New benzylidene festooned thiazolidinone-coumarin molecular hybrids targeting Human Breast adenocarcinoma cells: Design, synthesis, SAR, molecular Modelling and biological evaluation as CDK2 inhibitors

Abstract

Novel benzylidene-coumarin bearing thiazolidinone derivatives (5a-5j) are synthesized by coupling methodology using 7-(3-Chloro-propoxy)-4-methyl-chromen-2-one and substituted benzylidine-thiazolidine-2,4-one. The synthesized novel thiazolidinone-coumarin derivatives in the structure-based molecular hybridization approach are screened to learn their in-vitro cytotoxicity against the Human Breast cancer cells (MCF-7). Spectroscopic studies and elemental analysis were used to characterize the synthesized compounds. IC50 values (15.7 and 12.15 µg/ml) obtained from cytotoxicity studies against MCF-7 cancer cell lines indicate higher kinase inhibitory activities of compounds 5a and 5j among the synthesized derivatives which are on par to that of standard doxorubicin (7.50 µg/ml). Molecular docking simulation shows the involvement of CDK2 protein in the formation of three conventional hydrogen bonds with compound 5j. Superior LibDock score (145.146 kcal/mol) and -62.687 kcal/mol as a binding energy were due to 5j docked complex in its finest conformation with CDK2 protein. Finally, we discovered that these new scaffolds of 5-(benzylidene)-3-[3-(4-methyl-2-oxo-2H-chromen-7-yloxy)-propyl] thiazolidine-2,4-dione result in expedient compounds towards the treatment of cancer in upcoming days.