Novel Azine Linked Hybrids of 2-Indolinone and Thiazolodinone Scaffolds as CDK2 Inhibitors with Potential Anticancer Activity: In Silico Design, Synthesis, Biological, Molecular Dynamics and Binding Free Energy Studies

Abstract

Molecular hybrid of 2-indolinone-thiazolidinone is a well known scaffold for variable biological activities including anticancer activity. Accordingly, in the current work aided with structure-based molecular modeling studies, a library of novel twenty-six hybrids, 4(a-z), was designed and synthesized. Docking studies in the active site of CDK2, one of the key checkpoints enzymes, revealed that the binding scores of the designed molecules are comparable to the reference enzyme's inhibitors Sunitinib, Nintedanib, and Semaxanib. Variable antiproliferative activities are shown for these molecules against human liver (HepG2), breast (MCF7), and colon (HCT-29) cell lines considering Doxrubacin as a refrence drug. Compared to cytotoxic activities on the normal fibroblasts (WI-38), the tested molecules had better selectivity against the cancerous cells, expressed by their selectivity index (SI), than Doxrubacin and compound 4i was the safest compound. CDK2 inhibitory results of compounds 4f, 4g, 4h, and 4w showed IC₅₀ at 59.43, 143.6, 27.42, and 61.63 nM respectively, while that of Sunitinib was 23.8 nM. To clarify the obtained biological activities of these molecules, broad docking and molecular dynamic simulations studies were undertaken and confirmed the consistency between the computational and the in vitro CDK2 inhibitory activities. Furthermore, in silico ADME/Tox profiles were done for the most active molecules using SwissADME and pkCSM-pharmacokinetics web-based methods predicted good pharmacokinetics, bioavailability, and toxicity profiles for the tested compounds.

Keywords: 2-indolineone; Anticancer compounds; CDKase inhibitors; Indolin-2-one derivatives; Molecular dynamics; Molecular modeling; Thiazolidinone.