Letters in Drug Design & Discovery - Volume 10, Issue 2, 2013

Seventeen 4-substituted-5-(diphenylmethyl)-2,4-dihydro-3H-1,2,4-triazole-3-thiones were synthesized and the structures of the compounds were determined by 1H NMR and IR spectra. In vitro antibacterial potency of all title compounds was evaluated. Additionally, the initial in vitro toxicity screening was performed for one compound using the MTT assay technique. A structure-activity relationship (SAR) studies have been carried out to determine the relevance of the different parameters that define the potency of title s-triazoles.

A series of oxime ester derivatives containing dehydroabietyl group were synthesized from dehydroabietic acid. Their structures were characterized by IR, 1HNMR, MS, and elemental analysis. The preliminary antibacterial activity results indicate that these compounds display extensive anti-bacterial activity against Escherichia coli, Staphyloccocus aureu, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia aerogenes and Staphyloccocus epidermidis. Compounds (5a, 5b, 5c, 5d, 5e, 5f) exhibit excellent anti-bacterial activity against Escherichia coli with the diameter of inhibition zone is 10.91mm, 11.03mm, 12.92mm, 13.48mm , 11.59mm and 11.58mm respectively,compared with the diameter of inhibition zone of 9.66mm of the commercial compound bromogeramine. Furthermore, Compounds(5d) exhibited the same level of antibacterial activity against Staphyloccocus epidermidis when compared with bromogeramine and Ampicillin Na.

A series of 2-(5-(4-fluorophenyl)-pyrazolin-1-yl)thiazoles prepared as potential antimicrobial agents is described. The synthesis involved the reaction of 5-(4-fluorophenyl)-3-heterocycl-4,5-dihydro-1H-pyrazole-1- carbothioamides 4a,b with various hydrazonoyl chlorides 5 or phenacyl bromides 8-10. These compounds were structurally characterized. The structure of 7 was confirmed by studying the X-ray crystallographic. The antimicrobial evaluations of the newly synthesized products against broad spectrum of bacteria and fungi were performed.

A series of hexahydroindazole analogues of curcumin were synthesized and investigated for in vitro and in silico antimicrobial activity. The structures of synthesized compounds were identified on the basis of satisfactory analytical and spectral data (1H NMR, 13C NMR, EI-MASS techniques and elemental analysis). Synthesized compounds showed moderate to high activity against both bacterial and fungal strains. All compounds were docked computationally to the active site of enzyme L-glutamine: D-fructose-6-phosphate amido-transferase [GlcN-6-P] (EC 2.6.1.16). The autodock programme 4.0 was employed to perform automated molecular docking. (E)-1-(7-(3-methoxybenzylidene)-3-(3- methoxyphenyl)-3,3a,4,5,6,7-hexahydro-2H-indazol-2-yl)ethanone (A7) turned out to be the most potent analogue of the series, showing best activity against bacterial and fungal strains. Compound A7 showed minimum binding and docking energy and may be considered as good inhibitor of GlcN-6-P synthase. Further investigation and optimization of this lead could provide new antimicrobial molecules.

Proteasome inhibitors have been proved to be effective in regulated intracellular proteolysis. Three Dimensional Quantitative Structure Activity Relationships and Molecular docking methods were performed on naphthoquinone analogs as proteasome inhibitors. The bioactive conformation was explored by docking the potent compound 29 into the β5 and β6 subunit of the 20S proteasome. The constructed CoMFA and CoMSIA models produced statistically significant results with the cross-validated correlation coefficients q2 of 0.831 and 0.851, non-cross-validated correlation coefficients r2 of 0.974 and 0.965, and predicted correction coefficients r2 pred of 0.758 and 0.701, respectively. A set of 15 new analogs were proposed by utilizing the results revealed in the present study, and were predicted with significantly improved potencies in the developed models.

The synthesis of new organic compounds possessing properties, which can be used for biological or pharmaceutical purpose, is very challenging and is a current trend in heterocyclic chemistry. So benzofuroxans are of great interest from a medical and combinatory chemistry point of view, being effective biologically active compounds. They are easily available, easily tuned and functionalized allowing the creation of databases in which a chemist can find proper informations to prepare the structurally appropriate compound with the requested selective effect. In this work, heterocyclic compounds are prepared on the basis of the interaction of 4,6-dichloro-5-nitrobenzofuroxan with aromatic amines and diamines. Their ability to suppress and prevent genotoxic effects of UV-radiation in the wavelength range between 300–400 nm has been studied. It has been shown that these compounds are able to protect bacterial cells from destructive effects of the UV-radiation. Comparing the results obtained for various benzofuroxans to those obtained for the natural antioxidant α - tocopherol (vitamin E) and for the synthetic antioxidant trolox, which are references in this domain, we have shown that some benzofuroxans quantitatively exhibit a similar protective effect, and that compounds prepared from the reaction between 4,6-dichloro-5-nitrobenzofuroxan and ethylenedianiline possess potent protective potential.

A series of Andrographolide derivatives were described and evaluated for their in vitro anti-HIV activity. Compound 11 and 21 showed significant anti-HIV-1 activity in C8166 cells. Since compound 11 had no cytotoxicity, it was expected to be new lead for further development of anti-AIDS agents.

Tuberculosis is a major disease still today. Though instigation of Directly Observed Therapy, Short Course, (DOTS) has been widely implemented, new infection with tuberculosis in 2010-2011 was still recorded as 8.8 million. The synergy with multidrug resistant strains and HIV epidemics made the tuberculosis treatment difficult and necessitated the care discovery of new molecules and alternative drug targets. Mycobacterium tuberculosis is known for its capacity of latent infection and also has a peculiar mechanism of granuloma formation where the pathogen multiplies. This process is mediated by various factors and mitogen activated protein kinase (mt-MAPK) is one of those. It works by suppressing the tumor necrosis factor (TNF-α). Computational screening of few epoxide derivatives for their anti-tubercular activities were performed followed by non-toxicity screening, docking in Flex-X and Autodock 4.2 and half maximal inhibitory concentration (IC50) prediction. The docking score of one of the non-toxic derivative, (8S,9S,10S)-7,8,9,10-tetrahydrocyclopenta[ij]tetraphene-8,9,10-triol was found to be -26.07 and -6.02 Kcal/mol in Flex-X and Autodock 4.2 respectively and IC50 of 4.9x10-5 μM was found in quantitative structure activity relationship (QSAR) prediction. The docking and QSAR result suggested (8S,9S,10S)-7,8,9,10-tetrahydrocyclopenta[ij]tetraphene-8,9,10-triol to be considered as mt-MAPK targeted granuloma formation inhibitor in tuberculosis treatment.

Following "click chemistry" guidelines, a 1,2,3-triazole scaffold was introduced in place of a benzene ring to mimic the non-classical cannabinoid pharmacophore model in a novel class of compounds aimed at CB1 receptor agonism. The design, synthesis and results of receptor affinity tests for the new group of ligands are described. The obtained series exhibited a similar sidechainlength-activity relationship as in the initial pharmacophore model, with moderate CB1- selectivity.

The series of thirty new 1-[(4-arylpiperazin-1-yl)-alkyl]-3,3-diphenyl- and 3,3-dimethyl-pyrrolidine-2,5-diones was synthesized. The anticonvulsant properties were evaluated in maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure tests after intraperitoneal injection in mice. The motor impairment was determined in the rotorod test in parallel. Although no anti-seizure properties were found in the scPTZ screen, fourteen compounds showed protection in the MES test at a dose of 100 mg/kg which is known as animal model of human generalized tonicclonic seizures. Taking into consideration the role of 5-HT1A and 5-HT7 receptor subtypes in seizures control as well as the fact that all compounds obtained belong to the class of long-chain arylpiperazines (LCAPs), their 5-HT1A and 5-HT7 serotonin receptor affinities were determined. The most potent 5-HT1A receptor ligands are 2-OCH3 (20, 35), 3-Cl (32) and 3-CF3 (34) derivatives with Ki = 16 nM (20), 33 nM (35), 32 nM (32) and 26 nM (34). Compounds 32 and 35 reveled also high 5-HT7 receptors affinity with the the Ki values 70 nM and 47 nM, respectively. There was no correlation between anticonvulsant properties and 5-HT1A and/or 5-HT7 serotonin receptor affinity.

The high-efficiency synthesis of N,N'-diacetyl-β-chitobiosyl allosamizoline 2 was investigated. The Nbenzyloxycarbonyl (Cbz) protected trichloroacetimidate donors 11 and 13 were synthesized by routine method. The solidphase synthesis was performed using polystyrene as support and o-nitrobenzyl ether tether as linker. The target allosamidin analogue 2 was efficiently obtained by iterative glycosylation reactions, catalytic hydrogenation, acetylation, deacetylation, and photolysis, respectively.

A series of Schiff bases derivatives novel 3-(4-substitutedbenzylideneamino-5-mercapto-4H-[1,2,4]triazol-3- ylmethyl)-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one derivatives (7a–k) have been synthesized from compound (1) through a multi step reaction. The key intermediate (6) on condensation with various suitable aldehydes in the presence of sulfuric acid afforded a series of title compounds (7a–k). The structures of all newly synthesized compounds were established on the basis of their elemental analysis, IR, 1H-NMR, 13C-NMR and MS spectral data. All these novel compounds were screened for their in vitro antioxidant activity by employing DPPH, hydrogen peroxide, and nitric oxide radical scavenging assays. The compounds 7c, 7j, 7k, 7e and 7b showed significant radical savenging due to the presence of electron-withdrawing groups.