5-Arylidene-3-aryl-imidazol-4-ones as dual VEGFR-2/c-Met inhibitors: design, synthesis, and anticancer evaluation.

Cancer remains a major global health challenge characterized by uncontrolled proliferation, angiogenesis, and metastasis. Dysregulation of receptor tyrosine kinases, particularly VEGFR-2 and c-Met, plays a central role in tumor growth and vascularization, rendering their dual inhibition an attractive therapeutic strategy. Herein, a novel series of 5-arylidene-3-aryl-imidazol-4-ones 8a-i, thioacetyl aryl hydrazides 12a-d, and 4-chlorophenylthiazole thioacetamide analogs 16a-b were designed, synthesized, and evaluated for anticancer activity. In vitro cytotoxicity against HepG2 and HCT-116 cell lines was evaluated and the thioacetyl aryl hydrazide derivatives 12a and 12c were identified as the most potent compounds, exhibiting IC50 values of 5.34 and 3.92 μM against HepG2 and 3.26 and 1.38 μM against HCT-116, respectively. Enzyme inhibition assays confirmed their potent dual kinase inhibition: 12a exhibited IC50 values of 16.40 and 15.91 nM towards VEGFR-2 and c-Met, respectively, whereas 12c displayed respective IC50 values of 16.61 and 22.95 nM. Noteworthily, 12c did not exhibit a significant inhibition against EGFR, CDK2, CDK4, and Aurora A suggesting its VEGFR-2 and c-Met selectivity. Furthermore, in HCT-116 cells, 12c induced a marked increase in G2/M population up to 64.97%, with respect to 10.97% for the control and significantly enhanced apoptosis, elevating the total apoptotic fraction from 8.75% of the control to 22.27%. Moreover, 12c increased Bax, caspase-9, and Beclin-1 expression, while reducing Bcl-2 levels. Molecular docking studies revealed favorable binding affinities and stable binding conformations of 12c within VEGFR-2 and c-Met active sites. Collectively, these results highlight 12a and 12c as promising dual VEGFR-2/c-Met inhibitors with potent anticancer activity, meriting further optimization.