Cytotoxic Potential of Newly Synthesized 4-Aminoquinoline Hybrids on MDA-MB-231 Cells: Insights from Pharmacophore Modeling and Molecular Dynamics Simulation

Abstract

Objective: This study aimed to design, synthesize, and evaluate novel 4-aminoquinoline hybrids as effective inhibitors of the c-Met kinase domain and assess their anti-proliferative activity against the MDA-MB-231 breast cancer cell line. Methods: The compounds were computationally designed and synthesized. Pharmacophore modeling was used to identify key structural features. Molecular docking studies were conducted to analyze interactions within the c-Met kinase binding pocket, and molecular dynamics simulations were performed to evaluate the stability and conformational behavior of the compounds. Density Functional Theory (DFT) computations further confirmed the optimized geometry of the hybrids. Results and Discussion: Two synthesized compounds exhibited notable inhibitory activity: compound (VIb), with a methoxy group at the 3rd position and a hydroxy group at the 4th position, achieved an IC₅₀ of 4.28 ± 1.05 µg/mL. Compound (VIa), containing a thiazole ring, also demonstrated significant activity. Conclusions: The study employed pharmacophore modeling to identify key structural features of the synthesized hybrids, which facilitated the understanding of their interactions with the c-Met kinase binding pocket through molecular docking studies. Furthermore, molecular dynamics simulations confirmed the stability and conformational behavior of the hybrids, and DFT computations supported their optimized geometries. This comprehensive approach highlights the potential of these novel hybrids as c-Met-targeting agents for cancer therapy.