Synthesis of indole-tetrazole coupled aromatic amides; In vitro anticancer activity, in vitro tubulin polymerization inhibition assay and in silico studies

Abstract

Herein, we described the synthesis of indole-tetrazole coupled aromatic amides (6a-o) and evaluated their in vitro anticancer activity. Some of the compounds namely N-(4-methoxyphenyl)-2-(5-(1-methyl-1H-indol-3-yl)-2H-tetrazol-2-yl)acetamide (6a), N-(3,5-dimethoxyphenyl)-2-(5-(1-methyl-1H-indol-3-yl)-2H-tetrazol-2-yl)acetamide (6b) and N-(4-cyanophenyl)-2-(5-(1-methyl-1H-indol-3-yl)-2H-tetrazol-2-yl)acetamide (6f) were found to be more active than the standard etoposide against three human cancer cell lines such as MCF-7 (breast), A549 (lung) and SKOV3 (ovarian) with IC50 values in the range of 3.5–8.7 µM. The in vitro tubulin polymerization inhibitory activity reveals that the compounds 6a and 6f were having double potency in inhibiton of tubulin polymerization than the standard combretastatin A-4 (CA-4). The molecular docking studies of three active compounds 6a, 6b and 6f on α,β−tubulin were also conducted and found that they have good binding interactions with the target protein. Finally, the in silico ADMET of potent compounds 6a, 6b and 6f were also studied, where all the compounds following Lipinski rule, Ghose rule, Veber rule, Egan rule and Muegge rule without any deviation.