Design, synthesis, anticancer activity, and in silico computational studies of new imidazolone-based derivatives with potential multi-target kinase inhibitory activity.

A novel class of 5-(3,5-dimethoxybenzylidene)-2-thioxoimidazolidin-4-one-based derivatives, linked to various alkyl and aryl substituents 1a-d and 2a-h, was designed and synthesized as promising candidates for anti-colon cancer therapy with multi-targeting kinase suppression activity. The antiproliferative effect of the new compounds was assessed against HT-29 using the MTT assay. The congeners 1c and 2h demonstrated the most potent suppressive effects, with IC values 1.828 and 2.197 μg/mL, respectively. The latter derivatives were evaluated as multi-kinase inhibitors against VEGFR-2, c-Met, and PIM-1, exhibiting promising activity with IC values ranging from 0.081 ± 0.003 to 0.433 ± 0.017 μg/mL. Moreover, 2h induced an apoptotic effect and cell cycle arrest at G0/G1 of the mitotic cycle in HT-29 cells. Furthermore, 2h upregulated the oncogenic parameters, including caspase-3, caspase-9, and the Bax/Bcl-2 ratio. The docking results showed that compounds 1c, 2h, and 2e had strong binding energies and effectively interacted with the active sites of the VEGFR-2, c-Met, and PIM-1 receptors. According to the in-silico ADMET analysis the new compounds are anticipated to exhibit promising oral bioavailability, desirable drug-like qualities, and minimal toxicity risks. Molecular dynamics (MD) simulations indicated that 2h interacts consistently with the c-MET, PIM-1, and VEGFR-2 receptors. These results reinforce the potential of these compounds as candidates for further drug development.