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<p>This study reports the successful synthesis of a novel series of bicyclic benzylidene oxazole pyrimidine derivatives namely (Z)-6-benzoyl-2-benzylidene-5,7-diphenyl-5H-oxazolo[3,2-a]pyrimidin-3(2H)-one <b>(C1)</b>, (Z)-6-benzoyl-2-(3,4-dimethoxybenzylidene)-5,7-diphenyl-5H-oxazolo[3,2-a]pyrimidin-3(2H)-one <b>(C2)</b>, and (Z)-6-benzoyl-2-(4-fluorobenzylidene)-5,7-diphenyl-5H-oxazolo[3,2-a]pyrimidin-3(2H)-one <b>(C3)</b> via a one-pot Hantzsch heterocyclization and Knoevenagel condensation. The compounds were characterized by FTIR, <sup>1</sup>H-NMR, and <sup>13</sup>C-NMR spectroscopy, supported by theoretical calculations. Quantum chemical simulations using B3LYP/6-311G + (d,p) provided insights into electronic properties, including HOMO–LUMO gaps, MEP surfaces, Fukui functions, and topological parameters. Monte Carlo (MC) simulations evaluated adsorption behavior on Fe(110) and Cu(111), with <b>C2</b> exhibiting the strongest binding affinity. Drug-likeness and toxicity assessments classified the compounds in the 2nd toxicity class, with <b>C1</b> being BBB toxic, <b>C2</b> immunotoxic, and C3 neurotoxic and BBB toxic. Molecular docking (MD) studies indicated <b>C1</b> as a potent COX-2 inhibitor (− 10.137 XP GScore), stabilized by π⋅⋅⋅π interactions, while <b>C2</b> showed strong hydrogen bonding in the NF-κB pathway. Molecular dynamics simulations confirmed the stability of the COX-2-C1 complex, highlighting key ligand–protein interactions. These findings suggest <b>C1</b> as a promising COX-2 inhibitor and C2 as a potential NF-κB modulator, offering insights for future drug development.</p>

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Benzylidene Oxazolo[3,2-a]pyrimidine derivatives as promising anti-inflammatory agents: synthesis, quantum simulations, and molecular Docking

  • 期刊论文

  • 发表日期：

    2025年9月12日

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  • Abdalla Ali Amin,
  • Ali Rasw Hamad,
  • Yousif Hussein Azeez,
  • Karzan Mahmood Ahmed,
  • Rebaz Obaid Kareem,
  • Rzgar Faruq Rashid,
  • Khdir Ahmed Othman,
  • Rebaz Anwar Omer

摘要

This study reports the successful synthesis of a novel series of bicyclic benzylidene oxazole pyrimidine derivatives namely (Z)-6-benzoyl-2-benzylidene-5,7-diphenyl-5H-oxazolo[3,2-a]pyrimidin-3(2H)-one (C1), (Z)-6-benzoyl-2-(3,4-dimethoxybenzylidene)-5,7-diphenyl-5H-oxazolo[3,2-a]pyrimidin-3(2H)-one (C2), and (Z)-6-benzoyl-2-(4-fluorobenzylidene)-5,7-diphenyl-5H-oxazolo[3,2-a]pyrimidin-3(2H)-one (C3) via a one-pot Hantzsch heterocyclization and Knoevenagel condensation. The compounds were characterized by FTIR, 1H-NMR, and 13C-NMR spectroscopy, supported by theoretical calculations. Quantum chemical simulations using B3LYP/6-311G + (d,p) provided insights into electronic properties, including HOMO–LUMO gaps, MEP surfaces, Fukui functions, and topological parameters. Monte Carlo (MC) simulations evaluated adsorption behavior on Fe(110) and Cu(111), with C2 exhibiting the strongest binding affinity. Drug-likeness and toxicity assessments classified the compounds in the 2nd toxicity class, with C1 being BBB toxic, C2 immunotoxic, and C3 neurotoxic and BBB toxic. Molecular docking (MD) studies indicated C1 as a potent COX-2 inhibitor (− 10.137 XP GScore), stabilized by π⋅⋅⋅π interactions, while C2 showed strong hydrogen bonding in the NF-κB pathway. Molecular dynamics simulations confirmed the stability of the COX-2-C1 complex, highlighting key ligand–protein interactions. These findings suggest C1 as a promising COX-2 inhibitor and C2 as a potential NF-κB modulator, offering insights for future drug development.