Efficient Synthesis, Computational Drug-Likeness, and Molecular Docking Studies of Novel Bicyclic Benzylidene Thiazol3,2-APyrimidin-3(2H)-One Derivatives for Oncogenic and Neurotherapeutic Targets

This study reports the efficient synthesis of novel bicyclic benzylidene thiazole-pyrimidin-3(5H)-one derivatives, including (4-(4-fluorophenyl)-6-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-5-yl)(phenyl)methanone (4), (Z)-6-benzoyl-2-benzylidene-5-(4-fluorophenyl)-7-phenyl-5H-thiazolo3,2-apyrimidin-3(2H)-one (7a), (Z)-6-benzoyl-2-(4-fluorobenzylidene)-5-(4-fluorophenyl)-7-phenyl-5H-thiazolo3,2-apyrimidin-3(2H)-one (7b), (Z)-6-benzoyl-5-(4-fluorophenyl)-2-(4-(methylthio)benzylidene)-7-phenyl-5H-thiazolo3,2-apyrimidin-3(2H)-one (7c), (Z)-6-benzoyl-2-(3,4-dimethoxybenzylidene)-5-(4-fluorophenyl)-7-phenyl-5H-thiazolo3,2-apyrimidin-3(2H)-one (7d), and (Z)-6-benzoyl-2-(3,4-bis(trifluoromethyl)benzylidene)-5-(4-fluorophenyl)-7-phenyl-5H-thiazolo3,2-apyrimidin-3(2H)-one (7e), were comprehensively characterized using IR spectroscopy, 1H and 13C NMR, melting point analysis, and thin-layer chromatography (TLC). To evaluate their pharmacological potential, in silico drug-likeness assessments were performed using SwissADME, BOILED-Egg, and ProTox-II, revealing favorable solubility, gastrointestinal absorption, blood-brain barrier permeability, and toxicity profiles. Notably, molecular docking analyses against critical oncogenic and neurotherapeutic targets—D(2) Dopamine receptor (PDB: 6CM4), Nerve Growth Factor (NGF; PDB: 6NPT), and Melanocortin receptor 4 (MC4R; PDB: 6W25)—demonstrated strong ligand-protein interactions, suggesting their potential therapeutic relevance. Furthermore, molecular dynamics (MD) simulations, including root-mean-square deviation (RMSD) and root-mean-square fluctuation (RMSF) analyses, provided insights into the conformational stability of ligand-receptor complexes, reinforcing their potential as drug candidates. Computational toxicity evaluations classified the compounds under Toxicity Class 4, with LD50 values around 2000 mg/kg, while BOILED-Egg predictions highlighted their differential permeability and absorption properties. Notably, molecules 7a, 7b, 7c, and 7e exhibited blood-brain barrier (BBB) toxicity, and 7e demonstrated immunotoxicity. Binding affinity predictions underscored molecule 7c as the strongest D(2) Dopamine binder (–8.603 XP GScore), while molecule 7b exhibited optimal Nerve Growth Factor (NGF) interactions (–6.677 XP GScore) and molecule 7d showed enhanced binding with MC4R (–7.825 XP GScore). Structural insights from torsional profile analyses further emphasized conformational stability and ligand flexibility, crucial parameters for optimizing lead compounds in drug development.