Molecular Docking Studies Synthesis and Biological Evaluation of Novel Pyrimidine Derivatives as a potential Alk InhibitorsMolecular Docking Studies Synthesis and Biological Evaluation of Novel Pyrimidine Derivatives as a potential Alk Inhibitors

Abstract

Anaplastic lymphoma kinase (ALK) inhibitors have emerged as a promising therapeutic newlinestrategy in anticancer drug development, with several FDA-approved agents targeting newlineALK-driven malignancies. In this study, a rational design approach was employed to newlinedevelop novel ALK inhibitors by integrating computational and synthetic methodologies. newlineA pharmacophore model was generated using molecular docking and quantitative newlinestructure activity relationship (QSAR) analyses (both 2D and 3D), utilizing the crystal newlinestructure of the ALK protein (PDB ID: 4MKC) as the molecular target. Based on the newlinepharmacophore insights, a series of novel compounds incorporating the 2,4 newlinediarylaminopyrimidine scaffold were designed and synthesized. The synthetic protocol newlineinvolved conventional and modern organic synthesis techniques, reaction progression was newlinemonitored by thin-layer chromatography (TLC). Crude products were isolated, and final newlinecompounds were purified using silica-gel column chromatography. Structural elucidation newlinewas carried out using nuclear magnetic resonance (NMR) spectroscopy and mass newlinespectrometry (MS). The biological activity of the synthesized compounds was assessed newlinethrough ALK enzyme inhibition assays and in vitro cytotoxicity studies using the MTT newlineassay on A549 human lung cancer cell lines. Among the tested compounds, KEN18 and newlineB1 exhibited the most potent ALK inhibition, with ICand#8325;and#8320; values of 42.83 µM and 7.5 µM, newlinerespectively, compared to the standard crizotinib (ICand#8325;and#8320; = 2 µM). In conclusion, this study newlinesuccessfully identified and characterized novel heterocyclic compounds with promising newlineALK inhibitory activity. These findings highlight KEN18 and B1 as promising lead newlinemolecules for further development of targeted therapies against non-small cell lung cancer newline(NSCLC). newline