Design, Synthesis, Bioactivity, and Docking Studies of Isatin-Hydrazone Derivatives as Potential CDK-2 Inhibitors

Isatin derivatives are an important class of nitrogen-containing heterocyclic compounds that have exhibited a broad spectrum of pharmacological and biological activities. The condensation reaction of isatin readily forms C=N-bonded compounds due to the high reactivity of the 3-position carbonyl group. Hydrazone compounds also play an important role in research related to pesticide chemistry and medicinal chemistry. Therefore, we propose that the compound incorporates both indigo and hydrazone skeletons, which could confer excellent biological activity. The objective of this study is to synthesize novel isatinhydrazone derivatives that function as CDK2 inhibitors through molecular docking and bioactivity studies.

A series of isatin-hydrazone derivatives was synthesized and characterized using ¹H NMR, ¹³C NMR, and HRMS. The in vitro cytotoxicities of these compounds were assessed using an MTT assay against A549 (non-small cell lung cancer), HepG2 (hepatocellular carcinoma), and HeLa (cervical cancer) cell lines.

According to the results of the MTT assay, compounds 2e and 2f exhibited potent selectivity and activity against A549 (IC₅₀ = 5 nM) and HeLa cells (IC₅₀ = 6 nM), respectively. Compound 2h demonstrated dual efficacy against A549 (IC₅₀= 8 nM) and HepG2 (IC₅₀= 13 nM). In addition, molecular docking revealed strong binding affinities and stable interactions between active derivatives and key residues within the CDK2 active site.

These novel isatin-hydrazone derivatives, particularly 2e, 2f, and 2h, could be used as potential anticancer agents that inhibit CDK2 kinase activity.