Design, synthesis, and biological evaluation of 6-aryl-3-(3,4,5-trimethoxyphenyl)imidazo[1,2-a]pyridine derivatives as novel tubulin inhibitors with potent anticancer efficacy

Tubulin, the fundamental component of microtubules, remains a critical target in anticancer therapy. The development of small-molecule tubulin polymerization inhibitors continues to drive the discovery of novel chemotherapeutic agents. Through systematic analysis of known tubulin inhibitors and in silico binding pocket models, a focused series of 6-aryl-3-(3,4,5-trimethoxyphenyl)imidazo[1,2-a]pyridine derivatives was rationally designed and synthesized. Compound 8o exhibited superior antiproliferative potency, with IC₅。 values of 0.050-0.078 µM against HeLa, HCT116, and MCF-7 cancer cell lines. Mechanistic investigations confirmed that 8o effectively inhibits tubulin polymerization, disrupts the microtubule cytoskeleton, induces G₂/M phase arrest, and triggers apoptosis. Preliminary physicochemical assessment indicated that 8o adheres to Lipinski’s rule of five, supporting favorable drug-likeness. Collectively, these findings identify 8o as a potent, drug-like colchicine-site tubulin inhibitor with compelling anticancer efficacy, meriting further investigation as a promising lead compound.