Design, Synthesis, Antiproliferative Activity and In Silico Studies of 2-Oxo-1,2-Dihydroquinolin Derivatives

Abstract

Quinolines have long been recognized as a versatile scaffold for the development of various bioactive compounds. In this context, a series of quinoline-based compounds were designed and synthesized using two key building block synthons: chalcone and thiocarbohydrazone derivatives. These compounds were synthesized following a design strategy inspired by the bis-indolyl maleimide-based PDK1 ATP-competitive inhibitor BIM-1. The final compounds were evaluated for their in vitro antiproliferative activity against MCF7 and HCT116 human cancer cell lines. Antiproliferative activity revealed that compound 11 displayed the best activity with IC₅₀ of 7.09 and 6.18 µM against HCT116 and MCF7 cell lines respectively. Furthermore, an in silico molecular docking study was performed on the PDK1 enzyme to investigate the binding affinity of compounds at the ATP-binding site. The docking analysis provided insight into the molecular interactions and binding modes of these compounds. Compound 4 showed the highest affinity with a binding score of −11 kcal/mol and an estimated Ki of 8.65 nM. Additionally, ADME (Absorption, Distribution, Metabolism, and Excretion) predictions indicated favorable drug-likeness and oral bioavailability profiles. This study aims to contribute to the development of promising anticancer agents.