Design and synthesis of newer 1,3,4-oxadiazole and 1,2,4-triazole based Topsentin analogues as anti-proliferative agent targeting tubulin

Abstract

A set of two series of 1,3,4-oxadiazole (11a-n) and 1,2,4-Triazole (12a, c, e, g, h, j-n) based topsentin analogues were prepared by replacing imizadole moiety of topsentin through a multistep synthesis starting from indole. All the compounds synthesized were submitted for single dose (10 µM) screening against a NCI panel of 60-human cancer cell lines. Among all cancer cell lines, colon (HCC-2998) and Breast (MCF-7, T-47D) cancer cell lines were found to be more susceptible for this class of compounds. Among the compounds tested, compounds 11a, 11d, 11f, 12e and 12h, were exhibited good anti-proliferative activity against various cancer cell lines. Compounds 11d, 12e and 12h demonstrated better activity with IC₅₀ 2.42 µM, 3.06 µM, and 3.30 µM respectively against MCF-7 human cancer cell line than that of the standard drug doxorubicin IC₅₀ 6.31 µM. Furthermore, 11d induced cell cycle arrest at G0/G1 phase and also disrupted mitochondrial membrane potential with reducing cell migration potential of MCF-7 cells in dose dependent manner. In vitro microtubule polymerization assays found that compound 11d disrupt tubulin dynamics by inhibiting tubulin polymerization with IC₅₀ 3.89 μM compared with standard nocodazole (IC₅₀ 2.49 μM). In silico docking studies represented that 11d was binding at colchicine binding site of β-tubulin. Compound 11d emerged as lead molecule from the library of compounds tested and this may serve as a template for further drug discovery.

Keywords: 1,2,4-Triazole; 1,3,4-oxadiazole; Anti-proliferation; Cancer cell line; Colchicine; Topsentin; Tubulin.