Novel thioxoimidazolidinone derivatives as dual EGFR and CDK2 inhibitors: Design, synthesis, anticancer evaluation with in silico study

Fifteen thioxoimidazolidinone derivatives were designed as dual EGFR and CDK2 inhibitors and synthesized following Claisen and Knoevenagel condensation. Derivative 12 showed the best EGFR and CDK2 IC50 giving 0.098 μM and 0.087 μM, respectively, followed by 13 with IC50 0.108 μM and 0.144 μM, respectively. Both derivatives showed better cancerous cell line growth inhibition than erlotinib over HCT-116, MCF-7, and HepG-2. Furthermore, the colorectal HCT-116 was the most responsive to treatment with IC50 of 1.87 μM and 2.70 μM for 12 and 13, respectively in comparison to 15.40 μM of erlotinib. Moreover, the molecular docking simulation of 12 and 13 explained their astonishing kinase inhibition at the molecular level, where both exhibited better EGFR binding energy than its co-crystallized ligand consolidated with the crucial amino acid interactions. Similarly, derivative 12 showed comparable binding energy to CDK2 to its co-crystallized ligand and demonstrated the characteristic interactions with CDK2 binding site and gatekeeper residues.