In silico studies, synthesis and anticancer activity of novel diphenyl ether-based pyridine derivatives.

A series of novel 2-amino-4-(3-hydroxy-4-phenoxyphenyl)-6-(4-substituted phenyl) nicotinonitriles were synthesized and evaluated against HepG2, A-549 and Vero cell lines. Compounds 3b (IC50 16.74 ± 0.45 µM) and 3p (IC50 10.57 ± 0.54 µM) were found to be the most active compounds against A-549 cell line among the evaluated compounds. Further 3b- and 3p-induced apoptosis was characterized by AO/EB (acridine orange/ethidium bromide) nuclear staining method and also by DNA fragmentation study. A decrease in cell viability and initiation of apoptosis was clearly evident through the morphological changes in the A-549 cells treated with 3b and 3p when stained with this method. Fragmentation of DNA into nucleosomes was observed which further confirmed the cell apoptosis in cells treated with compound 3b. Flow cytometry studies confirmed the cell cycle arrest at G2/M phase in A549 cells treated with compound 3b. Further in silico studies performed supported the in vitro anticancer activity of these compounds as depicted by dock score and binding energy values.

Rational design and synthesis of novel diphenyl ether derivatives as antitubercular agents.

A series of triclosan mimic diphenyl ether derivatives have been synthesized and evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv. The binding mode of the compounds at the active site of enoyl-acyl carrier protein reductase of M. tuberculosis has been explored. Among them, compound 10b was found to possess antitubercular activity (minimum inhibitory concentration =12.5 µg/mL) comparable to triclosan. All the synthesized compounds exhibited low levels of cytotoxicity against Vero and HepG2 cell lines, and three compounds 10a, 10b, and 10c had a selectivity index more than 10. Compound 10b was also evaluated for log P, pKa, human liver microsomal stability, and % protein binding, in order to probe its druglikeness. Based on the antitubercular activity and druglikeness profile, it may be concluded that compound 10b could be a lead for future development of antitubercular drugs.

QSAR model for predicting the fungicidal action of 1,2,4-triazole derivatives against Candida albicans.

QSAR analysis of a series of previously synthesised 1-(1H-1,2,4-triazole-1-yl)-2-(2,4-difluorophenyl)-3-substituted-2-propanols(TDFPP) as analogues of fluconazole were tested for growth inhibitory activity against Candida albicans using computer assisted multiple regression analysis. This was in order to explore the selectivity requirements for fungicidal activity against C. albicans among these congeners. A training set comprising 40 analogues and a test set comprising ten analogues of 1-(1H-1, 2, 4-triazole-1-yl)-2-(2,4-difluorophenyl)-3-substituted-2-propanols were selected for the present investigation by using the sphere exclusion method embedded in the Vlife MDS 3.5 software. With respect to the modelling of the growth inhibitory activity of the reported compounds, the regression analysis shows that even in the mono-parametric correlations the topological and physicochemical parameters give significant regression coefficients. The validation of the QSAR models was performed by cross-validation and external test set prediction. The model is not only able to predict the activity of new compounds but also explains the important region in the molecules in a quantitative manner.