Letters in Drug Design & Discovery - Volume 12, Issue 4, 2015

The synthesis of risedronic acid and alendronate from 3-pyridylacetic acid and γ- aminobutyric acid, respectively, using phosphorus oxychloride and phosphorous acid as the P-reagents and methanesulfonic acid as the solvent was optimized, and the role of phosphorus oxychloride and phosphorous acid in the reaction was clarified.

The design, pharmacological properties and delivery characteristics in gastric and intestinal fluids of N-alkanoyl-4-methoxybicyclo[4.2.0]octa-1,3,5-trien-7-ethanamines, (I) and (II), are described. The biological activity of compounds (I) and (II) was determined in a specific model of melatonin action, the pigment aggregation response of Xenopus laevis melanophores. Both analogues were found to be powerful melatonin receptor agonists and showed satisfactory release characteristics, comparable to melatonin, from solid pharmaceutical formulations.

A group of 4H-1,2,4-triazole-derived thioureas was efficiently prepared and evaluated for antibacterial, antifungal and antiviral activities.The chemical identity of all derivatives was established on the basis of spectral methods. The molecular structures of 10 and 21 were determined by an X-ray crystallography. Compounds with phenyl (1), 3,4-dichlorophenyl (2) and p-methoxyphenyl (3) substituents were the most promising against fungi species. The derivative 12 has proved to be significantly active against CVB-5. The CNS-activity of five new 4H-1,2,4-triazolo-thiourea derivatives 2, 10, 12, 18 and 21 was investigated. The results proved that activity of all tested thiourea compounds may be connected with the serotonergic system. Derivatives 2, 10, 12, 18 acted as inhibitors of the head twitch responses (HTR).The biological activity of 21 was also linked with the endogenous opioid system. The derivative 18 diminished the spontaneous mobility and 10 reduced the amphetamineinduced activity of laboratory animals.

A series of tylophora alkaloids and their derivatives (1–38) were synthesized and systematically bioassayed for their anti-HIV activity for the first time. The results revealed that most of these alkaloids possess good HIV inhibitory effect. Especially, compounds 1, 4 and 25 displayed low nanomolar levels of anti-HIV activity (inhibitory effect at 50 nM: 1: 71%; 4: 60%; 25: 64%), which is about similar to that of the first HIV inhibitor AZT (inhibitory effect at 50 nM: 70%) and slightly lower than that of the first HIV integrase inhibitor MK-0518 (inhibitory effect at 50 nM: 82%). Present studies provide fundamental support for the development of tylophora alkaloids as novel HIV inhibitors.

Dipeptidyl Peptidase-IV (DPP-IV), an intracellular enzyme, plays a vital role in the management of diabetes mellitus via promoting secretion of insulin. Inhibitor of DPP-IV significantly improves the blood glucose and glycated hemoglobin A1c levels along with reducing adverse effects associated with current therapies. Extensive literature survey of DPP-IV inhibitors indicated that proline mimic pyrrolidine scaffold, demonstrated potent antidiabetic activity. Therefore, it was considered of interest to manually design and predict the mode and extent of binding of novel pyrrolidine derivatives using molecular docking studies by MVD software. The results of present studies revealed that the presence of bulky electropositive substituent at R1 while non bulky electronegative substituent at R2 position of pyrrolidine scaffold may be responsible for making expectant interactions with the key residue of DPP-IV enzyme active site. The information generated from the present work will be useful for the discovery of novel insulin promoter for the management of diabetes.

Structure based High-throughput Virtual Screening (HTVS) of ChikV nsP2 protease (PDB: 3TRK) with two publicly available database ZINC12 and BindingDB has been carried out to identify suitable inhibitors for the treatment of chikungunya infection. HTVS protocol implemented in GLIDE 5.0 (Schrodinger LLC) has been employed to screen the drug-like subset of ZINC12 (10,090,210) and protease inhibitors in BindingDB (83,000). One of the chemical scaffolds from the list of different chemical classes was selected for the synthesis of (ZINC04725220, compound 11). Few more schiff’s bases (13-21) were also synthesized with the intermediate 1,3-diphenyl-1H-pyrazole-4-carbaldehyde (4-6) and tested for anti-ChikV (strain OPY1, Reunion Island 2006) activity using Cytopathic effect reduction (CPE) assay. Surprisingly, only compound 11(IC50: 5µg/ml ie 14.15 µM) has shown inhibitory activity against ChikV. Further precise docking of compound 11 with target protein was carried out to understand the molecular interactions important for activity.

By means of a combined computational protocol involving hybrid ligand/receptor-based virtual screening, molecular dynamics simulations and per-residue energy contribution, two compounds were suggested as possible potential TB inhibitors. Using docking calculations, which were validated by molecular dynamics simulations, binding free energy calculations indicated that the suggested compounds showed better binding affinity with DprE1 when compared to CT319, a known DprE1 inhibitor. Results showed that compounds retrieved from both pharmacophore and shape-similarity libraries pose crucial hydrogen bond interactions with compound A and compound B. While compound B formed a hydrogen bond interaction with Lys418, compound A formed a stable hydrogen bond interaction with Leu317. Furthermore, both compounds exhibited apparent stability during molecular dynamics simulations with neither system exceeding an RMSD of 2.5 A. MM/GBSA based binding free energy profile of both top ranked compounds further validated the docking result as both of these hits showed a better binding free energy profile when compared with CT319. Also, the hydrogen bond interactions between crucial residues and the top two ligands were well stabilized during the simulation time. However, while further experimental investigations are required, the results obtained from this study could serve as a roadmap to assist medicinal and biological chemists in the process of design and development of potential anti-TB drugs.

In order to investigate the biological activity of novel thiourea compounds, some novel 1,2,3- thiadiazole derivatives containing 1,3,4-thiadiazole were synthesized under phase transfer catalyzed condition( PEG-600)by multi-step reactions. The chemical structures of all compounds were established by 1H NMR, FTIR, MS, and elemental analysis, and some of these compounds were investigated for fungicidal activity and plant growth regulatory activity. The bioassay results indicated that some of these compound exhibited moderate activities.

Curcumin (β-diketones diferuloylmethane), a biphenolic compound of Curcuma longa is reported to elicit a plethora of health protective effects. The present study was carried out to investigate the in vivo protective effect of curcumin (340 mg/kg b.w., oral) against HgCl2 induced oxidative stress in wistar rats. PON1 arylesterase activity, -SH value, and LDL oxidation susceptibility were determined in plasma of control, control+ curcumin, control+ HgCl2, HgCl2+ curcumin treated rats. Oxidative stress down-regulated PON1 activity, decreased -SH value and increased LDL oxidation susceptibility in plasma. Curcumin treatment significantly (p<0.05) increased PON1 activity, -SH value and reduced LDL oxidation susceptibility in healthy and HgCl2 treated rats. We show that curcumin protects PON1 activity, -SH value and LDL oxidation, and hypothesize that its supplementation may lower the incidence of those diseases where reduced PON1 activity and higher LDL oxidation is reported.

The emergence and rapid spread of Multi Drug Resistant (MDR) infectious microbial flora embracing a variety of bacterial, fungal as well as mycobacterium strains are causing a threat to public health worldwide. To cure this dilemma, a library of two series of coumarin based Schiff bases (4a-j) and thiourea derivatives (6a-j) was rationalized, synthesized and accessed for their in vitro antibacterial activity (against Staphylococcus aureus MTCC 96, Bacillus subtilis MTCC 441, Escherichia coli MTCC 739, Pseudomonas aeruginosa MTCC 741 and Klebsiella pneumoniae MTCC 109) and antifungal activity (against Aspergillus niger MTCC 282, Aspergillus fumigates MTCC 343, Aspergillus clavatus MTCC 1323, Candida albicans MTCC 183) using broth dilution technique. Furthermore all the newly synthesized congeners were also examined for in vitro antituberculosis activity (against Mycobacterium tuberculosis H37Rv) using BACTEC MGIT method as well as MIC method on Lowenstein–Jensen medium. Final analogous 4a, 6b, 6i and 6j possessing chloro or methyl group were proved to be highly potent antimicrobial agents. All the synthesized derivatives were well characterized by their IR, 1H NMR, 13C NMR, elemental analysis as well as mass spectroscopy.