Eco-friendly sequential one-pot synthesis, molecular docking, and anticancer evaluation of arylidene-hydrazinyl-thiazole derivatives as CDK2 inhibitors

One current approach in the treatment of cancer is the inhibition of cyclin dependent kinase (CDK) enzymes with small molecules. CDK are a class of enzymes, which catalyze the transfer of the terminal phosphate of a molecule of ATP to a protein that acts as a substrate. Among CDK enzymes, CDK2 has been implicated in a variety of cancers, supporting its potential as a novel target for cancer therapy across many tumor types. Here the discovery and development of arylidene-hydrazinyl-thiazole as a potentially CDK2 inhibitors is described, including details of the design and successful synthesis of the series analogs (27a-r) using one-pot approach under eco-friendly ultrasound and microwave conditions. Most of the newly synthesized compounds showed good growth inhibition when assayed for their in-vitro anti-proliferative activity against three cancer cell lines (HepG2, MCF-7 and HCT-116) compared to the reference drug roscovitine, with little toxicity on the normal fibroblast cell lines (WI-38). Furthermore, the compounds exhibiting the highest anti-proliferative activities were tested against a panel of kinase enzymes. These derivatives displayed an outstanding CDK2 inhibitory potential with varying degree of inhibition in the range of IC50 0.35-1.49 mu M when compared with the standard inhibitor roscovitine having an IC50 value 0.71 mu M. The most promising CDK2 inhibitor (27f) was selected for further studies to determine its effect on the cell cycle progression and apoptosis in HepG2 cell line. The results indicated that this compound implied inhibition in the G2/M phase of the cell cycle, and it is a good apoptotic agent. Finally, Molecular docking study was performed to identify the structural elements which involved in the inhibitory activity with the prospective target, CDK2, and to rationalize the structure-activity relationship (SAR).

Automated summary

This study describes the discovery and development process of a novel potential CDK2 inhibitor. The synthesized compounds showed strong growth inhibition against various cancer cell lines with low toxicity on normal fibroblast cells. One compound exhibited inhibitory effects on cell cycle progression and apoptosis. Molecular docking study identified the structural elements involved in the inhibitory activity and rationalized the structure-activity relationship.