Synthesis, in-silico studies, and biological evaluation of some novel 3-thiazolyl-indoles as CDK2–inhibitors

Abstract

The essential enzyme cyclin-dependent kinase 2 (CDK2) is a promising target for anticancer drug development due to its pivotal role in regulating the cell cycle. This study aimed to synthesize novel 3-thiazolyl-indole derivatives and assess their ability to inhibit CDK2 using molecular docking analyses. A series of these compounds was synthesized through a multistep approach, and various techniques, including NMR, IR, and mass spectrometry, were used for structural characterization. Prolonged molecular dynamics (MD) simulations were conducted to explore pharmacokinetics, toxicity profiles, binding interactions, and structural dynamics. Additionally, nine newly synthesized compounds were evaluated for in vitro cytotoxicity against three human cancer cell lines (HepG2, MCF-7, and HCT-116) in comparison to cisplatin. The results revealed that compounds 5c, 5b, and 10b displayed favorable activities when compared to the reference drug. Furthermore, the inhibitory activity of the most potent compounds (5a-c) was tested in an in vitro enzyme assay against CDK2. The findings indicated that several 3-thiazolyl-indole derivatives exhibited significant inhibitory activity against CDK2, with compound 5c being the most potent (IC50 value of 0.35 ± 1.07 µM compared to roscovitine's 0.39 ± 0.47 µM). Molecular docking revealed the compounds' binding modes in the CDK2 site. This research highlights the potential of 3-thiazolyl-indoles in anticancer drug development.

Keywords

• Indoles
• Thiazoles
• Thiosemicarbazones
• Hydrazonoyl halides
• Anticancer
• Molecular Docking