Design, synthesis and biological evaluation of indole-based [1,2,4] triazolo[4,3-a] pyridine derivatives as novel microtubule polymerization inhibitors

A series of indole-based [1,2,4]triazolo [4,3-a]pyridine derivatives was designed and synthesized as novel microtubulin polymerization inhibitors by using a conformational restriction strategy. These compounds exhibited moderate to potent anti-proliferative activities against a panel of cancer cell lines (HeLa, A549, MCF-7 and HCT116). Among them, compound 12d featuring a N-methyl-5-indolyl substituent at the C-6 position of the [1,2,4]triazolo [4,3-a]pyridine core exhibited the highest antiproliferative activity with the IC50 values ranging from 15 to 69 nM, and remarkable inhibitory effect on tubulin polymerization with an IC50 value of 1.64 mu M. Mechanistic studies revealed that compound 12d induced cellular apoptosis and cell cycle arrest at the G(2)/M phase in a dose-dependent fashion. Moreover, compound 12d significantly suppressed wound closure and disturbed microtubule networks. (C) 2021 Elsevier Masson SAS. All rights reserved.

Automated summary

A series of novel microtubulin polymerization inhibitors based on indole were designed and synthesized, among which compound 12d exhibited the highest antiproliferative activity by inducing cellular apoptosis, cell cycle arrest, and inhibiting tubulin polymerization.