Design, synthesis, anticancer activity, and mechanistic investigation of 4,5,6,7-tetrahydrobenzo[b]thiophene carboxamides as CDK-2 inhibitors: in vitro and in silico DFT and molecular docking study.

Utilising drug design methodologies including bioisosteric modification and substituents variation, sets of 4,5,6,7-tetrahydrobenzo[b]thiophene carboxamides were synthesised, by conventional heating and eco-friendly microwave-assisted techniques, as CDK-2 inhibitors. These entities were assessed for their antitumor effects against hepatic HepG-2 and breast MCF-7 and MDA-MB-231 carcinomas, in which dimethoxy 5 and dimethyl-bearing analogues 6 and 11 demonstrated significant cytotoxicity and selectivity against the examined cancer cells. Consequently, they were chosen for further assays to determine their mechanism. The findings suggest that these compounds may exert cytotoxicity by inhibiting CDK-2. Compound 11 displayed the highest CDK-2 inhibition, exceeding roscovitine by nearly threefold. Besides, it arrested the MDA-MB-231 cell cycle at the G0/G1 phase by apoptotic stimulation. Molecular modelling showed strong binding of the bioactive analogues to the active pocket of CDK-2 receptor, suggesting their potential as lead inhibitors.