New benzimidazole-2-urea derivates as tubulin inhibitors

Emerging drug resistance and other drawbacks limit tubulin inhibitors' therapeutic applications and developing novel tubulin inhibitors still attracts intensive efforts. We describe the discovery and structure-activity relationship study of a series of benzimidazole-2-urea derivatives as novel β tubulin inhibitors. The representative compound 6o potently suppressed the proliferation of a panel of human cancer cells (NCI-H460, Colo205, K562, A431, HepG2, Hela, MDA-MB-435S) with IC50 values of 0.040, 0.050, 0.006, 0.026, 1.774, 0.452 and 0.052 μM, respectively. Compound 6o obviously inhibited NCI-H460 spindles formation and induced cell cycle arrest at G2/M phase at 0.10 μM. Computational study suggested that 6o interacts with β tubulin in a novel binding mode. Our results suggested that benzimidazole-2-urea derivatives might be promising tubulin inhibitors with novel binding mode for further development.