl group in the meta or para position of the benzyl moiety resulted in a considerable improvement of the stereoselectivity compared to the non-substituted compounds. Optically pure quinuclidin-3-ols were prepared in high yields and enantiopurity by the usage of various N-benzyl protected groups and BChE as a biocatalyst.

  3. A fluorinated quinuclidine benzamide named LMA 10203 acts as an agonist of insect nicotinic acetylcholine receptors.

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    Mathé-Allainmat, Monique; Bodereau-Dubois, Béatrice; Lapied, Bruno; Lebreton, Jacques; Thany, Steeve H

    2012-06-01

    In the present study, we take advantage of the fact that cockroach dorsal unpaired median neurons express different nicotinic acetylcholine receptor subtypes to demonstrate that simple quinuclidine benzamides such as the 2-fluorinated benzamide LMA 10203, could act as an agonist of cockroach α-bungarotoxin-insensitive nicotinic acetylcholine receptor subtype, called nAChR2. Indeed, 1 mM LMA 10203 induced ionic currents which were partially blocked by 0.5 μM α-bungarotoxin and methyllycaconitine and completely blocked by 5 μM mecamylamine. Moreover, the current-voltage curve revealed that the ionic current induced by LMA 10203 increased from -30 mV to +20 mV confirming that it acted as an agonist of α-bungarotoxin-insensitive nAChR2. In addition, 1 mM LMA 10203 induced a depolarization of the sixth abdominal ganglion and this neuroexcitatory activity was completely blocked by 5 μM mecamylamine. These data suggest that nAChR2 was also expressed at the postsynaptic level on the synapse between the cercal afferent nerve and the giant interneurons. Interestingly, despite LMA 10203 being an agonist of cockroach nicotinic receptors, it had a poor insecticidal activity. We conclude that LMA 10203 could be used as an interesting compound to identify specific insect nAChR subtypes.

  4. Design of α7 nicotinic acetylcholine receptor ligands in quinuclidine, tropane and quinazoline series. Chemistry, molecular modeling, radiochemistry, in vitro and in rats evaluations of a [(18)F] quinuclidine derivative.

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    Pin, Frédéric; Vercouillie, Johnny; Ouach, Aziz; Mavel, Sylvie; Gulhan, Zuhal; Chicheri, Gabrielle; Jarry, Christian; Massip, Stephane; Deloye, Jean-Bernard; Guilloteau, Denis; Suzenet, Franck; Chalon, Sylvie; Routier, Sylvain

    2014-07-23

    In this report, we describe the synthesis of a novel library of α7 nAChR ligands based on the modulation of the quinuclidine, quinazoline and tropane moieties. Spirane derivatives were newly synthesized under stereo specific 1,3 dipolar cylcoadditions. Only amide derivatives bonded efficiently to the receptor with Ki measured between 14 and 133 nM. The best fluorinated candidate was selected and radiolabeled. The potent [(18)F]4 PET tracer was evaluated in rats and its brain accumulation quantified.

  5. Molecular structure and spectroscopic properties of the 1:1 complex of quinuclidine betaine with L-tartaric acid

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    Dega-Szafran, Z.; Katrusiak, A.; Szafran, M.

    2009-11-01

    The 1:1 complex of quinuclidine betaine (QNB) with L(+)-tartaric acid (TA) (1-carboxymethyl-1-azoniumbicyclo[2.2.2]octane semi-tartrate) has been synthesized and characterized by X-ray diffraction, FTIR, Raman and NMR spectroscopy, and DFT calculations. QNB-TA crystallizes in monoclinic space group P2 1. In the crystal quinuclidine betaine is protonated and interacts with semi-tartrate anion by the short O-H···O hydrogen bond of 2.472(4) Å. The semi-tartrate anions form infinite chains through the COOH···OOC hydrogen bond of 2.585(5) Å. The FTIR spectrum shows broad bands in the 2700-2200 and 2000-500 cm -1 regions typical of such short hydrogen bonds and are consistent with the X-ray results. In the optimized structures of the title complex at the B3LYP/6-31G(d,p) level of theory both in the monomer, QNB-TA, and dimer, (QNB-TA) 2, the betaine molecules are not protonated. The 1H and 13C NMR spectra elucidate the structure of the complex investigated in aqueous solutions.

  6. Quinuclidine compounds differently act as agonists of Kenyon cell nicotinic acetylcholine receptors and induced distinct effect on insect ganglionic depolarizations.

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    Mathé-Allainmat, Monique; Swale, Daniel; Leray, Xavier; Benzidane, Yassine; Lebreton, Jacques; Bloomquist, Jeffrey R; Thany, Steeve H

    2013-12-01

    We have recently demonstrated that a new quinuclidine benzamide compound named LMA10203 acted as an agonist of insect nicotinic acetylcholine receptors. Its specific pharmacological profile on cockroach dorsal unpaired median neurons (DUM) helped to identify alpha-bungarotoxin-insensitive nAChR2 receptors. In the present study, we tested its effect on cockroach Kenyon cells. We found that it induced an inward current demonstrating that it bounds to nicotinic acetylcholine receptors expressed on Kenyon cells. Interestingly, LMA10203-induced currents were completely blocked by the nicotinic antagonist α-bungarotoxin. We suggested that LMA10203 effect occurred through the activation of α-bungarotoxin-sensitive receptors and did not involve α-bungarotoxin-insensitive nAChR2, previously identified in DUM neurons. In addition, we have synthesized two new compounds, LMA10210 and LMA10211, and compared their effects on Kenyon cells. These compounds were members of the 3-quinuclidinyl benzamide or benzoate families. Interestingly, 1 mM LMA10210 was not able to induce an inward current on Kenyon cells compared to LMA10211. Similarly, we did not find any significant effect of LMA10210 on cockroach ganglionic depolarization, whereas these three compounds were able to induce an effect on the central nervous system of the third instar M. domestica larvae. Our data suggested that these three compounds could bind to distinct cockroach nicotinic acetylcholine receptors.

  7. Étude par la méthode de Monte Carlo de la phase plastique de la quinuclidine à différentes températures

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    Jumeau, Daniel; André, Daniel

    La phase plastique (c.f.c.) de la quinuclidine est étudiée à différentes températures par la méthode de Monte Carlo utilisant la technique des matrices de compatibilité. Afin de ne pas modifier la symétrie moyenne du réseau, les centres de masse de molécules sont supposés fixes. Les orientations moléculaires sont choisies de façon aléatoire parmi les 48 orientations équivalentes et discernables du groupe c.f.c. Cela permet une mémorisation préalable des énergies d'interaction entre molécules voisines et un gain de temps de calcul considérable. Nous observons alors un blocage des réorientations moléculaires à basse température, tandis que la symétrie cristalline devient monoclinique. Ceci est interprété en termes de transition de phase dont la température (215 K) et la variation d'énergie (5 kJ mol-1) sont très proches des valeurs expérimentales.

  8. Evaluation of (Z)-2-((1-benzyl-1H-indol-3-yl)methylene)-quinuclidin-3-one analogues as novel, high affinity ligands for CB1 and CB2 cannabinoid receptors.

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    Madadi, Nikhil Reddy; Penthala, Narsimha Reddy; Brents, Lisa K; Ford, Benjamin M; Prather, Paul L; Crooks, Peter A

    2013-04-01

    A small library of N-benzyl indolequinuclidinone (IQD) analogs has been identified as a novel class of cannabinoid ligands. The affinity and selectivity of these IQDs for the two established cannabinoid receptor subtypes, CB1 and CB2, was evaluated. Compounds 8 (R=R(2)=H, R(1)=F) and 13 (R=COOCH3, R(1)=R(2)=H) exhibited high affinity for CB2 receptors with Ki values of 1.33 and 2.50 nM, respectively, and had lower affinities for the CB1 receptor (Ki values of 9.23 and 85.7 nM, respectively). Compound 13 had the highest selectivity of all the compounds examined, and represents a potent cannabinoid ligand with 34-times greater selectivity for CB2R over CB1R. These findings are significant for future drug development, given recent reports demonstrating beneficial use of cannabinoid ligands in a wide variety of human disease states including drug abuse, depression, schizophrenia, inflammation, chronic pain, obesity, osteoporosis and cancer.

  9. Two different modes for copper(II ion coordination to quinine-type ligands

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    Rey Nicolás A.

    2006-01-01

    Full Text Available Three new copper(II complexes with the ligands quinuclidine [Cu(C7H13N2(OH2Cl]Cl.2H 2O (1, quinine [Cu(C20H23O2N2(OH 22]ClO4 (2, and hydroquinidine [Cu(C20H27O2N2(OH 2 Cl2]Cl.fraction one-halfH2O (3 have been isolated and characterized. The binding sites were assigned on the basis of vibrational spectroscopy, electron paramagnetic resonance, and thermal analysis results. The possibility of the involvement of the quinuclidinic nitrogen in the coordination was evidenced in complex 1, in which copper(II is coordinated to two quinuclidine molecules. In the case of quinine-type ligands, if the starting material is deprotonated in both nitrogens, copper(II coordination occurs through the quinuclidinic nitrogen, as in complex 2. In contrast, if the starting material is protonated in the quinuclidinic nitrogen the binding site is the quinolinic nitrogen, as in complex 3. Therefore, both nitrogens of quinine-type ligands constitute binding sites for copper(II ions.

  10. Demethylation of Quinine Using Anhydrous Aluminium Trichloride

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    Aiyi Asnawi; As’ari Nawawi; Rahmana Emran Kartasasmita; Slamet Ibrahim3)

    2011-01-01

    Quinine is a natural alkaloid having a methoxy group bound to quinoline ring and an allyl group bound to quinuclidine ring. Demethylation of quinine applying strong acid such as HBr or HI at high temperature was unsuccessful. The aim of this research was to obtain demethylated quinine by means of mild and selective demethylation procedure to prevent the addition reaction of allyl group. Selective demethylation of quinine has been carried out using anhydrous aluminium trichloride as reagent. T...

  11. Quininium tetra-chloridozinc(II).

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    Chen, Li-Zhuang

    2009-09-05

    The asymmetric unit of the title compound {systematic name: 2-[hydr-oxy(6-meth-oxy-quinolin-1-ium-4-yl)meth-yl]-8-vinyl-quinuclidin-1-ium tetra-chlorido-zinc(II)}, (C(20)H(26)N(2)O(2))[ZnCl(4)], consists of a double proton-ated quininium cation and a tetra-chloridozinc(II) anion. The Zn(II) ion is in a slightly distorted tetra-hedral coordination environment. The crystal structure is stabilized by inter-molecular N-H⋯Cl and O-H⋯Cl hydrogen bonds.

  12. Squalene Synthase As a Target for Chagas Disease Therapeutics

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    Chan, Hsiu-Chien; Li, Jikun; Zheng, Yingying; Huang, Chun-Hsiang; Ren, Feifei; Chen, Chun-Chi; Zhu, Zhen; Galizzi, Melina; Li, Zhu-Hong; Rodrigues-Poveda, Carlos A.; Gonzalez-Pacanowska, Dolores; Veiga-Santos, Phercyles; de Carvalho, Tecia Maria Ulisses; de Souza, Wanderley; Urbina, Julio A.; Wang, Andrew H.-J.; Docampo, Roberto; Li, Kai; Liu, Yi-Liang; Oldfield, Eric; Guo, Rey-Ting

    2014-01-01

    Trypanosomatid parasites are the causative agents of many neglected tropical diseases and there is currently considerable interest in targeting endogenous sterol biosynthesis in these organisms as a route to the development of novel anti-infective drugs. Here, we report the first x-ray crystallographic structures of the enzyme squalene synthase (SQS) from a trypanosomatid parasite, Trypanosoma cruzi, the causative agent of Chagas disease. We obtained five structures of T. cruzi SQS and eight structures of human SQS with four classes of inhibitors: the substrate-analog S-thiolo-farnesyl diphosphate, the quinuclidines E5700 and ER119884, several lipophilic bisphosphonates, and the thiocyanate WC-9, with the structures of the two very potent quinuclidines suggesting strategies for selective inhibitor development. We also show that the lipophilic bisphosphonates have low nM activity against T. cruzi and inhibit endogenous sterol biosynthesis and that E5700 acts synergistically with the azole drug, posaconazole. The determination of the structures of trypanosomatid and human SQS enzymes with a diverse set of inhibitors active in cells provides insights into SQS inhibition, of interest in the context of the development of drugs against Chagas disease. PMID:24789335

  13. Design of α7 nicotinic acetylcholine receptor ligands using the (het)Aryl-1,2,3-triazole core: Synthesis, in vitro evaluation and SAR studies.

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    Ouach, Aziz; Pin, Frederic; Bertrand, Emilie; Vercouillie, Johnny; Gulhan, Zuhal; Mothes, Céline; Deloye, Jean-Bernard; Guilloteau, Denis; Suzenet, Franck; Chalon, Sylvie; Routier, Sylvain

    2016-01-01

    We report here the synthesis of a large library of 1,2,3-triazole derivatives which were in vitro tested as α7 nAchR ligands. The SAR study revealed that several crucial factors are involved in the affinity of these compounds for α7 nAchR such as a (R) quinuclidine configuration and a mono C-3 quinuclidine substitution. The triazole ring was substituted by a phenyl ring bearing small OMe/CH2F groups or fluorine atom and by several heterocycles such as thiophenes, furanes, benzothiophenes or benzofuranes. Among the 30 derivatives tested, the two derivatives 10 and 39 with Ki in the nanomolar range were identified (2.3 and 3 nM respectively). They exhibited a strict selectivity toward the α4β2 nicotinic receptor (up to 1 μM) but interacted with the 5HT3 receptors with Ki around 3 nM. Synthesis, SAR studies and a full description of the derivatives are reported.

  14. Squalene synthase as a target for Chagas disease therapeutics.

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    Na Shang

    2014-05-01

    Full Text Available Trypanosomatid parasites are the causative agents of many neglected tropical diseases and there is currently considerable interest in targeting endogenous sterol biosynthesis in these organisms as a route to the development of novel anti-infective drugs. Here, we report the first x-ray crystallographic structures of the enzyme squalene synthase (SQS from a trypanosomatid parasite, Trypanosoma cruzi, the causative agent of Chagas disease. We obtained five structures of T. cruzi SQS and eight structures of human SQS with four classes of inhibitors: the substrate-analog S-thiolo-farnesyl diphosphate, the quinuclidines E5700 and ER119884, several lipophilic bisphosphonates, and the thiocyanate WC-9, with the structures of the two very potent quinuclidines suggesting strategies for selective inhibitor development. We also show that the lipophilic bisphosphonates have low nM activity against T. cruzi and inhibit endogenous sterol biosynthesis and that E5700 acts synergistically with the azole drug, posaconazole. The determination of the structures of trypanosomatid and human SQS enzymes with a diverse set of inhibitors active in cells provides insights into SQS inhibition, of interest in the context of the development of drugs against Chagas disease.

  15. Chiral modification of platinum: ab initio study of the effect of hydrogen coadsorption on stability and geometry of adsorbed cinchona alkaloids.

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    Hahn, Konstanze R; Seitsonen, Ari P; Baiker, Alfons

    2015-11-01

    The cinchona alkaloids cinchonidine and cinchonine belong to the most efficient chiral modifiers for the noble metal-catalyzed enantioselective hydrogenation of C=O and C=C bonds. Under reaction conditions these modifiers are coadsorbed on the noble metal surface with hydrogen. Using density functional theory, we studied the effect of coadsorbed hydrogen on the adsorption mode of cinchonidine and cinchonine on a Pt(111) surface at different hydrogen coverages. The theoretical study indicates that the presence of coadsorbed hydrogen affects both the adsorption geometry as well as the stability of the adsorbed cinchona alkaloids. At all hydrogen coverages the cinchona alkaloids are found to be adsorbed via anchoring of the quinoline moiety. In the absence of hydrogen as well as at low hydrogen coverage the quinoline moiety adsorbs nearly parallel to the surface, whereas at higher hydrogen coverage it becomes tilted. Higher hydrogen coverage as well as partial hydrogenation of the quinoline part of the cinchona alkaloid and hydrogen transfer to the C[double bond, length as m-dash]C double bond at 10, 11 position of the quinuclidine moiety destabilize the adsorbed cinchona alkaloid, whereas hydrogen transfer to the nitrogen atom of the quinoline and the quinuclidine moiety stabilizes the adsorbed molecule. The stability as well as the adsorption geometry of the cinchona alkaloids are affected by the coadsorbed hydrogen and are proposed to influence the efficiency of the enantiodifferentiating ability of the chirally modified platinum surface.

  16. Synthesis of tritium labelled (R) and (S)-3-aminoquinuclidine: a ubiquitous component of serotonin receptor ligands. Pt. 2

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    Masjedizadeh, M.R.; Parnes, Howard [Syntex Discovery Research, Palo Alto, CA (United States). Chemical Research and Development

    1996-01-01

    (S)-3-Aminoquinuclidine-{sup 3}H 10c-S having a specific activity of 66 Ci/mmol was prepared in eight steps from isonicotinic acid (2). Reduction of 2 with carrier free tritium gas over PtO{sub 2} in DMF gave isonipecotic acid-{sup 3}H 3c. Conversion to {alpha}-bromo ketone 5c followed by cyclization afforded 3-quinuclidone-{sup 3}H 6c. Racemic 3-amino-quinuclidine-{sup 3}H 8c was prepared by conversion of 6c to oxime 7c followed by reduction with NaBH{sub 4}/NiCl{sub 2}.6H{sub {sub 2}}O. Racemic 8c was resolved with (R)-methylbenzyl isocyanate. Hydrolysis of 9c-S.R afforded (S)-3-aminoquinuclidine-{sup 3}H 10c-S. The enantiopurity was >99.5% (S). (author).

  17. Salts of phenylacetic acid and 4-hydroxyphenylacetic acid with Cinchona alkaloids: Crystal structures, thermal analysis and FTIR spectroscopy

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    Amombo Noa, Francoise M.; Jacobs, Ayesha

    2016-06-01

    Seven salts were formed with phenylacetic acid (PAA), 4-hydroxyphenylacetic acid (HPAA) and the Cinchona alkaloids; cinchonidine (CIND), quinidine (QUID) and quinine (QUIN). For all the structures the proton was transferred from the carboxylic acid of the PAA/HPAA to the quinuclidine nitrogen of the respective Cinchona alkaloid. For six of the salts, water was included in the crystal structures with one of these also incorporating an isopropanol solvent molecule. However HPAA co-crystallised with quinine to form an anhydrous salt, (HPAA-)(QUIN+). The thermal stability of the salts were determined and differential scanning calorimetry revealed that the (HPAA-)(QUIN+) salt had the highest thermal stability compared to the other salt hydrates. The salts were also characterized using Fourier transform infrared spectroscopy. (PAA-)(QUID+)·H2O and (PAA-)(QUIN+)·H2O are isostructural and Hirshfeld surface analysis was completed to compare the intermolecular interactions in these two structures.

  18. Vibrational Spectroscopic Study of the Cocrystal Products Formed by Cinchona Alkaloids with 5-Nitrobarbituric Acid

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    Harry G. Brittain

    2015-01-01

    Full Text Available X-ray powder diffraction, differential scanning calorimetry, infrared absorption spectroscopy, and Raman spectroscopy have been used to study the phenomenon of cocrystal formation in the molecular complexes formed by 5-nitrobarbituric acid with four cinchona alkaloids. The cocrystal products were found to contain varying degrees of hydration, ranging from no hydration in the nitrobarbiturate-quinidine cocrystal up to a 4.5-hydrate species in the nitrobarbiturate-cinchonine cocrystal. For the nitrobarbiturate cocrystals with cinchonine, cinchonidine, and quinidine, the predominant interaction was with the quinoline ring system of the alkaloid. However, for quinine, the predominant interaction was with the quinuclidine group of the alkaloid. These properties serve to demonstrate the utility of 5-nitrobarbituric acid as a preferred reagent for chemical microscopy, since the differing range of hydrate and structural types would serve to easily differentiate the cinchona alkaloids from each other, even when different compounds contained the same absolute configurations at their dissymmetric centers.

  19. Controlled Synthesis of Polyenes by Catalytic Methods. Progress Report, December 1, 1989 -- November 30, 1992

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    Schrock, R. R.

    1992-01-01

    A more direct approach to polyenes by the direct polymerization of acetylenes has been achieved. We were able to show that polymerization of acetylene itself can be controlled with a well- characterized alkylidene catalyst, but only if a base such as quinuclidine is present in order to slow down the rate of propagation relative to initiation. (Quinuclidine may also stabilize vinylalkylidene intermediates formed in the reaction). Unfortunately, living polyenes were no more stable than isolated polyenes, and so this approach had its limitations. Direct polymerization of acetylene by Mo(CH-t-Bu)(NAr)(O-t-Bu){sub 2} was more successful, but inherent polyene instability was still a problem. The most important result of the past grant period is the finding that dipropargyl derivatives (HC=CCH{sub 2}XCH{sub 2}C=CH; X = CH{sub 2}, C(CO{sub 2}R){sub 2}, SiR{sub 2}, etc.), which have been reported to be cyclopolymerized by various classical catalysts by as yet unknown mechanisms, are polymerized by Mo(CH-t-Bu)(NAr)[OCMe(CF{sub 3}){sub 2}]{sub 2} in dimethoxyethane. We speculate that intramolecular formation of a five-membered ring in the product of {alpha} addition is fast enough to yield another terminal alkylidene on the time scale of the polymerization reaction, while a six-membered ring is formed in a reaction involving a more reaction terminal alkylidene. Either intermediate alkylidene, but most likely the terminal alkylidene, could react with additional monomer to lead to growth of a chain having dangling triple bonds that eventually could be employed to form crosslinks.

  20. Structure-property relationship of quinuclidinium surfactants--Towards multifunctional biologically active molecules.

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    Skočibušić, Mirjana; Odžak, Renata; Štefanić, Zoran; Križić, Ivana; Krišto, Lucija; Jović, Ozren; Hrenar, Tomica; Primožič, Ines; Jurašin, Darija

    2016-04-01

    Motivated by diverse biological and pharmacological activity of quinuclidine and oxime compounds we have synthesized and characterized novel class of surfactants, 3-hydroxyimino quinuclidinium bromides with different alkyl chains lengths (CnQNOH; n=12, 14 and 16). The incorporation of non conventional hydroxyimino quinuclidinium headgroup and variation in alkyl chain length affects hydrophilic-hydrophobic balance of surfactant molecule and thereby physicochemical properties important for its application. Therefore, newly synthesized surfactants were characterized by the combination of different experimental techniques: X-ray analysis, potentiometry, electrical conductivity, surface tension and dynamic light scattering measurements, as well as antimicrobial susceptibility tests. Comprehensive investigation of CnQNOH surfactants enabled insight into structure-property relationship i.e., way in which the arrangement of surfactant molecules in the crystal phase correlates with their solution behavior and biologically activity. The synthesized CnQNOH surfactants exhibited high adsorption efficiency and relatively low critical micelle concentrations. In addition, all investigated compounds showed very potent and promising activity against Gram-positive and clinically relevant Gram-negative bacterial strains compared to conventional antimicrobial agents: tetracycline and gentamicin. The overall results indicate that bicyclic headgroup with oxime moiety, which affects both hydrophilicity and hydrophobicity of CnQNOH molecule in addition to enabling hydrogen bonding, has dominant effect on crystal packing and physicochemical properties. The unique structural features of cationic surfactants with hydroxyimino quinuclidine headgroup along with diverse biological activity have made them promising structures in novel drug discovery. Obtained fundamental understanding how combination of different functionalities in a single surfactant molecule affects its physicochemical

  1. Chiral modification of platinum by co-adsorbed cinchonidine and trifluoroacetic acid: origin of enhanced stereocontrol in the hydrogenation of trifluoroacetophenone.

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    Meemken, Fabian; Baiker, Alfons; Schenker, Sebastian; Hungerbühler, Konrad

    2014-01-27

    Cinchonidine (CD) adsorbed onto a platinum metal catalyst leads to rate acceleration and induces strong stereocontrol in the asymmetric hydrogenation of trifluoroacetophenone. Addition of catalytic amounts of trifluoroacetic acid (TFA) significantly enhances the enantiomeric excess from 50 to 92%. The origin of the enantioselectivity bestowed by co-adsorbed CD and TFA is investigated by using in situ attenuated total reflection infrared spectroscopy and modulation excitation spectroscopy. Molecular interactions between the chiral modifier (CD), acid additive (TFA) and the trifluoro-activated substrate at the solid-liquid interface are elucidated under conditions relevant to catalytic hydrogenations, that is, on a technical Pt/Al2O3 catalyst in the presence of H2 and solvent. Monitoring of the unmodified and modified surface during the hydrogenation provides an insight into the phenomenon of rate enhancement and the crucial interactions of CD with the ketone, corresponding product alcohol, and TFA. Comparison of the diastereomeric interactions occurring on the modified surface and in the liquid solution shows a striking difference for the chiral preferences of CD. The spectroscopic data, in combination with calculations of molecular structures and energies, sheds light on the reaction mechanism of the heterogeneous asymmetric hydrogenation of trifluoromethyl ketones and the involvement of TFA in the diastereomeric intermediate surface complex: the quinuclidine N atom of the adsorbed CD forms an N-H-O-type hydrogen-bonding interaction not only with the trifluoro-activated ketone but also with the corresponding alcohol and the acid additive. Strong evidence is provided that it is a monodentate acid/base adduct in which the carboxylate of TFA resides at the quinuclidine N-atom of CD, which imparts a better stereochemical control.

  2. Multi-modal applicability of a reversed-phase/weak-anion exchange material in reversed-phase, anion-exchange, ion-exclusion, hydrophilic interaction and hydrophobic interaction chromatography modes.

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    Lämmerhofer, Michael; Nogueira, Raquel; Lindner, Wolfgang

    2011-06-01

    We recently introduced a mixed-mode reversed-phase/weak anion-exchange type separation material based on silica particles which consisted of a hydrophobic alkyl strand with polar embedded groups (thioether and amide functionalities) and a terminal weak anion-exchange-type quinuclidine moiety. This stationary phase was designed to separate molecules by lipophilicity and charge differences and was mainly devised for peptide separations with hydroorganic reversed-phase type elution conditions. Herein, we demonstrate the extraordinary flexibility of this RP/WAX phase, in particular for peptide separations, by illustrating its applicability in various chromatographic modes. The column packed with this material can, depending on the solute character and employed elution conditions, exploit attractive or repulsive electrostatic interactions, and/or hydrophobic or hydrophilic interactions as retention and selectivity increments. As a consequence, the column can be operated in a reversed-phase mode (neutral compounds), anion-exchange mode (acidic compounds), ion-exclusion chromatography mode (cationic solutes), hydrophilic interaction chromatography mode (polar compounds), and hydrophobic interaction chromatography mode (e.g., hydrophobic peptides). Mixed-modes of these chromatographic retention principles may be materialized as well. This allows an exceptionally flexible adjustment of retention and selectivity by tuning experimental conditions. The distinct separation mechanisms will be outlined by selected examples of peptide separations in the different modes.

  3. Iron(III) protoporphyrin IX complexes of the antimalarial Cinchona alkaloids quinine and quinidine.

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    de Villiers, Katherine A; Gildenhuys, Johandie; le Roex, Tanya

    2012-04-20

    The antimalarial properties of the Cinchona alkaloids quinine and quinidine have been known for decades. Surprisingly, 9-epiquinine and 9-epiquinidine are almost inactive. A lack of definitive structural information has precluded a clear understanding of the relationship between molecular structure and biological activity. In the current study, we have determined by single crystal X-ray diffraction the structures of the complexes formed between quinine and quinidine and iron(III) protoporphyrin IX (Fe(III)PPIX). Coordination of the alkaloid to the Fe(III) center is a key feature of both complexes, and further stability is provided by an intramolecular hydrogen bond formed between a propionate side chain of Fe(III)PPIX and the protonated quinuclidine nitrogen atom of either alkaloid. These interactions are believed to be responsible for inhibiting the incorporation of Fe(III)PPIX into crystalline hemozoin during its in vivo detoxification. It is also possible to rationalize the greater activity of quinidine compared to that of quinine.

  4. Structure-affinity relationship of the cocaine-binding aptamer with quinine derivatives.

    Science.gov (United States)

    Slavkovic, Sladjana; Altunisik, Merve; Reinstein, Oren; Johnson, Philip E

    2015-05-15

    In addition to binding its target molecule, cocaine, the cocaine-binding aptamer tightly binds the alkaloid quinine. In order to understand better how the cocaine-binding aptamer interacts with quinine we have used isothermal titration calorimetry-based binding experiments to study the interaction of the cocaine-binding aptamer to a series of structural analogs of quinine. As a basis for comparison we also investigated the binding of the cocaine-binding aptamer to a set of cocaine metabolites. The bicyclic aromatic ring on quinine is essential for tight affinity by the cocaine-binding aptamer with 6-methoxyquinoline alone being sufficient for tight binding while the aliphatic portion of quinine, quinuclidine, does not show detectable binding. Compounds with three fused aromatic rings are not bound by the aptamer. Having a methoxy group at the 6-position of the bicyclic ring is important for binding as substituting it with a hydrogen, an alcohol or an amino group all result in lower binding affinity. For all ligands that bind, association is driven by a negative enthalpy compensated by unfavorable binding entropy.

  5. Acylated mono-, bis- and tris- Cinchona-Based Amines Containing Ferrocene or Organic Residues: Synthesis, Structure and in Vitro Antitumor Activity on Selected Human Cancer Cell Lines

    Directory of Open Access Journals (Sweden)

    Emese Gál

    2012-02-01

    Full Text Available A series of novel functionalized mono-, bis- and tris-(S-{[(2S,4R,8R-8-ethyl-quinuclidin-2-yl](6-methoxyquinolin-4-yl}methanamines including ferrocene-containing derivatives was obtained by the reaction of the precursor amine with a variety of acylation agents. Their in vitro antitumor activity was investigated against human leukemia (HL-60, human neuroblastoma (SH-SY5Y, human hepatoma (HepG2 and human breast cancer (MCF-7 cells by the 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT-assay and the 50% inhibitory concentration (IC50 values were determined. Our data indicate that the precursor amine has no antitumor activity in vitro, but the bis-methanamines with ureido-, thioureido and amide-type linkers display attractive in vitro cytotoxicity and cytostatic effects on HL-60, HepG2, MCF-7 and SH-SY5Y cells. Besides 1H- and 13C-NMR methods the structures of the new model compounds were also studied by DFT calculations.

  6. Mechanism of phosphine borane deprotection with amines: the effects of phosphine, solvent and amine on rate and efficiency.

    Science.gov (United States)

    Lloyd-Jones, Guy C; Taylor, Nicholas P

    2015-03-27

    The kinetics of borane transfer from simple tertiary phosphine borane adducts to a wide range of amines have been determined. All data obtained, including second-order kinetics, lack of cross-over, and negative entropies of activation for reaction of triphenylphosphine borane with quinuclidine and triethylamine, are consistent with a direct (SN 2-like) transfer process, rather than a dissociative (SN 1-like) process. The identities of the amine, phosphine, and solvent all impact substantially on the rate (k) and equilibrium (K) of the transfer, which in some cases vary by many orders of magnitude. P-to-N transfer is more efficient with cyclic amines in apolar solvents due to reduced entropic costs and ground-state destabilisation. Taken as a whole, the data allow informed optimisation of the deprotection step from the stand-point of rate, or synthetic convenience. In all cases, both reactants should be present at high initial concentration to gain kinetic benefit from the bimolecularity of the process. Ultimately, the choice of amine is dictated by the identity of the phosphine borane complex. Aryl-rich phosphine boranes are sufficiently reactive to allow use of diethylamine or pyrrolidine as a volatile low polarity solvent and reactant, whereas more alkyl-rich phosphines benefit from the use of more reactive amines, such as 1,4-diaza[2.2.2]bicyclooctane (DABCO), in apolar solvents at higher temperatures.

  7. [Use of antihistamines in a physician's clinical practice].

    Science.gov (United States)

    Luss, L V

    2014-01-01

    Histamine that belongs to one of the most important mediators involved in the regulation of the body's vital functions plays a great role in the pathogenesis of different diseases. Histamine is released during inflammatory and allergic reactions, anaphylactic and anaphylactoid shock, pseudoallergic reactions, and others. Acting through histamine receptors, it leads to increased intracellular concentration of cyclic guanosine monophosphate, enhanced chemotaxis of eosinophils and neutrophils, production of prostaglandins and thromboxane B, suppressed synthesis of lymphokines, etc. and causes contraction of smooth muscles of particularly the bronchi and intestine, dilation of vessels and their increased permeability, mucus hypersecretion in the upper airways, lower blood pressure, angioedema and itch, etc. In this connection, antihistamines that block histamine-induced reactions in various ways: by inhibiting its biosynthesis, enhancing its neutralization, blocking the access to receptors, and suppressing the release from mast cells, occupy a prominent place in clinical practice. The review covers the classification, main mechanisms of pharmacological action, and indications for the use of antihistamines that not only have the well-known antihistamine properties, but have also a broad spectrum of anti-inflammatory activity. There are data on the benefits of a group of antihistamines, the quinuclidine derivatives (quifenadine, sequifenadine) that were designed by Academician M.D. Mashkovsky and are one of the first examples of designing new classes of multifunctional non-sedating antihistamines, which combines a high selective activity to block histamine type 1 receptors and an ability to block serotonin and to break down histamine directly in tissues.

  8. Theoretical study on the mechanism and stereochemistry of the cinchona-thiourea organocatalytic hydrophosphonylation of an α-ketoester.

    Science.gov (United States)

    Li, Weiyi; Huang, Dongfeng; Lv, Yajing

    2013-11-21

    The mechanism and stereochemistry of the hydrophosphonylation of an α-ketoester with dimethylphosphonate (DMHP) catalyzed by a thiourea-cinchona organocatalyst have been studied by the ONIOM method. The calculations show that the catalytic cycle is a three-step process, including the deprotonation of DMHP, C-P bond formation via nucleophilic addition and proton transfer with the regeneration of the catalyst. The deprotonation of DMHP mediated by the basicity of the quinuclidine nitrogen atom is the rate-determining step for the entire reaction. The activation of the α-ketoester by the thiourea or protonated cinchona moiety of the bifunctional catalyst is comparatively investigated, and the former is energy-preferred. AIM combined with NBO analysis indicate that the multiple hydrogen bonds play essential roles in activating substrates, facilitating charge transfer and stabilizing transition states and intermediates. The stereochemistry of the reaction is controlled by the C-P bond formation step and originated from the chiral induction of the multiple hydrogen-bonding interactions. The bulkier substituent groups on the chiral scaffold of the catalyst may increase rigidity of the catalyst and the asymmetric induction to the substrates. The calculations predict that alkyl substituted α-ketoesters might also be converted to chiral α-hydroxyl phosphonates with high enantioselectivity.

  9. Cardiovascular and antihypertensive actions of 1-methyl-3-keto-4-phenylquinuclidinium bromide.

    Science.gov (United States)

    Vidrio, H; Hong, E

    1976-01-01

    The sympatholytic and norepinephrine depleting drug 1-methyl-3-keto-4-phenylquinuclidinium bromide (MA540) possessed significant chronic antihypertensive activity in mecamylamine- and renal-hypertensive dogs. The compound was approximately four times more potent than guanethidine in the former model and three times as potent in the latter. MA540 reduced orthostatic blood pressure responses in unanesthetized rabbits, but was approximately ten times less potent than guanethidine. The quinuclidine derivative did not affect cardiac output, heart rate or stroke volume in anesthetized open chest dogs and moderately increased mean blood pressure and total peripheral resistance. It produced diuresis and saluresis in anesthetized dogs, but did not influence water or electrolyte urinary excretion in conscious rats. In the latter test, guanethidine produced antidiuresis and antisaluresis. It was concluded that MA540 is a potent, orally effective antihypertensive agent acting through adrenergic neuron blockade, that it lacks undesirable effects on cardiac and renal functions, and that compared with guanethidine, it is more potent in lowering blood pressure but less so in interfering with orthostatic cardiovascular reflexes.

  10. In Vitro and In Vivo Activities of E5700 and ER-119884, Two Novel Orally Active Squalene Synthase Inhibitors, against Trypanosoma cruzi

    Science.gov (United States)

    Urbina, Julio A.; Concepcion, Juan Luis; Caldera, Aura; Payares, Gilberto; Sanoja, Cristina; Otomo, Takeshi; Hiyoshi, Hironobu

    2004-01-01

    Chagas' disease is a serious public health problem in Latin America, and no treatment is available for the prevalent chronic stage. Its causative agent, Trypanosoma cruzi, requires specific endogenous sterols for survival, and we have recently demonstrated that squalene synthase (SQS) is a promising target for antiparasitic chemotherapy. E5700 and ER-119884 are quinuclidine-based inhibitors of mammalian SQS that are currently in development as cholesterol- and triglyceride-lowering agents in humans. These compounds were found to be potent noncompetitive or mixed-type inhibitors of T. cruzi SQS with Ki values in the low nanomolar to subnanomolar range in the absence or presence of 20 μM inorganic pyrophosphate. The antiproliferative 50% inhibitory concentrations of the compounds against extracellular epimastigotes and intracellular amastigotes were ca. 10 nM and 0.4 to 1.6 nM, respectively, with no effects on host cells. When treated with these compounds at the MIC, all of the parasite's sterols disappeared from the parasite cells. In vivo studies indicated that E5700 was able to provide full protection against death and completely arrested the development of parasitemia when given at a concentration of 50 mg/kg of body weight/day for 30 days, while ER-119884 provided only partial protection. This is the first report of an orally active SQS inhibitor that is capable of providing complete protection against fulminant, acute Chagas' disease. PMID:15215084

  11. Asymmetric hydrogenation on chirally modified Pt: origin of hydrogen in the N-H-O interaction between cinchonidine and ketone.

    Science.gov (United States)

    Maeda, Nobutaka; Hungerbühler, Konrad; Baiker, Alfons

    2011-12-14

    An understanding of the chiral site-substrate interaction is a necessary prerequisite for the rational design and development of efficient heterogeneous asymmetric catalysts. For the enantioselective hydrogenation of α-ketoesters on cinchona-modified platinum, it has earlier been proposed that the crucial interaction is an N-H-O type hydrogen bonding between the quinuclidine N atom of cinchonidine and the α-carbonyl O atom of the substrate. The involved hydrogen atom has been proposed to originate either from protonation (in protic solvent) or from dissociatively adsorbed hydrogen (in aprotic solvent), but experimental evidence for the latter was lacking so far. In this study, in situ attenuated total reflection infrared spectroscopy combined with modulation excitation spectroscopy and phase sensitive detection provides clear evidence that in aprotic media, hydrogen dissociated on Pt is involved in the N-H-O interaction between the chiral modifier, cinchonidine, and the ketone. In the absence of Pt (pure alumina support), no such interaction occurs, indicating the crucial role of dissociated hydrogen in the formation of the diastereomeric transition complex.

  12. Thermochemistry of Alane Complexes for Hydrogen Storage: A Theoretical and Experimental Comparison

    CERN Document Server

    Wong, Bryan M; Nielsen, Ida M B; Graetz, Jason; Allendorf, Mark D; 10.1021/jp112258s

    2011-01-01

    Knowledge of the relative stabilities of alane (AlH3) complexes with electron donors is essential for identifying hydrogen storage materials for vehicular applications that can be regenerated by off-board methods; however, almost no thermodynamic data are available to make this assessment. To fill this gap, we employed the G4(MP2) method to determine heats of formation, entropies, and Gibbs free energies of formation for thirty-eight alane complexes with NH3-nRn (R = Me, Et; n = 0-3), pyridine, pyrazine, triethylenediamine (TEDA), quinuclidine, OH2-nRn (R = Me, Et; n = 0-2), dioxane, and tetrahydrofuran (THF). Monomer, bis, and selected dimer complex geometries were considered. Using these data, we computed the thermodynamics of the key formation and dehydrogenation reactions that would occur during hydrogen delivery and alane regeneration, from which trends in complex stability were identified. These predictions were tested by synthesizing six amine-alane complexes involving trimethylamine, triethylamine, di...

  13. SN2' versus SN2 reactivity: control of regioselectivity in conversions of Baylis-Hillman adducts.

    Science.gov (United States)

    Baidya, Mahiuddin; Remennikov, Grygoriy Y; Mayer, Peter; Mayr, Herbert

    2010-01-25

    TiCl(4)-induced Baylis-Hillman reactions of alpha,beta-unsaturated carbonyl compounds with aldehydes yield the (Z)-2-(chloromethyl)vinyl carbonyl compounds 5, which react with 1,4-diazabicyclo[2.2.2]octane (DABCO), quinuclidine, and pyridines to give the allylammonium ions 6. Their combination with less than one equivalent of the potassium salts of stabilized carbanions (e.g. malonate) yields methylene derivatives 8 under kinetically controlled conditions (S(N)2' reactions). When more than one equivalent of the carbanions is used, a second S(N)2' reaction converts 8 into their thermodynamically more stable allyl isomers 9. The second-order rate constants for the reactions of 6 with carbanions have been determined photometrically in DMSO. With these rate constants and the previously reported nucleophile-specific parameters N and s for the stabilized carbanions, the correlation log k (20 degrees C)=s(N + E) allowed us to calculate the electrophilicity parameters E for the allylammonium ions 6 (-19 reactions to proceed via an addition-elimination mechanism with a rate-determining addition step.

  14. Study on 1,3,5-triazine chemistry in dehydrocondensation: gauche effect on the generation of active triazinylammonium species.

    Science.gov (United States)

    Kunishima, Munetaka; Ujigawa, Takae; Nagaoka, Yoshie; Kawachi, Chiho; Hioki, Kazuhito; Shiro, Motoo

    2012-12-03

    The reaction of 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) with various nitrogen-containing compounds, particularly tertiary amines (tert-amines), has been studied for the preparation of 2-(4,6-dimethoxy-1,3,5-triazinyl)trialkylammonium salts [DMT-Am(s)]. DMT-Ams derived from aliphatic tert-amines exhibited activity for the dehydrocondensation between a carboxylic acid and an amine to form an amide in a model reaction. Based on a conformational analysis of DMT-Ams and tert-amines by NMR and X-ray diffraction methods, we concluded that a β-alkyl group maintained in a gauche relationship with the nitrogen lone pair of tert-amines significantly hinders the approach of CDMT to the nitrogen. Thus, trimethylamine and quinuclidine without such alkyl groups readily react with CDMT whereas triethylamine, possessing two or three such gauche β-alkyl groups in the stable conformations, does not react at all. The theory of "gauche β-alkyl group effect" proposed here provides useful guidelines for the preparation of DMT-Ams possessing various tertiary amine moieties. An investigation of the dehydrocondensation activity of tert-amines in a CDMT/tert-amine system that involves in situ generation of DMT-Am, showed that the gauche effect of the β-alkyl group becomes quite pronounced; the yield of the amide decreases significantly with tert-amines possessing an unavoidable gauche β-alkyl group. Thus, the tert-amine/CDMT systems are useful for judging whether tert-amines can readily react with CDMT without isolation of DMT-Ams.

  15. Docking studies of benzylidene anabaseine interactions with α7 nicotinic acetylcholine receptor (nAChR) and acetylcholine binding proteins (AChBPs): application to the design of related α7 selective ligands.

    Science.gov (United States)

    Kombo, David C; Mazurov, Anatoly; Tallapragada, Kartik; Hammond, Philip S; Chewning, Joseph; Hauser, Terry A; Vasquez-Valdivieso, Montserrat; Yohannes, Daniel; Talley, Todd T; Taylor, Palmer; Caldwell, William S

    2011-11-01

    AChBPs isolated from Lymnaea stagnalis (Ls), Aplysia californica (Ac) and Bulinus truncatus (Bt) have been extensively used as structural prototypes to understand the molecular mechanisms that underlie ligand-interactions with nAChRs [1]. Here, we describe docking studies on interactions of benzylidene anabaseine analogs with AChBPs and α7 nAChR. Results reveal that docking of these compounds using Glide software accurately reproduces experimentally-observed binding modes of DMXBA and of its active metabolite, in the binding pocket of Ac. In addition to the well-known nicotinic pharmacophore (positive charge, hydrogen-bond acceptor, and hydrophobic aromatic groups), a hydrogen-bond donor feature contributes to binding of these compounds to Ac, Bt, and the α7 nAChR. This is consistent with benzylidene anabaseine analogs with OH and NH(2) functional groups showing the highest binding affinity of these congeners, and the position of the ligand shown in previous X-ray crystallographic studies of ligand-Ac complexes. In the predicted ligand-Ls complex, by contrast, the ligand OH group acts as hydrogen-bond acceptor. We have applied our structural findings to optimizing the design of novel spirodiazepine and spiroimidazoline quinuclidine series. Binding and functional studies revealed that these hydrogen-bond donor containing compounds exhibit improved affinity and selectivity for the α7 nAChR subtype and demonstrate partial agonism. The gain in affinity is also due to conformational restriction, tighter hydrophobic enclosures, and stronger cation-π interactions. The use of AChBPs structure as a surrogate to predict binding affinity to α7 nAChR has also been investigated. On the whole, we found that molecular docking into Ls binding site generally scores better than when a α7 homology model, Bt or Ac crystal structure is used. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

  16. Radiosynthesis of (S)-[(18)F]T1: The first PET radioligand for molecular imaging of α3β4 nicotinic acetylcholine receptors.

    Science.gov (United States)

    Sarasamkan, Jiradanai; Fischer, Steffen; Deuther-Conrad, Winnie; Ludwig, Friedrich-Alexander; Scheunemann, Matthias; Arunrungvichian, Kuntarat; Vajragupta, Opa; Brust, Peter

    2017-03-18

    Recent pharmacologic data revealed the implication of α3β4 nicotinic acetylcholine receptors (nAChRs) in nicotine and drug addiction. To image α3β4 nAChRs in vivo, we aimed to establish the synthesis of a [(18)F]-labelled analog of the highly affine and selective α3β4 ligand (S)-3-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)quinuclidine ((S)-T1). (S)-[(18)F]T1 was synthesized from ethynyl-4-[(18)F]fluorobenzene ([(18)F]5) and (S)-azidoquinuclidine by click reaction. After a synthesis time of 130min (S)-[(18)F]T1 was obtained with a radiochemical yield (non-decay corrected) of 4.3±1.3%, a radiochemical purity of >99% and a molar activity of >158 GBq/μmol. The brain uptake and the brain-to-blood ratio of (S)-[(18)F]T1 in mice at 30min post injection were 2.02 (SUV) and 6.1, respectively. According to an ex-vivo analysis, the tracer remained intact (>99%) in brain. Only one major radiometabolite was detected in plasma and urine samples. In-vitro autoradiography on pig brain slices revealed binding of (S)-[(18)F]T1 to brain regions associated with the expression of α3β4 nAChRs, which could be reduced by the α3β4 nAChR selective drug AT-1001. These findings make (S)-[(18)F]T1 a potential tool for the non-invasive imaging of α3β4 nAChRs in the brain by PET.

  17. An Umeclidinium membrane sensor; Two-step optimization strategy for improved responses.

    Science.gov (United States)

    Yehia, Ali M; Monir, Hany H

    2017-09-01

    In the scientific context of membrane sensors and improved experimentation, we devised an experimentally designed protocol for sensor optimization. Two-step strategy was implemented for Umeclidinium bromide (UMEC) analysis which is a novel quinuclidine-based muscarinic antagonist used for maintenance treatment of symptoms accompanied with chronic obstructive pulmonary disease. In the first place, membrane components were screened for ideal ion exchanger, ionophore and plasticizer using three categorical factors at three levels in Taguchi design. Secondly, experimentally designed optimization was followed in order to tune the sensor up for finest responses. Twelve experiments were randomly carried out in a continuous factor design. Nernstian response, detection limit and selectivity were assigned as responses in these designs. The optimized membrane sensor contained tetrakis-[3,5-bis(trifluoro- methyl)phenyl] borate (0.44wt%) and calix[6]arene (0.43wt%) in 50.00% PVC plasticized with 49.13wt% 2-ni-tro-phenyl octylether. This sensor, along with an optimum concentration of inner filling solution (2×10(-4)molL(-1) UMEC) and 2h of soaking time, attained the design objectives. Nernstian response approached 59.7mV/decade and detection limit decreased by about two order of magnitude (8×10(-8)mol L(-1)) through this optimization protocol. The proposed sensor was validated for UMEC determination in its linear range (3.16×10(-7) -1×10(-3)mol L(-1)) and challenged for selective discrimination of other congeners and inorganic cations. Results of INCRUSE ELLIPTA(®) inhalation powder analyses obtained from the proposed sensor and manufacturer's UPLC were statistically compared. Moreover the proposed sensor was successfully used for the determination of UMEC in plasma samples. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. A search for pure compounds suitable for use as matrix in spectroscopic studies of radiation-produced radical cations. III. A selection of compounds based on the thermochemistry of hydrogen and proton transfer reactions between neutral molecules and their cations

    Science.gov (United States)

    Van den Bosch, Ann; Ceulemans, Jan

    A systematic investigation is made of the thermochemistry of hydrogen and proton transfer between neutral molecules and their cations covering the entire organic chemistry, with the aim of selecting those compounds that are suitable for use as matrices in spectroscopic studies of radiation-produced radical cations. Compounds that are characterized by positive reaction enthalpies may be considered promising for use as matrices in such studies. Calculations are based on experimentally determined ionization energies and proton affinities and on carbon-hydrogen bond strengths that are arbitrarily taken as 418 kJ.mol -1 (100 kcal.mol -1). Effects of actual deviations from this value are considered. In the aliphatic series of compounds, reaction enthalpies depend strongly on functional groups present. Marked positive reaction enthalpies are obtained for alkenes, alkadienes, thioethers, mercaptans, iodoalkanes and tertiary amines. Non-aromatic cyclic compounds generally behave as their aliphatic counterparts. Thus, positive reaction enthalpies are generally obtained for unsaturated alicyclic hydrocarbons and cyclic thioethers. Positive reaction enthalpies are also obtained for piperidine, quinuclidine, manxine and derivatives. In the homocyclic aromatic series of compounds, reaction enthalpies are generally positive. Thus, positive reaction enthalpies are obtained for aromatic hydrocarbons, fluoro- and chlorobenzenes, aromatic amines (amino group attached directly to the ring) and halo- and methoxyanilines. In the heterocyclic aromatic series of compounds reaction enthalpies are generally negative. This is for instance the case for a large number of pyridine derivatives, di- and triazines and a number of bi- and tricyclic compounds. Positive reaction enthalpies are however obtained for furan and pyrrole.

  19. Sterol Biosynthesis Pathway as Target for Anti-trypanosomatid Drugs

    Directory of Open Access Journals (Sweden)

    Wanderley de Souza

    2009-01-01

    Full Text Available Sterols are constituents of the cellular membranes that are essential for their normal structure and function. In mammalian cells, cholesterol is the main sterol found in the various membranes. However, other sterols predominate in eukaryotic microorganisms such as fungi and protozoa. It is now well established that an important metabolic pathway in fungi and in members of the Trypanosomatidae family is one that produces a special class of sterols, including ergosterol, and other 24-methyl sterols, which are required for parasitic growth and viability, but are absent from mammalian host cells. Currently, there are several drugs that interfere with sterol biosynthesis (SB that are in use to treat diseases such as high cholesterol in humans and fungal infections. In this review, we analyze the effects of drugs such as (a statins, which act on the mevalonate pathway by inhibiting HMG-CoA reductase, (b bisphosphonates, which interfere with the isoprenoid pathway in the step catalyzed by farnesyl diphosphate synthase, (c zaragozic acids and quinuclidines, inhibitors of squalene synthase (SQS, which catalyzes the first committed step in sterol biosynthesis, (d allylamines, inhibitors of squalene epoxidase, (e azoles, which inhibit C14α-demethylase, and (f azasterols, which inhibit Δ24(25-sterol methyltransferase (SMT. Inhibition of this last step appears to have high selectivity for fungi and trypanosomatids, since this enzyme is not found in mammalian cells. We review here the IC50 values of these various inhibitors, their effects on the growth of trypanosomatids (both in axenic cultures and in cell cultures, and their effects on protozoan structural organization (as evaluted by light and electron microscopy and lipid composition. The results show that the mitochondrial membrane as well as the membrane lining the protozoan cell body and flagellum are the main targets. Probably as a consequence of these primary effects, other important changes take

  20. Effect of stereogenic centers on the self-sorting, depolymerization, and atropisomerization kinetics of porphyrin-based aggregates.

    Science.gov (United States)

    Helmich, Floris; Smulders, Maarten M J; Lee, Cameron C; Schenning, Albertus P H J; Meijer, E W

    2011-08-10

    We present our results on the mixing of different porphyrin molecules in supramolecular assemblies. Herein, chiral amplification experiments reveal the subtle role of the structural (mis)match between these monomers. We show that according to the "sergeant-and-soldiers" principle, a chiral porphyrin "sergeant" efficiently mixes with achiral "soldiers" in the same helical aggregate and strongly biases its handedness. However, when we mix two porphyrin enantiomers in a majority-rules experiment, no chiral amplification is observed at all, which is due to their narcissistic self-sorting into conglomerate-like aggregates. The mixing between two enantiomers in the same stack only occurs in a diluted-majority-rules experiment, in which enantiomeric mixtures of sergeants are diluted with achiral soldiers. The different outcomes of these chiral amplification phenomena are verified by modeling studies that reveal high mismatch penalties, which are ascribed to the high stereocenter loading of 12 methyl groups onto the monomers. Mixed-metal chiral amplification experiments between copper- and zinc-porphyrins show the same distinction in their mixing behavior, which is further supported by fluorescence measurements. The selective removal of chiral Zn-porphyrins from these mixed-metal systems is performed with the Lewis base quinuclidine that depolymerizes the Zn-porphyrins upon axial ligation. This extraction process proceeds at different time scales, depending on the mixed state: slow extraction kinetics for the mixed sergeant-and-soldiers and diluted-majority-rules systems and an instant extraction for the phase-separated majority-rules system. By simultaneously monitoring the supramolecular chirality during extraction, a chiral memory effect is observed for both mixed systems that show slow extraction kinetics. For the sergeant-and-soldiers system, the remaining supramolecular backbone contains achiral monomers only, which give rise to a long lasting chiral memory with slow

  1. Vladimir Prelog i Zavod za organsku kemiju

    Directory of Open Access Journals (Sweden)

    Jakopčić, K.

    2007-03-01

    -operation from the small but prosperous pharmaceutical company "Kaštel" in Zagreb. On behalf of the agreement, Prelog and his department obtained funds to fit up the laboratory and to start very prosperous research in the synthesis and studies of pharmaceutically interesting compounds. With his assistants, students and other collaborators, Prelog started research of cinchona bark alkaloids, preferentially oriented to the synthesis of quinine. For example, Prelog's method of double intramolecular alkylation to synthetize the quinuclidine moiety of quinine was patented by "Kaštel". With R. Seiwerth he developed the first useful synthesis of adamantane. Prelog's group started research in the field of sulphonamides and commercial success of "Streptazole" stimulated the development of the research laboratories within "Kaštel". The collaboration in the research continued in fields of other chemotherapeutics, analeptics, spasmolitics, barbiturates etc. Within the period 1935-1941, Prelog published 48 scientific papers and 8 patents. In less than seven years, his results enormously influenced the entire organic chemistry in Zagreb till nowadays. Under the confused and uncertain circumstances caused by the beginning of World War II, Prelog left Zagreb in 1941 and continued his extraordinary scientific career at the ETH in Zürich.During the war (1942-1945 the tuition and the Department were run by Dr. Rativoj Seiwerth, former collaborator and first assistant to V. Prelog. In almost unbelievable conditions, the young assistant, then assistant professor (since January 1943, R. Seiwerth fully succeeded in continuing most activities founded by Professor Prelog. After the war (1945, R. Seiwerth was forced to resign. Nevertheless, soon after R. Seiwerth continued his research work, firstly in the Institute for Industrial Research in Zagreb (1946-1952, and later in the Research Institute of "Pliva" in Zagreb. He retired in 1980.In post-war conditions (1945/46, the activity of the Technical