Green synthesis and biological evaluation of novel thio-/seleno-imidazo[1,2-a]pyridine derivatives as novel and potent colchicine-site tubulin inhibitors.

The discovery of novel structural scaffolds targeting the tubulin colchicine site is an active area of anticancer drug design. In this study, an efficient, sustainable, catalyst- and additive-free three-component cascade reaction was developed to construct a diverse library of novel thio- and seleno-imidazo[1,2-a]pyridine derivatives. By utilizing the biomass-derived solvent 2-methyltetrahydrofuran (2-MeTHF), this methodology aligns well with green chemistry principles. Subsequent biological evaluation identified compound 63, featuring a characteristic 3,4,5-trimethoxyphenyl pharmacophore, as a highly potent antitumor agent. It exhibited excellent sub-micromolar antiproliferative activities against multiple human cancer cell lines, including HCT116, Jurkat, HepG2, and MCF-7. Mechanistic investigations revealed that compound 63 successfully binds to the colchicine site of tubulin and significantly inhibits microtubule polymerization. Furthermore, this disruption of microtubule dynamics leads to profound G2/M cell cycle arrest and the induction of cellular apoptosis in HCT116 cells. This work not only provides an environmentally benign route to access bioactive heterocycles but also highlights compound 63 as a promising tubulin-targeting candidate for cancer therapy.