Synthesis and structure–activity relationships of pyridinyl-1H-1,2,3-triazolyldihydroisoxazoles as potent inhibitors of tubulin polymerization

•Novel pyridinyl-1H-1,2,3-triazoles, triazolylisoxazoles, triazolyldihydroisoxazoles were designed as anti-cancer agents.•Triazolyldihydroisoxazoles 28b and 28c shown potent anti-cancer activity and inhibited tubulin polymerization.•FACS analysis was performed on HeLa cell lines for compounds 28b and 28c.•Molecular modelling studies revealed that the compounds 28b and 28c binds well in the colchicine binding site of α,β-tubulin.

Three series of compounds; pyridinyl-1H-1,2,3-triazoles, pyridinyl-1H-1,2,3-triazolylisoxazoles and pyridinyl-1H-1,2,3-triazolyldihydroisoxazoles with TMP moiety were designed, synthesized and screened for their anti-cancer and anti-tubulin properties. By sequentially designing three series of compounds comprising of dihydroisoxazole in the linker, a small substituent like chlorine on one side (R1) and aromatic group (R) on the pyridine ring, we have optimized the anti-cancer as well as anti-tubulin activity. Pyridinyl-1H-1,2,3-triazolyldihydroisoxazoles 28b and 28c were found to be potent anti-cancer agents against all the cell lines tested with a concomitant accumulation of cells in the G2/M phase of the cell cycle. Molecular modeling suggests that the trimethoxyphenyl ring in 28b and 28c occupies the cholchicine binding domain of β-tubulin, whereas, the dihydroisoxazole extends towards the interface of α,β-tubulin.

Graphical abstractThree series of compounds were prepared and among them, pyridinyl-1H-1,2,3-triazolyldihydroisoxazoles (28b and 28c) with TMP was found to be potent anti-cancer agents and tubulin inhibitors.Figure optionsDownload full-size imageDownload as PowerPoint slide