Design, synthesis, and anticancer evaluation of novel coumarin/thiazole congeners as potential CDK2 inhibitors with molecular dynamics.

A series of novel coumarin-thiazoles was designed and synthesized as a possible CDK2 inhibitor with anticancer activity with low toxicity. The design relied on having hydrazine thiazole or its open-form thioamide to form H-bonds with the ATP binding site while coumarin maintained the crucial hydrophobic interactions for proper fitting. The biological evaluation revealed that the hydroxycoumarin-thiazole derivative 6c demonstrated the best inhibition with HepG2 and HCT116 IC50 2.6 and 3.5 µM, respectively. Similarly, its open thioamide chain congener 5c exhibited potent inhibition on MCF-7 and HepG2 with IC50 of 4.5 and 5.4 µM, respectively. Molecular docking simulations supported the assumption of inhibiting CDK2 by preserving the crucial interaction pattern with the hinge ATP site and the surrounding hydrophobic (HPO) side chains. Furthermore, molecular dynamics simulations of 5c and 6c established satisfactory stability and affinity within the CDK2 active site.

Recyclization of morpholinochromonylidene-thiazolidinone using nucleophiles: facile synthesis, cytotoxic evaluation, apoptosis, cell cycle and molecular docking studies of a novel series of azole, azine, azepine and pyran derivatives.

A convenient synthetic approach for construction of a novel series of substituted azoles, azines, azepines and pyrans clubbed with a morpholinothiazolidinone hybrid was achieved. The methodology depended on ring-opening and ring-closure (RORC) of chromone ring in 2-(morpholinoimino)-5-[(4-oxo-4H-chromen-3-yl)methylene]-3-phenylthiazolidin-4-one (3) through its reaction with a series of nitrogen and carbon nucleophiles under mild reaction conditions. The cytotoxic effects of all products were evaluated against three cancerous cell lines (MCF-7, HepG-2 and SKOV-3) by the standard SRB method. Fortunately, the products 7, 11, 12, 15, 19, 22, 26 and 28 were found to be the most active against all cancer cell lines, comparable to doxorubicin. Apoptosis was determined using flow cytometry along with cell cycle analysis and supported by molecular docking. The products 7, 11, 12, 15, 19, 22, 26 and 28 induced a significant early-and late-apoptotic effect against all tumor cells. In addition, these products preferred to arrest all cancer cells in the G1 and G2 phases. Finally, molecular docking was attempted to investigate the binding mode of products 12 and 22 with p53-MDM2 protein receptor.