Design, Synthesis, and In Vitro Cytotoxicity Studies of 1H-Benzimidazol-2-yl–Enaminone Hybrids as Tubulin Polymerization Inhibitors

Abstract Tubulin polymerization inhibitors play a pivotal role in cancer therapy due to their ability to disrupt microtubule dynamics, which are essential for mitotic cell division. Taking this into consideration, a series of novel 1H-benzimidazol-2-yl–enaminone hybrids were designed and synthesized to explore their potential as tubulin polymerization inhibitors. In vitro assays demonstrated that (2E)-1-(1-ethyl-1H-benzimidazol-2-yl)-3-pyrrolidin-1-ylprop-2-en-1-one displayed significant cytotoxic effects against various cancer cell lines, with a low IC50 value of 5.18 ± 1.07 μM for the HCT-116 cell line, compared with that of the standard drug paclitaxel (20.32 ± 1.18 μM). This hybrid selectively targeted cancer cells over nonmalignant cells, inducing apoptosis. Our findings highlighted the potential of this derivative to inhibit the G2/M phase of the cell cycle. The compound also demonstrated tubulin inhibition, establishing itself as a promising lead candidate for anticancer therapy and paving the way for the development of more-effective tubulin-targeting agents in drug discovery.