Design, synthesis and anticancer evaluation of novel 1,3-imidazole-type phenylhistin derivatives: Dual mechanism via P53 induction and microtubulin inhibition

To enhance biological activity and deepen the understanding of the structure-activity relationship, a systematic study was conducted on the 5-position of the 1,3-imidazol-4-yl group in phenylahistin. The interaction between phenylahistin derivative 16j and the colchicine-binding site was first analyzed in detail, leading to the development of a fragment library to replace the tert-butyl group. A series of 20 novel phenylhistin derivatives were designed, synthesized, and characterized. In vitro activity screening using the NCI-H460 human non-small cell lung Cancer line showed strong inhibitory activity for most compounds. Among these, compounds 8 f and 8 g exhibited superior activities, with IC₅₀ values of 10 nM and 2 nM, respectively. Notably, 8 f displayed activity comparable to that of plinabulin, while 8 g was five times more potent. Both compounds 8 f and 8 g were further evaluated across various tumor cell lines showing nanomolar-level potency. Furthermore, detailed biological assays revealed that 8 g and 8 f disrupted microtubule integrity and significantly affected the P53 signaling pathway, strongly inducing G2/M phase arrest, and simultaneously promoting Apoptosis in NCI-H460 cells. Molecular docking studies confirmed higher binding scores and stronger affinities for these derivatives at the colchicine-binding site of α, β-tubulin. These findings suggest that the apoptosis-inducing and cytotoxic activities of these derivatives may offer potential clinical value for tumor therapy.

Anticancer; Microtubulin inhibition; P53 induction; Phenylahistin; Structure-based.