Gautam Patel

Synthesis and anticancer activities of novel 3,5-disubstituted-1,2,4-oxadiazoles

A series of 3,5-disubstituted-1,2,4-oxadiazoles were synthesized and evaluated for their in vitro anti-proliferative activities against various cancer cell lines. Formation of 1,2,4-oxadiazole ring was accomplished by the reaction of amidoxime with carboxylic acids. The in vitro cytotoxic effects of 3,5-disubstituted-1,2,4-oxadiazoles have been demonstrated across a wide array of tumor cell types and a few compounds exhibited specificity towards pancreatic (3f, 3h, 3j, and 3k) and prostate (3n) cancer cells. Among the prepared 3,5-disubstituted-1,2,4-oxadiazoles, compound 3n is the most selective (>450-fold) and compound 3p is the most cytotoxic (10nM) against prostate cancer cell lines.

Synthesis of novel 1,2,4-oxadiazoles and analogues as potential anticancer agents.

A library of 3,5-disubstituted-1,2,4-oxadiazoles 7-9 and their bioisosters, 1,3,4-oxadiazole 14 and 1,3,4-thiadiazole 16, were synthesized and evaluated in vitro for their anticancer potential against a panel of six human cancer cell lines. The key step in the synthesis of oxadiazoles 7-9 involve coupling of amidoxime 6 with an appropriate carboxylic acid followed by thermal cyclization. The bioisosteres, 1,3,4-oxadiazole 14 and 1,3,4-thiadiazole 16 were prepared from the reaction of a common precursor diacylhydrazine 13 with thionyl chloride and Lawessons reagent, respectively. The anticancer studies on the synthesized compounds revealed that presence of a cyclopentyloxy or n-butyloxy on the C-3 aryl ring and piperdin-4-yl or trichloromethyl at the C-5 position of 1,2,4-oxadiazole is essential for good activity. In particular, 1,2,4-oxadiazole 7i and analogue 1,3,4-thiadiazole 16 exhibited significant activity against DU145 (IC(50): 9.3 μM) and MDA-MB-231 (IC(50): 9.2 μM) cell lines, respectively.

Screening for In Vitro Antimycobacterial Activity and Three-Dimensional Quantitative Structure–Activity Relationship (3D-QSAR) Study of 4-(arylamino)coumarin Derivatives

The resurgence of tuberculosis and the emergence of multidrug‐resistant strains of Mycobacteria necessitate the search for new classes of antimycobacterial agents. We have synthesized a small library of 50 analogues of 4‐(arylamino)coumarins with various aromatic amines at the C4‐ position of the coumarin scaffold. The compounds were evaluated for antimycobacterial activity against Mycobacterium tuberculosis H37Rv with rifampicin as the standard. Of the molecules synthesized, compound 9 was found to be most potent with a minimum inhibitory concentration >6.25u2003μg/mL for 100% inhibition. In an effort to develop new and more effective molecules in this series, the relationship between structure and activity was investigated by comparative molecular field analysis. Various models were generated using comparative molecular field analysis alone and comparative molecular field analysis plus a hydropathy field (HINT). In all, eight models were generated with atom‐fit and field‐fit alignment strategies. The comparative molecular field analysis models (Models 3a and 4a) based on field‐fit alignment were the best with statistically good correlation coefficients (r2) and cross‐validated q2. The values of r2pred for the validation set were 0.469 and 0.516. Based on the comparative molecular field analysis contours, some insights into the structure–activity relationship of the compounds could be gained.

Synthesis and binary QSAR study of antitubercular quinolylhydrazides

In continuation with our previous work in anti-TB research area, in the present study we have demonstrated the structural diversity of quinolylhydrazides as potent anti-tuberculars. The compound library was synthesized by molecular hybridization approach and tested in vitro against Mycobacterium tuberculosis H37Rv strains. Among the designed conjugates, the most promising molecules were found to exhibit 100% Growth Inhibition (GI) at MIC <6.25 μg/mL. Moreover, several analogs in the designed series were also turned out as excellent anti-tuberculars. To probe the structural characteristics influencing on the SAR, the classification model was generated using a binary QSAR approach termed recursive partitioning (RP) analysis. The significant features outlined by the RP model act as a guide in order to design the lead compound.

Design and Synthesis of 3,5-Disubstituted-1,2,4-Oxadiazoles as Potent Inhibitors of Phosphodiesterase4B2

A series of 3,5‐disubstituted‐1,2,4‐oxadiazoles has been prepared and evaluated for phosphodiesterase inhibition (PDE4B2). Among the prepared 3,5‐disubstituted‐1,2,4‐oxadiazoles, compound 9a is the most potent inhibitor (PDE4B2 IC50u2003=u20035.28u2003μm). Structure–activity relationship studies of 3,5‐disubstituted‐1,2,4‐oxadiazoles revealed that substituents 3‐cyclopentyloxy‐4‐methoxyphenyl group at 3‐position and cyclic ring bearing heteroatoms at 5‐position are important for activity. Molecular modeling study of the 3,5‐disubstituted‐1,2,4‐oxadiazoles with PDE4B has shown similar interactions of 3‐cyclopentyloxy‐4‐methoxyphenyl group; however, heteroatom ring is slightly deviating when compared to Piclamilast. 3‐(3‐Cyclopentyloxy‐4‐methoxyphenyl)‐5‐(piperidin‐4‐yl)‐1,2,4‐oxadiazole (9a) exhibited good analgesic and antiinflammatory activities in formalin‐induced pain in mice and carrageenan‐induced paw edema model in rat.

Synthesis and X-ray structure conformation of novel unsymmetrical 1,4-dihydropyridine

Methyl 2,6-dimethyl-5-(2-methylphenylcarbamoyl)-4-(3-nitrophenyl)-1,4-dihydropyridine-2-carboxylate (3) was prepared by known Hantzch method and its structure was elucidated by X-ray diffraction method.