Design, Synthesis, Characterization and In-vitro Evaluation of Novel Isatin derivatives as Anti-lung Cancer agents inhibiting CDK2 Enzyme

Abstract

Lung cancer is one of the most prevalent and lethal malignancies globally, responsible for more than 1.3 million deaths each year. Cyclin-dependent kinase 2(CDK2) plays a crucial role in cell cycle regulation and has emerged as a promising therapeutic target in cancer drug development. This study focused on the design, synthesis, and evaluation of novel isatin-piperazine derivatives as potential antilung cancer agents targeting the CDK2 enzyme. A total of 110 ligands were designed using in silico drug design strategies and screened through molecular docking with AutoDock Tools 4.2 version 1.5.6. The compounds were evaluated for drug-likeness according to Lipinski's rule of five, along with ADMET properties and toxicity predictions using Molinspiration and Osiris Property Explorer. Among the designed molecules, five derivatives with high docking scores and synthetic feasibility were selected for synthesis. Structural characterization was conducted using IR, HNMR spectroscopic techniques. In vitro anticancer evaluation of the selected compounds TK1 and TK4 against the A549 lung cancer cell line, using the MTT assay, yielded IC values of 46.49µg/mL and 77.97µg/mL, respectively, demonstrating superior cytotoxic activity compared to the reference drug, artemisinin (IC 100µg/mL). These results indicate that is at in-based scaffolds show significant potential as CDK2 inhibitors and may serve as leads for the development of novel antilung cancer therapeutics.