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.