Novel pyridine-thiazolidinone-triazole hybrid glycosides targeting EGFR and CDK-2: Design, synthesis, anticancer evaluation, and molecular docking simulation

Abstract

The observed toxicity of newly designed anticancer drugs is considered as an impediment challenging phenomenon of intense concern arising from diversity in drug targets and the latter concern is therefore still in need for further research. The current investigation reports the design and synthesis of a new series of pyridine-thiazole hybrids and their derived 1,2,3-triazole analogues incorporating with varied sugar moieties and their acyclic analogues 3–11 and 13–18. The newly synthesized compounds were investigated for their cytotoxic activities against human liver HepG-2 and breast MCF-7 cancer cell lines. The pyridine-thiazolidinone-triazole based targets 16–18 revealed the potent cytotoxic activities. Also, all synthesized derivatives afforded promising safety antiproliferative margins against the normal human diploid cell line WI-38. The promising analogues 16–18 were further studied for their inhibitory assessment against EGFR and CDK-2/cyclin A2 kinases. The pyridine-thiazolidinone-1,2,3-triazole based glycosides 17 and 18 displayed promising and relatively equipotent inhibitory activity against EGFR enzyme compared with the reference drug, erlotinib (IC50= 0.19, 0.12, and 0.15 μM, respectively). While, the three glycosides 16–18 showed superior inhibitory potency against CDK-2/cyclin A2 kinases compared to the standard roscovitine (IC50 = 0.26, 0.22, 0.18 and 0.42 μM, respectively). The impact of triazole glycoside 18 upon cell cycle and apoptosis induction was determined to detect its mechanism of action. Additionally, it upregulated the levels of caspase-3, Bax and Bcl-2 in MCF-7 cells. Finally, molecular docking study was simulated to achieve a better rationalization and gain an insight into the binding affinity of the potent derivatives with their targeted enzymes, which prompts their application as optimum leads for further modification in the anticancer field.