Design, Synthesis, and Biological Evaluation of Quinoline‐Thiazolinone Hybrids as Potential Anticancer Agents: An Integrated In Silico Study Using Molecular Docking, Molecular Dynamics Simulation, MM/GBSA, and ADME Prediction

Abstract

This study aimed to design and synthesize a novel series of ten quinoline‐thiazolinone hybrid derivatives ( KSP4‐1 to KSP4‐10 ) as potential anticancer agents. All synthesized compounds were characterized by 1 H NMR, 1 3 C NMR, and HRMS spectroscopic data. In vitro antiproliferative activity was evaluated against human breast (MCF‐7) and lung (A549/WT‐EGFR) cancer cell lines using the MTT assay, complemented by molecular docking against four EGFR crystal structures (PDB: 4I22, 2JIV, 6LUD, and 5D41), 100 ns molecular dynamics simulations with MM‐GBSA binding free energy calculations, and in silico ADME profiling. Among the synthesized derivatives, KSP4‐6 (IC 50 = 2.15 µM on MCF‐7; 2.10 µM on A549) and KSP4‐9 (IC 50 = 2.10 µM on MCF‐7; 2.15 µM on A549) emerged as the most potent compounds, comparable to the reference drug doxorubicin, while docking studies revealed that KSP4‐8 outperformed the allosteric reference inhibitor EAI045 at the 5D41 binding site (−8.6 kcal/mol). Molecular dynamics simulations confirmed the stable binding of the KSP4‐1 /2JIV complex, supported by a favorable MM‐GBSA binding free energy (−62.22 kcal/mol), and in silico ADME predictions indicated favorable drug‐likeness and compliance with Lipinski's Rule of Five for all compounds. Collectively, these findings establish the quinoline‐thiazolinone scaffold as a promising pharmacophore for the further development of next‐generation EGFR‐targeted anticancer therapeutics.