A Series of Isatin-Hydrazones with Cytotoxic Activity and CDK2 Kinase Inhibitory Activity: A Potential Type II ATP Competitive Inhibitor

Abstract

Isatin derivatives potentially act on various biological targets. In this article, a series of novel isatin-hydrazones were synthesized in excellent yields. Their cytotoxicity was tested against human breast adenocarcinoma (MCF7) and human ovary adenocarcinoma (A2780) cell lines using MTT assay. Compounds <b>4j</b> (IC₅₀ = 1.51 ± 0.09 µM) and <b>4k</b> (IC₅₀ = 3.56 ± 0.31) showed excellent activity against MCF7, whereas compound <b>4e</b> showed considerable cytotoxicity against both tested cell lines, MCF7 (IC₅₀ = 5.46 ± 0.71 µM) and A2780 (IC₅₀ = 18.96± 2.52 µM), respectively. Structure-activity relationships (SARs) revealed that, halogen substituents at 2,6-position of the C-ring of isatin-hydrazones are the most potent derivatives. In-silico absorption, distribution, metabolism and excretion (ADME) results demonstrated recommended drug likeness properties. Compounds <b>4j</b> (IC₅₀ = 0.245 µM) and <b>4k</b> (IC₅₀ = 0.300 µM) exhibited good inhibitory activity against the cell cycle regulator CDK2 protein kinase compared to imatinib (IC₅₀ = 0.131 µM). A molecular docking study of <b>4j</b> and <b>4k</b> confirmed both compounds as type II ATP competitive inhibitors that made interactions with ATP binding pocket residues, as well as lacking interactions with active state DFG motif residues.