Synthesis, Cytotoxicity, Docking Study, and Tubulin Polymerization Inhibitory Activity of Novel 1-(3,4-Dimethoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-1H-1,2,4-triazole-3-carboxanilides

A series of novel 1-(3,4-methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-1H-1,2,4-triazole-3-carboxylic acid derivatives (4a-n) were synthesized and evaluated for their in vitro cytotoxic activity against the growth of four different human cell lines (hepatocarcinoma HepG2, breast adenocarcinoma MCF-7, colon carcinoma DLD-1, and leukemia HL-60). The anilides of m-anisidine 4e, o-anisidine 4f, and 3,5-difluoroaniline 4l demonstrated best results on MCF-7 cells and mean IC50 values of 7.79, 10.79, and 13.20 mu M, respectively. The compounds produced a significant reduction in cellular microtubules at a concentration of 25 mu g/mL, for microtubule loss. Molecular modeling studies involving compounds 4d, 4e, 4f, and 4l with the colchicine binding site of ,-tubulin revealed hydrogen bonding and hydrophobic interactions with several amino acids in the colchicine binding site of beta-tubulin.