Sample records for dioxoles

  1. (E-1-(2-Aminophenyl-3-(benzo[d][1,3]dioxol-5-ylprop-2-en-1-one

    Rodrigo Abonia


    Full Text Available The title chalcone (E-1-(2-aminophenyl-3-(benzo[d][1,3]dioxol-5-ylprop-2-en-1-one was obtained in 76% yield from a NaOH catalyzed Claisen–Schmidt condensation reaction between o-aminoacetophenone and piperonal. This product will be used as a key precursor for the development of an alternative route for the total synthesis of the alkaloid Graveoline. Single crystals of the title compound suitable for X-ray diffraction were grown via slow evaporation in ethanol at room temperature. A complete crystallographic study was performed in depth to unequivocally confirm its structure. The crystal structure of the title o-aminochalcone, C16H13NO3, shows two molecules per asymmetric unit (Z = 4 and adopts an E configuration about the C=C double bond. In the title compound, the mean plane of the non-H atoms of the central chalcone fragment C—C(O—C—C—C is as follow: [root-mean-square (r.m.s. deviation = 0.0210 Å for A–B and 0.0493 for C–D molecules]. In the crystal, molecules are linked by N–H...O and C–H...O, hydrogen bonds forming S(6, R22(6 and edge-fused R44(24rings along with C(18 chains running parallel to (110.

  2. Design and Synthesis of 5-Substituted Benzo[d][1,3]dioxole Derivatives as Potent Anticonvulsant Agents.

    Dong, Shiyang; Wang, Tiantian; Hu, Chundi; Chen, Xiaodong; Jin, Yi; Wang, Zengtao


    A series of 5-substituted benzo[d][1,3]dioxole derivatives was designed, synthesized, and tested for anticonvulsant activity using the maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) screens. Neurotoxicity was determined by rotarod test. In the preliminary screening, six compounds, 3a, 3c, 3d, and 4d-f, showed promising anticonvulsant activities in the MES model, and compounds 4c and 4d exhibited full protection against seizures at doses of 300 mg/kg in the scPTZ model. Among the synthesized compounds, 3c as the most active compound showed high protection against the MES-induced seizures with an ED50 value of 9.8 mg/kg and a TD50 value of 229.4 mg/kg after intraperitoneal injection into mice, thus providing compound 3c with a high protective index (TD50 /ED50 ) of 23.4 comparable to those of reference antiepileptic drugs. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  3. Design, synthesis and evaluation of dialkyl 4-(benzo[d][1,3]dioxol-6-yl)-1,4-dihydro-2,6-dimethyl-1-substituted pyridine-3,5-dicarboxylates as potential anticonvulsants and their molecular properties prediction.

    Prasanthi, G; Prasad, K V S R G; Bharathi, K


    The present study is on the development of dialkyl 4-(benzo[d][1,3]dioxol-6-yl)-1,4-dihydro-2,6-dimethyl-1-substituted pyridine-3,5-dicarboxylate derivatives as isosteric analogues of isradipine and nifedipine, by the replacement of benzofurazanyl and 2-nitrophenyl groups respectively with benzo[d][1,3]dioxo-6-yl group, as potential anticonvulsants. Fivfteen new derivatives (8a-8o) were synthesized and tested for anticonvulsant activity using maximal electroshock and subcutaneous pentylenetetrazole induced seizure methods. Compound 8f possessing free NH group in 1,4-dihydropyridine ring, diethyl ester functionality at the positions 3 and 5 showed significant anticonvulsant and antioxidant activities. This was also supported by molecular properties prediction data. Selected compounds were evaluated for antinociceptive activity in capsaicin induced nociception assay at 10 mg/kg body weight, but displayed no significant activity at the tested dose.

  4. Ryecyanatines A and B and ryecarbonitrilines A and B, substituted cyanatophenol, cyanatobenzo[1,3]dioxole, and benzo[1,3]dioxolecarbonitriles from rye (Secale cereale L.) root exudates: Novel metabolites with allelopathic activity on Orobanche seed germination and radicle growth.

    Cimmino, Alessio; Fernández-Aparicio, Mónica; Avolio, Fabiana; Yoneyama, Koichi; Rubiales, Diego; Evidente, Antonio


    Orobanche and Phelipanche species (the broomrapes) are root parasitic plants, some of which represent serious weed problems causing heavy yield losses on important crops. Current control relies on the use of certain agronomic practices, resistant crop varieties, and herbicides, albeit success has been marginal. Agronomic practices such as the use of allelopathic species in intercropping or cover crops, or the use of direct seedling over residues of allelopathic species incorporate the principle of allelopathy exerted by molecules exuded from roots or released by crop residues to control broomrapes. In addition, the isolation of natural substances from root exudates of plants with potential to inhibit broomrape development opens the door to the design of new herbicides based on natural and benign sources. Ryecyanatines A and B and ryecarbonitrilines A and B, the first new substituted cyanatophenol, substituted cyanatobenzo[1,3]dioxole, and the latter two new substituted benzo[1,3]dioxolecarbonitriles were isolated from rye (Secale cereale L.) root exudates. They were characterized as 4-cyanato-2-methoxyphenol, 2-cyanato-benzo[1,3]dioxole, 2-methoxybenzo[1,3]dioxole-5-carbonitrile and benzo[1,3]dioxole-2-carbonitrile by spectroscopic (essentially NMR and HRESI MS spectra) methods. These compounds were investigated for allelopathic activity on Orobanche germination and development. Ryecarbonitriline A induced germination of Orobanche cumana seeds, and this germination can be considered as suicidal because O. cumana does not parasite rye roots and cannot survive without host resources beyond germination stage. In addition, ryecyanatine A promotes a rapid cessation of O. cumana, Orobanche crenata and Orobanche minor radicle growth with the promotion of a layer of papillae at the radicle tip in O. cumana and O. crenata hampering the contact of the parasite to the host. Ryecarbonitriline B also displayed the same activity although being less active than ryecyanatine A and

  5. Synthesis, spectroscopic investigations (FT-IR, NMR, UV-Vis, and TD-DFT), and molecular docking of (E)-1-(benzo[d][1, 3]dioxol-6-yl)-3-(6-methoxynaphthalen-2-yl)prop-2-en-1-one

    Therasa Alphonsa, A.; Loganathan, C.; Athavan Alias Anand, S.; Kabilan, S.


    The compound (E)-1-(benzo [d] [1, 3] dioxol-6-yl)-3-(6-methoxy naphthalen-2-yl) prop-2-en-1-one (AKN) was synthesized and characterized by FT-IR, NMR, and UV-Vis spectrometer. The optimized molecular geometry, bond lengths, bond angles, atomic charges, harmonic vibrational wave numbers and intensities of vibrational bonds of the title compound have been investigated by Time dependent- Density Functional Theory (TD-DFT) using a standard B3LYP method with 6-31 G (d, p) basis set available in the Gaussian 09W package. 1H and 13C NMR chemical shifts of the molecule were calculated using Gauge-independent atomic orbital method (GIAO). Experimental excitation energies of the molecules were matched with the theoretically calculated energies. The atomic charge distributions of the various atoms present in the AKN were obtained by Mulliken charge population analysis. The Molecular Electrostatic Potential (MEP) analysis reveals the sites for electrophilic attack and nucleophilic reactions in the molecule. The difference between the observed and scaled frequencies was small. The HOMO to LUMO transition implies an electron density transfer. The intramolecular contacts have been interpreted using Natural Bond Orbital (NBO) analysis. The calculation results were applied to simulate spectra of the title compound, which show excellent agreement with observed spectra. To provide information about the interactions between human cytochrome protein and the novel compound theoretically, docking studies were carried out using Schrödinger software.

  6. Toxicological evaluation and metabolism of two N-alkyl benzamide umami flavour compounds: N-(heptan-4-ylbenzo[d][1,3]dioxole-5-carboxamide and (R-N-(1-methoxy-4-methylpentan-2-yl-3,4-dimethylbenzamide

    Donald S. Karanewsky


    Full Text Available Toxicological evaluations of two N-alkyl benzamide umami flavour compounds, N-(heptan-4-ylbenzo[d][1,3]dioxole-5-carboxamide (S807, CAS 745047-51-2 and (R-N-(1-methoxy-4-methylpentan-2-yl-3,4-dimethylbenzamide (S9229, CAS 851669-60-8, were completed for the purpose of assessing their safety for use in food and beverage applications. Both S807 and S9229 undergo rapid oxidative metabolism by both rat and human liver microsomes in vitro. In pharmacokinetic studies in rats, the systemic exposure to S9229 on oral administration is very low at all doses (% F < 1%, while that of S807 demonstrated a non-linear dose dependence. In metabolism studies in rats, hydroxylation of the C-4 aryl methyl group was found to be the dominant metabolic pathway for S9229. The dominant metabolic pathway for S807 in the rat involved oxidative scission of the methylenedioxy moiety to produce the corresponding 3,4-dihydroxybenamide which is further converted by Phase II metabolic enzymes to the 3- and 4-O-methyl ethers as well as their corresponding glucuronides. Both S807 and S9229 were not found to be mutagenic or clastogenic in vitro, and did not induce micronuclei in polychromatic erythrocytes in vivo. In a subchronic oral toxicity study in rats, the no-observed-effect-level (NOEL for S807 was 20 mg/kg bw/day when administered in the diet for 13 weeks. The no-observed-adverse-effect-level (NOAEL for S9229 in rats was 100 mg/kg bw/day (highest dose tested when administered in the diet for 28 consecutive days.

  7. 3-(Benzo[d][1,3]dioxol-5-ylamino)-N-(4-fluorophenyl)thiophene-2-carboxamide overcomes cancer chemoresistance via inhibition of angiogenesis and P-glycoprotein efflux pump activity.

    Mudududdla, Ramesh; Guru, Santosh K; Wani, Abubakar; Sharma, Sadhana; Joshi, Prashant; Vishwakarma, Ram A; Kumar, Ajay; Bhushan, Shashi; Bharate, Sandip B


    3-((Quinolin-4-yl)methylamino)-N-(4-(trifluoromethoxy)phenyl)thiophene-2-carboxamide (OSI-930, 1) is a potent inhibitor of c-kit and VEGFR2, currently under phase I clinical trials in patients with advanced solid tumors. In order to understand the structure-activity relationship, a series of 3-arylamino N-aryl thiophene 2-carboxamides were synthesized by modifications at both quinoline and amide domains of the OSI-930 scaffold. All the synthesized compounds were screened for in vitro cytotoxicity in a panel of cancer cell lines and for VEGFR1 and VEGFR2 inhibition. Thiophene 2-carboxamides substituted with benzo[d][1,3]dioxol-5-yl and 2,3-dihydrobenzo[b][1,4]dioxin-6-yl groups 1l and 1m displayed inhibition of VEGFR1 with IC50 values of 2.5 and 1.9 μM, respectively. Compounds 1l and 1m also inhibited the VEGF-induced HUVEC cell migration, indicating its anti-angiogenic activity. OSI-930 along with compounds 1l and 1m showed inhibition of P-gp efflux pumps (MDR1, ABCB1) with EC50 values in the range of 35-74 μM. The combination of these compounds with doxorubicin led to significant enhancement of the anticancer activity of doxorubicin in human colorectal carcinoma LS180 cells, which was evident from the improved IC50 of doxorubicin, the increased activity of caspase-3 and the significant reduction in colony formation ability of LS180 cells after treatment with doxorubicin. Compound 1l showed a 13.8-fold improvement in the IC50 of doxorubicin in LS180 cells. The ability of these compounds to display dual inhibition of VEGFR and P-gp efflux pumps demonstrates the promise of this scaffold for its development as multi-drug resistance-reversal agents.

  8. Synthesis and biological evaluation of benzo[d][1,3]dioxol-5-yl chalcones as antiproliferating agents.

    Kamal, Ahmed; Balakrishna, Moku; Loka Reddy, Velatooru; Riyaz, Syed; Bagul, Chandrakant; Satyanarayana, Bethu Murali; Venkateswar Rao, Janapala


    A series of chalcone derivatives were designed, synthesized, and evaluated for their cytotoxic potential. These molecules have showed promising cytotoxic activity with IC50 values ranging from 5.24 to 63.12 μm. Among them, conjugates 16k, 16m and 16t showed significant antiproliferative activity with IC50 values ranging from 5.24 to 10.39 μm in MDA-MB-231 cell line. These compounds were further investigated for their effect on cell membrane blebbing, chromatin condensation, DNA fragmentation, Hoechst staining, annexin V, and cell cycle arrest (G2/M). The Western blot experiments revealed up regulation of pro-apoptotic Bax and downregulation of antiapoptotic Bcl-2. The studies also indicated reduction of mitochondrial membrane potential and increase in the levels of caspase-3 and caspase-7.

  9. Methyl 2-(2,2-dimethyl-3a,6a-dihydrofuro[3,2-d][1,3]dioxol-5-yl-4-oxo-4H-chromene-3-carboxylate

    Devadasan Velmurugan


    Full Text Available In the title molecule, C18H16O7, the dioxolane ring adopts an envelope conformation with the dimethyl-substituted C atom as the flap. The furan ring is almost coplanar with the pyran ring, with a dihedral angle of 1.04 (10° between the planes, and it makes a dihedral angle of 67.97 (11° with the mean plane of the dioxolane ring. The latter makes a dihedral angle of 67.15 (10° with the pyran ring. The O atom attached to the pyran ring deviates by −0.009 (1 Å. The crystal packing features C—H...O hydrogen bonds, forming a three-dimensional structure. The methoxycarbonyl atoms are disordered over two positions, with a refined occupancy ratio of 0.508 (18:0.492 (18.

  10. 9-{[4-(Dimethylaminobenzyl]amino}-5-(4-hydroxy-3,5-dimethoxyphenyl-5,5a,8a,9-tetrahydrofuro[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-6(8H-one methanol monosolvate

    Hong Chen


    Full Text Available In the title compound, C30H32N2O7·CH4O, the tetrahydrofuran ring and the six-membered ring fused to it both display envelope conformations, with the ring C atom opposite the carbonyl group and the adjacent bridgehead C atom as the flaps, respectively. In the crystal structure, intermolecular O—H...O hydrogen bonds link all moieties into ribbons along [010]. Weak intermolecular C—H...O interactions consolidate the crystal packing further.

  11. Quantum chemical and RRKM/master equation studies of isoprene ozonolysis: Methacrolein and methacrolein oxide

    Kuwata, Keith T.; Valin, Lukas C.


    Methacrolein is a major product of isoprene ozonolysis, and methacrolein oxide is an important ozonolysis intermediate. We use CBS-QB3 and RRKM/master equation calculations to characterize all methacrolein formation pathways and all the unimolecular reactions of methacrolein oxide. Our predicted methacrolein yield agrees with experiment if we assume that all of the dioxirane formed from methacrolein oxide decomposes to methacrolein. The vinyl group of methacrolein oxide allows the species to cyclize to a dioxole with a reaction barrier lower than the barriers to either hydroperoxide or dioxirane formation. Two dioxole derivatives, 1,2-epoxy-2-methyl-3-propanal and 2-methyl-3-oxopropanal, should be measurable products of isoprene ozonolysis.

  12. Thermal, photosynthesis and antibacterial studies of bioactive safrole derivative as precursor for natural flavor and fragrance

    Suzan A. Khayyat


    Full Text Available Safrole [5-allylbenzo[d][1,3]dioxole] was subjected to photochemical oxidation reaction with hydrogen peroxide in the presence of sodium lamp to give the corresponding epoxy derivative [5-oxiranylmethylbenzo[1,3]dioxole. The thermal oxidation of safrole with 3-chloroperoxybenzoic acid at room temperature gave the same epoxide derivative in quantitative yield. Antibacterial studies were carried out on safrole and its photoproducts (safrole epoxide and safrole hydroperoxide. The results revealed that safrole hydroperoxide was the most effective than safrole epoxide than safrole against Gram-positive bacteria Bacillus subtilis ATCC6633, Staphylococcus aureus ATCC25923, and Gram negative bacteria Escherichia coli ATCC25422. This result proved that safrole derivatives are beneficial to human health, having the potential to be used for medical purposes.

  13. Crystal structure of 3-O-benzyl-4(R-C-(1-benzyl-1H-1,2,3-triazol-4-yl-1,2-O-isopropylidene-α-d-erythrofuranose

    Nikita Semjonovs


    Full Text Available The title compound, C23H25N3O4, {systematic name: 1-benzyl-4-[(3aR,5R,6R,6aR-6-benzyloxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]-1H-1,2,3-triazole}, consists of a substituted 2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole. The furanose ring adopts an envelope conformation close to C3-exo, where the C atom substituted by the benzyloxy group is the flap. The fused dioxolane ring also adopts an envelope conformation, with the methylene C atom as the flap. In the crystal, molecules are linked by weak C—H...O hydrogen bonds, forming zigzag chains along [010].

  14. Antioxidant Activity of Novel Fused Heterocyclic Compounds Derived from Tetrahydropyrimidine Derivative.

    Salem, Marwa Sayed; Farhat, Mahmoud; Errayes, Asma Omar; Madkour, Hassan Mohamed Fawzy


    6-(Benzo[d][1,3]dioxol-5-yl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile has been utilized for synthesis of the fused heterocyclic compounds namely thiazolopyrimidines, tetrazolopyrimidine, pyrimidoquinazoline, pyrimidothiazolopyrimidine, pyrimidothiazolotriazine and pyrrolothiazolopyrimidine derivatives. The newly synthesized compounds were characterized by IR, (1)H-NMR, (13)C-NMR, and mass spectral data. Antioxidant activities of all synthesized compounds were investigated.

  15. Dehydration processes using membranes with hydrophobic coating

    Huang, Yu; Baker, Richard W; Aldajani, Tiem; Ly, Jennifer


    Processes for removing water from organic compounds, especially polar compounds such as alcohols. The processes include a membrane-based dehydration step, using a membrane that has a dioxole-based polymer selective layer or the like and a hydrophilic selective layer, and can operate even when the stream to be treated has a high water content, such as 10 wt % or more. The processes are particularly useful for dehydrating ethanol.

  16. Synthesis and characterization of related substances of Azilsartan Kamedoxomil

    Maddi N. V. D. Harikiran


    Full Text Available Azilsartan Kamedoxomil is an AT1-subtype angiotensin II receptor blocker (ARB. During the laboratory synthesis of Azilsartan Kamedoxomil, four related substances of Azilsartan Kamedoxomil were observed and identified. These were 2-Ethoxy-3-[[4-[2- [4-[(5-methyl-2-oxo-1,3-dioxol-4-ylmethyl]-5-oxo-1,2,4-oxadiazol-3-yl]phenyl]phenyl] methyl] benzimidazole-4-carboxylic acid (azilsartan N-medoxomil, 9, (5-methyl-2-oxo- 1,3-dioxol-4-ylmethyl 2-ethoxy-3-[[4-[2-[4-[(5-methyl-2-oxo-1,3-dioxol-4-ylmethyl]-5- oxo-1,2,4-oxadiazol-3-yl]phenyl]phenyl] methyl] benzimidazole-4-carboxylate (azilsartan dimedoxomil, 10, (5-methyl-2-oxo-1,3-dioxo-4-ylmethyl 1-[2’-(4,5-dihydro-5-oxo-4H- 1,2,4-oxadiazol-3-ylbiphenyl-4-yl]methyl]-2-methoxy-1H-benzimidazole-7-carboxylate (methoxy analogue of azilsartan medoxomil, 11, Methyl 1-((2’-amidobiphenyl-4-yl methyl-2-ethoxy-1H-benzo[d]imidazole-7-carboxylate (amide methyl ester, 12. The present work describes the origin, synthesis and characterization of these related substances.

  17. Synthesis and odour properties of floral smelling compounds.

    Anselmi, C; Centini, M; Sega, A; Napolitano, E; Pelosi, P; Scesa, C


    Synopsis To provide further information on the relationships between chemical structure and floral odour, here we report the synthesis and the odour evaluation of some spirane derivatives, designed as conformational models of our previously described floral odorants. One of the new compounds (5-methyl-benzo[1,3]dioxole-2-spiro-1-cyclohexane), in particular, is endowed with a particularly pleasant odour of white flowers, can be easily prepared from commercial products and is more stable than other odorants of the same class; these characteristics make this odorant suitable for being used as an additive in perfumery and cosmetics.

  18. Evaluation of the analgesic effects of ammoxetine, a novel potent serotonin and norepinephrine reuptake inhibitor

    Zhang, Ting-Ting; Xue, Rui; Zhu, Lei; Li, Juan; Fan, Qiong-yin; Zhong, Bo-hua; Li, Yun-Feng; Ye, Cai-ying; Zhang, You-zhi


    Aim: The selective serotonin (5-HT) and norepinephrine (NE) reuptake inhibitors (SNRIs) are commonly used for the treatment of neuropathic pain and fibromyalgia. Ammoxetine ((±)-3-(benzo[d] [1,3]dioxol-4-yloxy)-N-methyl-3-(thiophen-2-yl)propan-1-amine) has been identified as a novel potent SNRI. In this study, we evaluated the acute analgesic properties of ammoxetine in different animal models of pain, and examined the involvement of monoamines in its analgesic actions. Methods: The analgesic...

  19. Cytotoxic Lignan from the Non-Transformed Root Culture of Phyllanthus amarus

    Barbara Sparzak


    Full Text Available A new lignan from the non-transformed root in vitro cultures of Phyllanthus amarus was isolated. The structure of the compound was established on the basis of one- and two-dimensional NMR, as well as mass spectrometry data, as 7'-oxocubebin dimethylether (1,4-bis(benzo[d][1,3]dioxol-5-yl-2,3-bis(methoxymethylbutan-1-on. The non-transformed root cultures of P. amarus showed to be a selective source of this compound. The lignan revealed strong cytotoxic activity against HeLa cell line with an IC50 value of 3.8 µg/mL.

  20. Synthesis of -aryl--lactones and relationship: Structure – antifeedant and antifungal activity

    Andrzej Skrobiszewski; Witold Gładkowski; Paulina Walczak; Anna Gliszczyńska; Gabriela Maciejewska; Tomasz Klejdysz; Jan Nawrot; Czesław Wawrzeńczyk


    Eighteen racemic -aryl--lactones derived from simple aromatic aldehydes have been obtained in the chemical synthesis. Iodolactones (5c and 6c) were synthesized from ()-4-(benzo[][1′,3′]-dioxol-5′-yl)- but-3-en-2-one (1). Reductive dehalogenation of iodolactones 5a–c and 6a–c afforded -ethyl--lactones (7a–c, 8a–c) whereas the unsaturated lactones (9a–c, 10a–c) were obtained by dehydrohalogenation of iodolactones. All synthesized lactones were fully characterized by spectroscopic data (NMR, IR, HRMS) and subjected to the tests on the antifeedant activity towards Tribolium confusum, Trogoderma granarium and Sitophilus granaries as well to the tests on the antifungal activity towards four Fusarium species. The biological tests allowed to find some relationships between the structure and biological activity of the compounds studied. -Ethyl--lactones 7a–c, 8a–c and unsaturated lactones 9a–c, 10a-c were usually stronger antifeedants than their parent iodolactones 5a–c and 6a–c. trans-Iodolactones 6a–c were more active than cis isomers 5a-c both in antifeedant and antifungal assays. The structure of aromatic substituent was the key factor in antifungal activity. The lactones with benzo [][1,3]dioxole ring (5c, 6c, 7c, 8c, 9c) were the most active whereas those with unsubstituted benzene ring exhibited almost no activity.

  1. Structure-activity relationship study of pyrimido[1,2-c][1,3]benzothiazin-6-imine derivatives for potent anti-HIV agents.

    Mizuhara, Tsukasa; Oishi, Shinya; Ohno, Hiroaki; Shimura, Kazuya; Matsuoka, Masao; Fujii, Nobutaka


    3,4-Dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine (PD 404182) is an antiretroviral agent with submicromolar inhibitory activity against human immunodeficiency virus-1 (HIV-1) and HIV-2 infection. In the current study, the structure-activity relationships of accessory groups at the 3- and 9-positions of pyrimido[1,2-c][1,3]benzothiazin-6-imine were investigated for the development of more potent anti-HIV agents. Several different derivatives containing a 9-aryl group were designed and synthesized using Suzuki-Miyaura cross-coupling and Ullmann coupling reactions. Modification of the m-methoxyphenyl or benzo[d][1,3]dioxol-5-yl group resulted in improved anti-HIV activity. In addition, the 2,4-diazaspiro[5.5]undec-2-ene-fused benzo[e][1,3]thiazine derivatives were designed and tested for their anti-HIV activities. The most potent 9-(benzo[d][1,3]dioxol-5-yl) derivative was two-threefold more effective against several strains of HIV-1 and HIV-2 than the parent compound, PD 404182. Copyright © 2012 Elsevier Ltd. All rights reserved.

  2. New chlorinated amphetamine-type-stimulants disinfection-by-products formed during drinking water treatment.

    Huerta-Fontela, Maria; Pineda, Oriol; Ventura, Francesc; Galceran, Maria Teresa


    Previous studies have demonstrated high removal rates of amphetamine-type-stimulants (ATSs) through conventional drinking water treatments; however the behaviour of these compounds through disinfection steps and their transformation into disinfection-by-products (DBPs) is still unknown. In this work, for the first time, the reactivity of some ATSs such as amphetamine, methamphetamine, 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyethylamphetamine (MDEA) with chlorine has been investigated under simulated and real drinking water treatment conditions in order to evaluate their ability to give rise to transformation products. Two new DBPs from these illicit drugs have been found. A common chlorinated-by-product (3-chlorobenzo)-1,3-dioxole, was identified for both MDA and MDEA while for MDMA, 3-chlorocatechol was found. The presence of these DBPs in water samples collected through drinking water treatment was studied in order to evaluate their formation under real conditions. Both compounds were generated through treatment from raw river water samples containing ATSs at concentration levels ranging from 1 to 15 ng/L for MDA and from 2.3 to 78 ng/L for MDMA. One of them, (3-chlorobenzo)-1,3-dioxole, found after the first chlorination step, was eliminated after ozone and GAC treatment while the MDMA DBP mainly generated after the postchlorination step, showed to be recalcitrant and it was found in final treated waters at concentrations ranging from 0.5 to 5.8 ng/L.

  3. Design and synthesis of 3,4-methylenedioxy-6-nitrophenoxyacetylhydrazone derivatives obtained from natural safrole: new lead-agents with analgesic and antipyretic properties.

    Bezerra-Netto, Heleno J C; Lacerda, Daniel I; Miranda, Ana Luisa P; Alves, Hélio M; Barreiro, Eliezer J; Fraga, Carlos A M


    In this work, we reported the synthesis and evaluation of the analgesic, anti-inflammatory, and antipyretic properties of new 2-(6-nitro-benzo[1,3]dioxol-5-yloxy)-acetylhydrazone derivatives (3), designed exploring molecular hybridization and isosteric replacement approaches between nimesulide (1) and carbanalogue NAH series (2) developed at LASSBio. Target compounds were synthesized in very good yields exploiting abundant Brazilian natural product safrole (4) as starting material. The evaluation of the antinociceptive properties of this series led us to discover a new potent prototype of analgesic and antipyretic agent, that is, NAH derivative 3c, named LASSBio-891, which showed to be more potent than dipyrone used as standard.

  4. Enhanced flow injection analysis for measurements of S-nitrosothiols species in biological samples using highly selective amperometric nitric oxide sensor

    Chun Cui Huang; Hui Bo Shao


    A highly selective nitric oxide (NO) sensor is fabricated and applied to devise an enhanced flow injection analysis (FIA) system for S-nitrosothiols (RSNOs) measurement in biological samples.The NO sensor is prepared using a polytetrafluoroethylene (PTFE) gas-permeable membrane loaded with Teflon AF(R) solution,a copolymer of tetrafluoroethylene and 2,2-bis(trifluoroethylene)-4,5-difluoro-1,3-dioxole,to improve selectivity.This method is much simpler and possesses good performance over a wide range of RSNOs concentrations.Standard deviation for three parallel measurements of blood plasma is 4.0%.The use of the gas sensing configuration as the detector enhances selectivity of the FIA measurement vs.using less selective electrochemical detectors that do not use PTFE/Teflon type outer membranes.

  5. Crystallographic investigations of select cathinones: emerging illicit street drugs known as `bath salts'.

    Wood, Matthew R; Lalancette, Roger A; Bernal, Ivan


    The name `bath salts', for an emerging class of synthetic cathinones, is derived from an attempt to evade prosecution and law enforcement. These are truly illicit drugs that have psychoactive CNS (central nervous system) stimulant effects and they have seen a rise in abuse as recreational drugs in the last few years since first having been seen in Japan in 2006. The ease of synthesis and modification of specific functional groups of the parent cathinone make these drugs particularly difficult to regulate. MDPV (3,4-methylenedioxypyrovalerone) is commonly encountered as its hydrochloride salt (C16H21NO3·HCl), in either the hydrated or the anhydrous forms. This `bath salt' has various names in the US, e.g. `Super Coke', `Cloud Nine', and `Ivory Wave', to name just a few. We report here the structures of two forms of the HCl salt, one as a mixed bromide/chloride salt, C16H22NO3(+)·0.343Br(-)·0.657Cl(-) [systematic name: 1-(benzo[d][1,3]dioxol-5-yl)-2-(pyrrolidin-1-ium-1-yl)pentan-1-one bromide/chloride (0.343/0.657)], and the other with the H7O3(+) cation, as well as the HCl counter-ion [systematic name: hydroxonium 1-(benzo[d][1,3]dioxol-5-yl)-2-(pyrrolidin-1-ium-1-yl)pentan-1-one dichloride, H7O3(+)·C16H22NO3(+)·2Cl(-)]. This is one of a very few structures (11 to be exact) in which we have a new example of a precisely determined hydroxonium cation. During the course of researching the clandestine manufacture of MDPV, we were surprised by the fact that a common precursor of this illicit stimulant is known to be the fragrant species piperonal, which is present in the fragrances of orchids, most particularly in the case of the vanilla orchid. We found that MDPV can be made by a Grignard reaction of this heliotropin. This may also explain the unexpected appearance of the bromide counter-ion in some of the salts we encountered (C16H21NO3·HBr), one of which is presented here [systematic name: 1-(benzo[d][1,3]dioxol-5-yl)-2-(pyrrolidin-1-ium-1-yl)pentan-1-one

  6. Structure-based design, synthesis, molecular docking study and biological evaluation of 1,2,4-triazine derivatives acting as COX/15-LOX inhibitors with anti-oxidant activities.

    Khoshneviszadeh, Mehdi; Shahraki, Omolbanin; Khoshneviszadeh, Mahsima; Foroumadi, Alireza; Firuzi, Omidreza; Edraki, Najmeh; Nadri, Hamid; Moradi, Alireza; Shafiee, Abbas; Miri, Ramin


    A set of 1,2,4-triazine derivatives were designed as cyclooxygenase-2 (COX-2) inhibitors. These compounds were synthesized and screened for inhibition of cyclooxygenases (COX-1 and COX-2) based on a cellular assay using human whole blood (HWB) and lipoxygenase (LOX-15) that are key enzymes in inflammation. The results showed that 3-(2-(benzo[d][1,3]dioxol-5-ylmethylene)hydrazinyl)-5,6-bis(4-methoxyphenyl)-1,2,4-triazine (G11) was identified as the most potent COX-2 inhibitor (78%) relative to COX-1 (50%). Ferric reducing anti-oxidant power (FRAP) assay revealed that compound G10 possesses the highest anti-oxidant activity. The compound G3 with IC50 value of 124 μM was the most potent compound in LOX inhibitory assay. Molecular docking was performed and a good agreement was observed between computational and experimental results.

  7. Electrochemical oxidation of methylenedioxyamphetamines.

    Squella, J A; Cassels, B K; Arata, M; Bavestrello, M P; Nuñez-Vergara, L J


    Four amphetamine derivatives bearing a methylenedioxy group at positions 3 and 4 of the benzene ring and differing in their substitution at C(6) were studied by differential pulse voltammetry in aqueous media. These experiments showed a single oxidation peak for the C(6)-H, -Br and -Cl compounds, while the C(6)-NO(2) analogue was not oxidized. The oxidation peak is interpreted as due to the removal of one electron from the aromatic electrophore with formation of a radical cation stabilized by the dioxole ring. The linear relationship between the peak current and the concentration of the derivatives is appropriate for development of a quantitative method for their determination. pK' values were determined using both electrochemical and spectrophotometric methods.

  8. Effect of amorphous fluorinated coatings on photocatalytic properties of anodized titanium surfaces

    Persico, Federico [Dipartimento di Chimica, Materiali e Ingegneria Chimica “Giulio Natta”, Politecnico di Milano, via Mancinelli 7, 20131, Milano (Italy); Consorzio Interuniversitario Nazionale per la Scienza e Tecnologia dei Materiali, Via G. Giusti, 9, 50121 Firenze (Italy); Sansotera, Maurizio, E-mail: [Dipartimento di Chimica, Materiali e Ingegneria Chimica “Giulio Natta”, Politecnico di Milano, via Mancinelli 7, 20131, Milano (Italy); Consorzio Interuniversitario Nazionale per la Scienza e Tecnologia dei Materiali, Via G. Giusti, 9, 50121 Firenze (Italy); Diamanti, Maria Vittoria [Dipartimento di Chimica, Materiali e Ingegneria Chimica “Giulio Natta”, Politecnico di Milano, via Mancinelli 7, 20131, Milano (Italy); Magagnin, Luca; Venturini, Francesco; Navarrini, Walter [Dipartimento di Chimica, Materiali e Ingegneria Chimica “Giulio Natta”, Politecnico di Milano, via Mancinelli 7, 20131, Milano (Italy); Consorzio Interuniversitario Nazionale per la Scienza e Tecnologia dei Materiali, Via G. Giusti, 9, 50121 Firenze (Italy)


    The photocatalytic activity promoted by anodized titanium surfaces coated with different amorphous perfluoropolymers was evaluated. A copolymer between tetrafluoroethylene and perfluoro-4-trifluoromethoxy-1,3-dioxole and two perfluoropolyethers containing ammonium phosphate and triethoxysilane functionalities, respectively, were tested as coating materials. These coatings revealed good adhesion to the anodized titanium substrate and conferred to it both hydrophobicity and oleophobicity. The photocatalytic activity of the coating on anodized titanium was evaluated by monitoring the degradation of stearic acid via Infrared spectroscopy. The degradation rate of stearic acid was reduced but not set to zero by the presence of the fluorinated coatings, leading to the development of advanced functional coatings. The morphological variations of the coatings as a result of photocatalysis were also determined by atomic force microscopy. - Highlights: • Coated anodized titanium surfaces show a decreased wettability. • Evaluation of the stability of perfluorinated coatings towards photocatalysis. • Amorphous perfluorinated coatings do not hinder photocatalytic activity.

  9. (E-N-(1,3-Benzodioxol-5-yl-1-(4-{[1-(prop-2-en-1-yl-1H-1,2,3-triazol-4-yl]methoxy}phenylmethanimine

    Mehmet Akkurt


    Full Text Available In the title compound, C20H18N4O3, the dihedral angles between the central benzene ring and the 1H-1,2,3-triazole ring and the fused benzene ring are 65.34 (19 and 3.64 (18°, respectively. The dioxole ring adopts a shallow envelope conformation, with the methylene C atom displaced by 0.156 (5 Å from the other four atoms (r.m.s. deviation = 0.007Å. In the crystal, the molecules are linked by C—H...O and C—H...N hydrogen bonds, generating a three-dimensional network.

  10. In vivo formation of N7-guanine DNA adduct by safrole 2',3'-oxide in mice.

    Shen, Li-Ching; Chiang, Su-Yin; Lin, Ming-Huan; Chung, Wen-Sheng; Wu, Kuen-Yuh


    Safrole, a naturally occurring product derived from spices and herbs, has been shown to be associated with the development of hepatocellular carcinoma in rodents. Safrole 2',3'-oxide (SFO), an electrophilic metabolite of safrole, was shown to react with DNA bases to form detectable DNA adducts in vitro, but not detected in vivo. Therefore, the objective of this study was to investigate the formation of N7-(3-benzo[1,3]dioxol-5-yl-2-hydroxypropyl)guanine (N7γ-SFO-Gua) resulting from the reaction of SFO with the most nucleophilic site of guanine in vitro and in vivo with a newly developed isotope-dilution high performance liquid chromatography electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) method. N7γ-SFO-Gua and [(15)N(5)]-N7-(3-benzo[1,3]dioxol-5-yl-2-hydroxypropyl)guanine ([(15)N(5)]-N7γ-SFO-Gua) were first synthesized, purified, and characterized. The HPLC-ESI-MS/MS method was developed to measure N7γ-SFO-Gua in calf thymus DNA treated with 60 μmol of SFO for 72 h and in urine samples of mice treated with a single dose of SFO (30 mg/kg body weight, intraperitoneally). In calf thymus DNA, the level of N7γ-SFO-Gua was 2670 adducts per 10(6)nucleotides. In urine of SFO-treated mice, the levels of N7γ-SFO-Gua were 1.02±0.14 ng/mg creatinine (n=4) on day 1, 0.73±0.68 ng/mg creatinine (n=4) on day 2, and below the limit of quantitation on day 3. These results suggest that SFO can cause in vivo formation of N7γ-SFO-Gua, which may then be rapidly depurinated from the DNA backbone and excreted through urine.

  11. Fluorous polymeric membranes for ionophore-based ion-selective potentiometry: how inert is Teflon AF?

    Lai, Chun-Ze; Koseoglu, Secil S; Lugert, Elizabeth C; Boswell, Paul G; Rábai, József; Lodge, Timothy P; Bühlmann, Philippe


    Fluorous media are the least polar and polarizable condensed phases known. Their use as membrane materials considerably increases the selectivity and robustness of ion-selective electrodes (ISEs). In this research, a fluorous amorphous perfluoropolymer was used for the first time as a matrix for an ISE membrane. Electrodes for pH measurements with membranes composed of poly[4,5-difluoro-2,2-bis(trifluoromethyl)-1,3-dioxole]-co-poly(tetrafluoroethylene) (87% dioxole monomer content; known as Teflon AF2400) as polymer matrix, a linear perfluorooligoether as plasticizer, sodium tetrakis[3,5-bis(perfluorohexyl)phenyl]borate providing for ionic sites, and bis[(perfluorooctyl)propyl]-2,2,2-trifluoroethylamine as H+ ionophore were investigated. All electrodes had excellent potentiometric selectivities, showed Nernstian responses to H+ over a wide pH range, exhibited enhanced mechanical stability, and maintained their selectivity over at least 4 weeks. For membranes of low ionophore concentration, the polymer affected the sensor selectivity noticeably at polymer concentrations exceeding 15%. Also, the membrane resistance increased quite strongly at high polymer concentrations, which cannot be explained by the Mackie-Meares obstruction model. The selectivities and resistances depend on the polymer concentration because of a functional group associated with Teflon AF2400, with a concentration of one functional group per 854 monomer units of the polymer. In the fluorous environment of these membranes, this functional group binds to Na+, K+, Ca2+, and the unprotonated ionophore with binding constants of 10(3.5), 10(1.8), 10(6.8), and 10(4.4) M(-1), respectively. Potentiometric and spectroscopic evidence indicates that these functional groups are COOH groups formed by the hydrolysis of carboxylic acid fluoride (COF) groups originally present in Teflon AF2400. The use of higher ionophore concentrations removes the undesirable effect of these COOH groups almost completely

  12. Novel furfurylidene N-acylhydrazones derived from natural safrole: discovery of LASSBio-1215, a new potent antiplatelet prototype.

    Rodrigues, Ana Paula C; Costa, Luciana M M; Santos, Bruna L R; Maia, Rodolfo C; Miranda, Ana L P; Barreiro, Eliezer J; Fraga, Carlos A M


    We describe herein the discovery of (E)-N-methyl-N'-((5-nitrofuran-2-yl)methylene)benzo[d]( 1 , 3 ) dioxole-5-carbohydrazide (9e), named LASSBio-1215, as a novel antiplatelet agent belonging to the N-methyl-N-acylhydrazone class, which exert their antiaggregating actions on human and rabbit platelets induced by different agonists, through cyclooxygenase-1 (COX-1) or thromboxane synthase inhibition. This compound was elected after screening of a series of functionalized furyl N-acylhydrazone derivatives, synthesized from natural safrole 10. In vitro assays showed that compound 9e presents platelet-aggregating activity in rabbit platelet-rich plasma (PRP) induced by arachidonic acid (IC(50) = 0.7 µM) and collagen (IC(50) = 4.5 µM). Moreover, LASSBio-1215 also inhibited almost completely the second wave of adenosine diphosphate-induced platelet aggregation in human PRP, and this effect was correlated with their ability to block the production of pro-aggregating autacoid thromboxane A(2).

  13. Structural elucidation and estimation of the acute toxicity of the major UV-visible photoproduct of fludioxonil - detection in both skin and flesh samples of grape.

    Lassalle, Yannick; Nicol, Édith; Genty, Christophe; Bourcier, Sophie; Bouchonnet, Stéphane


    Ultraviolet (UV)-visible irradiation of fludioxonil was investigated with two photoreactors using either a mercury or xenon vapor lamp. In both cases, it led to the formation of only one photoproduct in significant amount: 2-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)-2-(nitrosomethylene)-4-oxobutanenitrile, which has been characterized using Liquid Chromatography - High Resolution - Tandem Mass Spectrometry (LC-HR-MS/MS) coupling. A photolysis pathway has been proposed to rationalize its formation in degassed water. In vitro bioassays on Vibrio fischeri bacteria showed that UV-vis irradiation of an aqueous solution of fludioxonil significantly increases its toxicity. Because no other by-product was detected in significant amount, the photoproduct mentioned above may be considered mainly responsible for this increase in toxicity. Grape berries treated with a 50 ppm aqueous solution of fludioxonil were submitted to UV-visible irradiation under laboratory conditions. The fungicide and photoproduct were detected in both skin and flesh of berries, even after they have been rinsed with water. The ability of the photoproduct to pass through the fruit skin is comparable with that of fludioxonil. These results are of concern for consumers because they mean that water tap rinsing does not lead to efficient removing of both compounds. Copyright © 2015 John Wiley & Sons, Ltd.

  14. Monitoring the redox cycle of low-molecular peptides using a modified target plate in MALDI-MS.

    Borissova, Maria; Mahlapuu, Riina; Vaher, Merike


    A new method is being proposed for preparing MALDI target plates with a hydrophobic polymer coating and hydrophilic anchors. The particles of the MALDI matrix were pre-mixed with a poly[4,5-difluoro-2,2-bis(trifluoromethyl)-1,3-dioxole-co-tetrafluoroethylene] solution prior to their placement on a mass-spectrometric sample support. This technique led to the formation of matrix microspots with a diameter of less than 1mm inside the polymer. The polymer and matrix concentration as well as the amount of suspension placed on the target plate influenced the size and quality of microspots to a great extent. The sensitivity of the mass-spectrometric analysis was confirmed by obtaining the mass spectra of fmole concentrations of an apomyoglobin tryptic digest. The potential proteomic application of this type of MALDI surface preparation was demonstrated by performing the redox cycle using glutathione and its analogue. All reactions were carried out directly on a MALDI plate, which accommodates low volumes of reagents and prevents sample loss.

  15. Vibrational spectroscopic studies, Fukui functions, HOMO-LUMO, NLO, NBO analysis and molecular docking study of (E)-1-(1,3-benzodioxol-5-yl)-4,4-dimethylpent-1-en-3-one, a potential precursor to bioactive agents

    Al-Wabli, Reem I.; Resmi, K. S.; Sheena Mary, Y.; Yohannan Panicker, C.; Attia, Mohamed I.; El-Emam, Ali A.; Van Alsenoy, C.


    The FT-IR and FT-Raman spectra of (E)-1-(1,3-benzodioxol-5-yl)-4,4-dimethylpent-1-en-3-one were recorded and analyzed experimentally and theoretically. The observed experimental and theoretical wavenumbers were assigned using potential energy distribution. The NLO properties were evaluated by the determination of first and second hyperpolarizabilities of the title compound. From the frontier molecular orbital study, the HOMO centers over the entire molecule except the methyl groups, while the LUMO is over the entire molecule except the CH2 group with the dioxole ring and one of the methyl groups. From the MEP plot, it is evident that the negative region covers the carbonyl and Cdbnd C groups and the positive region is over CH2 groups. The Fukui functions are also reported. The calculated geometrical parameters are in agreement with the XRD results. From the molecular docking study, the docked ligand title compound forms a stable complex with the androgen receptor and gives a binding affinity value of -8.1 kcal/mol and the results suggest that the compound might exhibit inhibitory activity against androgen receptor.

  16. Virtual screening-based discovery and mechanistic characterization of the acylthiourea MRT-10 family as smoothened antagonists.

    Manetti, Fabrizio; Faure, Helene; Roudaut, Hermine; Gorojankina, Tatiana; Traiffort, Elisabeth; Schoenfelder, Angele; Mann, Andre; Solinas, Antonio; Taddei, Maurizio; Ruat, Martial


    The seven-transmembrane receptor Smoothened (Smo) is the major component involved in signal transduction of the Hedgehog (Hh) morphogens. Smo inhibitors represent a promising alternative for the treatment of several types of cancers linked to abnormal Hh signaling. Here, on the basis of experimental data, we generated and validated a pharmacophoric model for Smo inhibitors constituted by three hydrogen bond acceptor groups and three hydrophobic regions. We used this model for the virtual screening of a library of commercially available compounds. Visual and structural criteria allowed the selection of 20 top scoring ligands, and an acylthiourea, N-(3-benzamidophenylcarbamothioyl)-3,4,5-trimethoxybenzamide (MRT-10), was identified and characterized as a Smo antagonist. The corresponding acylurea, N-(3-benzamidophenylcarbamoyl)-3,4,5-trimethoxybenzamide (MRT-14), was synthesized and shown to display, in various Hh assays, an inhibitory potency comparable to or greater than that of reference Smo antagonists cyclopamine and N-((3S,5S)-1-(benzo[d][1,3]dioxol-5-ylmethyl)-5-(piperazine-1-carbonyl)pyrrolidin-3-yl)-N-(3-methoxybenzyl)-3,3-dimethylbutanamide (Cur61414). Focused virtual screening of the same library further identified five additional related antagonists. MRT-10 and MRT-14 constitute the first members of novel families of Smo antagonists. The described virtual screening approach is aimed at identifying novel modulators of Smo and of other G-protein coupled receptors.

  17. Metabolite profiling of (14)C-omacetaxine mepesuccinate in plasma and excreta of cancer patients.

    Nijenhuis, Cynthia M; Lucas, Luc; Rosing, Hilde; Robertson, Philmore; Hellriegel, Edward T; Schellens, Jan H M; Beijnen, And Jos H


    Omacetaxine mepesuccinate (hereafter referred to as omacetaxine) is a protein translation inhibitor approved by the US Food and Drug Administration for adult patients with chronic myeloid leukemia with resistance and/or intolerance to two or more tyrosine kinase inhibitors. The objective was to investigate the metabolite profile of omacetaxine in plasma, urine and faeces samples collected up to 72 h after a single 1.25-mg/m(2) subcutaneous dose of (14)C-omacetaxine in cancer patients. High-performance liquid chromatography mass spectrometry (MS) (high resolution) in combination with off-line radioactivity detection was used for metabolite identification. In total, six metabolites of omacetaxine were detected. The reactions represented were mepesuccinate ester hydrolysis, methyl ester hydrolysis, pyrocatechol conversion from the 1,3-dioxole ring. Unchanged omacetaxine was the most prominent omacetaxine-related compound in plasma. In urine, unchanged omacetaxine was also dominant, together with 4'-DMHHT. In feces very little unchanged omacetaxine was found and the pyrocatechol metabolite of omacetaxine, M534 and 4'-desmethyl homoharringtonine (4'-DMHHT) was the most abundant metabolites. Omacetaxine was extensively metabolized, with subsequent renal and hepatic elimination of the metabolites. The low levels of the metabolites found in plasma indicate that the metabolites are unlikely to contribute materially to the efficacy and/or toxicity of omacetaxine.

  18. Sarniensine, a mesembrine-type alkaloid isolated from Nerine sarniensis, an indigenous South African Amaryllidaceae, with larvicidal and adulticidal activities against Aedes aegypti.

    Masi, Marco; van der Westhuyzen, Alet E; Tabanca, Nurhayat; Evidente, Marco; Cimmino, Alessio; Green, Ivan R; Bernier, Ulrich R; Becnel, James J; Bloomquist, Jeffrey R; van Otterlo, Willem A L; Evidente, Antonio


    A new mesembrine-type alkaloid, named sarniensine, was isolated together with tazettine, lycorine, the main alkaloid, and 3-epimacronine from Nerine sarniensis, with the last two produced for the first time by this plant. This Amaryllidaceae, which is indigenous of South Africa, was investigated for its alkaloid content, because the organic extract of its bulbs showed strong larvicidal activity with an LC50 value of 0.008μgμL(-1) against first instar Aedes aegypti larvae and with an LD50 value 4.6μg/mosquito against adult female Ae. aegypti, which is the major vector for dengue, yellow fever and the Zika virus. The extract did not show repellency at MED value of 0.375mgcm(2) against adult Ae. aegypti. Sarniensine was characterized using spectroscopic and chiroptical methods as (3aR,4Z,6S,7aS)-6-methoxy-3a-(2'-methoxymethyl-benzo [1,3]dioxol-1'-yl)-1-methyl-2,3,3a,6,7,7a-hexahydro-1H-indole. It was less effective against larva at the lowest concentration of 0.1μgμL(-1), however it showed strong adulticidal activity with an LD50 value of 1.38±0.056μgmosquito(-1).

  19. Alkaloids with Activity against the Zika Virus Vector Aedes aegypti (L.—Crinsarnine and Sarniensinol, Two New Crinine and Mesembrine Type Alkaloids Isolated from the South African Plant Nerine sarniensis

    Marco Masi


    Full Text Available Two new Amaryllidaceae alkaloids, belonging to the mesembrine- and crinine-types, named crinsarnine (1 and sarniensinol (2, were isolated from the dried bulbs of Nerine sarniensis together with bowdensine (3, sarniensine (4, hippadine (5 and 1-O-acetyl-lycorine (6. Crinsarnine (1 and sarniensinol (2 were characterized using spectroscopic and chiroptical methods as (1S,2S,4aR,10bS-2,7-dimethoxy-1,2,3,4,4a,6-hexahydro-5,11b-ethano[1,3]dioxolo-[4,5-j]phenanthridin-1-yl acetate and (6-(3aR,4Z,6S,7aS-6-methoxy-1-methyl-2,3,3a,6,7,7a-hexa-hydro-1H-indol-3a-ylbenzo[d][1,3]dioxol-5-ylmethanol, respectively. Furthermore, the complete spectroscopic characterization of bowdensine (3 is reported for the first time. Compounds 1–6 were evaluated against the Orlando reference strain of Aedes aegypti. None of compounds showed mortality against 1st instar Ae. aegypti larvae at the concentrations tested. In adult topical bioassays, only 1 displayed adulticidal activity with an LD50 = 2.29 ± 0.049 μg/mosquito. As regards the structure-activity relationship, the pretazettine and crinine scaffold in 2 and 4 and in 1 and 3 respectively, proved to be important for their activity, while the pyrrole[de]phenanthridine scaffold present in 5 and 6 was important for their reactivity. Among the pretazettine group compounds, opening of the B ring or the presence of a B ring lactone as well as the trans-stereochemistry of the A/B ring junction, appears to be important for activity, while in crinine-type alkaloids, the substituent at C-2 seems to play a role in their activity.

  20. Ungeremine and Its hemisynthesized analogues as bactericides against Flavobacterium columnare.

    Schrader, Kevin K; Avolio, Fabiana; Andolfi, Anna; Cimmino, Alessio; Evidente, Antonio


    The Gram-negative bacterium Flavobacterium columnare is the cause of columnaris disease, which can occur in channel catfish ( Ictalurus punctatus ). In a previous study, the betaine-type alkaloid ungeremine, 1, obtained from Pancratium maritimum L. was found to have strong antibacterial activity against F. columnare. In this study, analogues of 1 were evaluated using a rapid bioassay for activity against F. columnare to determine if the analogues might provide greater antibacterial activity and to determine structure-activity relationships of the test compounds. Several ungeremine analogues were prepared by hydrochlorination of the alkaloid and by selenium dioxide oxidation of both lycorine, 7, and pseudolycorine, 8, which yielded the isomer of ungeremine, 3, and zefbetaine, 4, respectively. The treatment of lycorine with phosphorus oxychloride allowed the synthesis of an anhydrolycorine lactam, 5, showing, with respect to 1, the deoxygenation and oxygenation of C-2 and C-7 of the C and B rings, respectively. The results of the structure-activity relationship studies showed that the aromatization of the C ring and the oxidation to an azomethine group of C-7 of the B ring are structural features important for antibacterial activity. In addition, the position of the oxygenation of the C ring as well as the presence of the 1,3-dioxole ring joined to the A ring of the pyrrolo[de]phenanthridine skeleton also plays a significant role in imparting antibacterial activity. On the basis of 24-h 50% inhibition concentration (IC(50)) results, ungeremine hydrochloride, 2, was similar in toxicity to 1, whereas 5 had the lowest activity. Analogue 2 is soluble in water, which may provide the benefit for use as an effective feed additive or therapeutant compared to ungeremine.

  1. Stability-Indicating Related Substances HPLC Method for Droxidopa and Characterization of Related Substances Using LC-MS and NMR.

    Kumar, Thangarathinam; Ramya, Mohandass; Arockiasamy Xavier, S J


    Stress degradation studies using high-performance liquid chromatography (HPLC) was performed and validated for Droxidopa (L-DOPS). Droxidopa was susceptible to acid hydrolysis (0.1 N HCl), alkaline hydrolysis (0.15 N NaOH) and thermal degradation (105°C). It was found to be resistant to white light, oxidation and UV light exposure (72 h). The thermal, acid and alkali degradation impurities were detected with the retention time (RT) of 12.7, 19.25 and 22.95 min. Our HPLC method detected process impurities (2R,3R)-2-amino-3-(3,4-dihydroxyphenyl)-3-hydroxypropionic acid (Impurity H), N-Hydroxypthalimide (Impurity N), (2R,3S)-2-amino-3-(benzo[d][1,3]dioxol-5-yl)-3-hydroxypropionic acid (Impurity L) and L-threo n-phthaloyl-3-(3, 4-dihydroxyphenyl)-serine (Intermediate) with RTs of 3.48, 15.5, 25.76 and 28.0 min. The related substances were further characterized and confirmed by liquid chromatography-mass spectroscopy (LC-MS), and nuclear magnetic resonance spectroscopy analysis. Our HPLC method detected up to 0.05 µg/mL of Droxidopa with S/N > 3.0 and quantified up to 0.10 µg /mL of Droxidopa with S/N ratio > 10.0. Droxidopa was highly stable for 12 h after its preparation for HPLC analysis. Our newly developed HPLC method was highly precise, specific, reliable and accurate for the analysis of Droxidopa and its related substances.

  2. Monoacylglycerol lipase (MAGL inhibition attenuates acute lung injury in mice.

    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.

  3. Synthesis and characterization of mixed-ligand diimine-piperonal thiosemicarbazone complexes of ruthenium(II): Biophysical investigations and biological evaluation as anticancer and antibacterial agents.

    Beckford, Floyd A; Thessing, Jeffrey; Shaloski, Michael; Mbarushimana, P Canisius; Brock, Alyssa; Didion, Jacob; Woods, Jason; Gonzalez-Sarrías, Antonio; Seeram, Navindra P


    We have used a novel microwave-assisted method developed in our laboratories to synthesize a series of ruthenium-thiosemicarbazone complexes. The new thiosemicarbazone ligands are derived from benzo[d][1,3]dioxole-5-carbaldehyde (piperonal) and the complexes are formulated as [(diimine)(2)Ru(TSC)](PF(6))(2) (where the TSC is the bidentate thiosemicarbazone ligand). The diimine in the complexes is either 2,2'-bipyridine or 1,10-phenanthroline. The complexes have been characterized by spectroscopic means (NMR, IR and UV-Vis) as well as by elemental analysis. We have studied the biophysical characteristics of the complexes by investigating their anti-oxidant ability as well as their ability to disrupt the function of the human topoisomerase II enzyme. The complexes are moderately strong binders of DNA with binding constants of 10(4) M(-1). They are also strong binders of human serum albumin having binding constants on the order of 10(4) M(-1). The complexes show good in vitro anticancer activity against human colon cancer cells, Caco-2 and HCT-116 and indeed show some cytotoxic selectivity for cancer cells. The IC(50) values range from 7 - 159 μM (after 72 h drug incubation). They also have antibacterial activity against Gram-positive strains of pathogenic bacteria with IC(50) values as low as 10 μM; little activity was seen against Gram-negative strains. It has been established that all the compounds are catalytic inhibitors of human topoisomerase II.

  4. 超声辅助或无溶剂Claisen-Schmidt反应合成含胡椒环的吲哚查尔酮%A facile synthesis of 1,3-benzodioxole-bearing indole-based chalcone via ultrasound-assisted or solvent-free Claisen-Schmidt condensation reaction



    A structurally novel 1,3-benzodioxole-bearing indole-based chalcone,namely(E)-3-(benzo[d][1,3]dioxol-5-yl)-1-(2-chloro-1-(4-chlorobenzyl)-1H-indol-3-yl) prop-2-en-1-one(3) was synthesized,involving the ultrasound-assisted or solvent-free Claisen-Schmidt condensation reaction of 3-acetyl-2-chloro-1-(4-chlorobenzyl) indole and piperonaldehyde. The ultrasound-assisted Claisen-Schmidt condensation reaction was carried out using 1,4-dioxane as solvent and KOH as catalyst at room temperature to give the product 3 in 78%yield. Alternatively,the reaction could also be conducted under solvent-free condition by physical grinding in a mortar and pestle to obtain 3 in comparable yield of 75%. The two procedures offered easy access to 1,3-benzodioxole-bearing indole-based chalcone in short reaction time and good yield under mild conditions.%3-乙酰基-2-氯-1-(4-氯苄基)吲哚与胡椒醛通过超声辅助或无溶剂的Claisen-Schmidt缩合反应首次合成含胡椒环的吲哚查尔酮,即(E)-3-(5-胡椒基)-1-(2-氯-1-(4-氯苄基)-1H-3-吲哚查尔酮(3)。超声辅助的合成方法使用5%KOH作为催化剂,1,4-二氧六环作为溶剂,以78%的收率得到产品3。另外,这一 Claisen-Schmidt反应也可以在无溶剂研磨条件下进行,同样也以类似的收率获得产品3(75%)。这两种方法具有操作简便、反应条件温和、收率高等优点。

  5. Selective activation of beta3-adrenoceptors by octopamine: comparative studies in mammalian fat cells.

    Carpéné, C; Galitzky, J; Fontana, E; Atgié, C; Lafontan, M; Berlan, M


    Numerous synthetic agonists selectively stimulate beta3-adrenoceptors (ARs). The endogenous catecholamines, noradrenaline and adrenaline, however, stimulate all the beta-AR subtypes, and no selective physiological agonist for beta3-ARs has been described so far. The aim of this study was to investigate whether any naturally occurring amine can stimulate selectively beta3-ARs. Since activation of lipolysis is a well-known beta-adrenergic function, the efficacy and potency of various biogenic amines were compared with those of noradrenaline, isoprenaline, and beta3-AR agonists 4-(-{[2-hydroxy-(3-chlorophenyl)ethyl]-amino} propyl)phenoxyacetate (BRL 37,344) and (R,R)-5-(2-{[2-(3-chlorophenyl )-2-hydroxyethyl]-amino} propyl)-1,3-benzo-dioxole-2,2-dicarboxylate (CL 316,243) by testing their lipolytic action in white fat cells. Five mammalian species were studied: rat, hamster and dog, in which selective beta-AR agonists act as full lipolytic agents, and guinea-pigs and humans, in which beta3-AR agonists are less potent activators of lipolysis. Several biogenic amines were inefficient (e.g. dopamine, tyramine and beta-phenylethylamine) while others (synephrine, phenylethanolamine, epinine) were partially active in stimulating lipolysis in all species studied. Their actions were inhibited by all the beta-AR antagonists tested, including those selective for beta1- or beta2-ARs. Octopamine was the only amine fully stimulating lipolysis in rat, hamster and dog fat cells, while inefficient in guinea-pig or human fat cells, like the beta3-AR agonists. In rat white fat cells, beta-AR antagonists inhibited the lipolytic effect of octopamine with a relative order of potency very similar to that observed against CL 316,243. Competitive antagonism of octopamine effect resulted in the following apparent pA2 [-log(IC50), where IC50 is the antagonist concentration eliciting half-maximal inhibition] values: 7.77 (bupranolol), 6.48 [3-(2-ethyl-phenoxy)-1[(1 S)-1,2,3,4-tetrahydronaphth-1