Synthesis and Computational Studies of Novel Manganese Paracetamol Complexes: Insights from DFT and Docking Approaches for Reduced Hepatotoxicity and Enhanced Bioactivity

Abstract In this study, novel manganese (II) complexes were synthesized using paracetamol (APAP) as primary ligand, with histidine and proline as secondary ligands to enhance coordination. The main objective was to attenuate APAP‐induced hepatotoxicity, which is commonly associated with its bioaccumulation and the induction of oxidative stress. Manganese was intentionally chosen owing to its important role in metabolic processes. The structural integrity of the complexes was confirmed through physicochemical characterization, including elemental analysis, infrared and UV‐visible spectroscopies. To evaluate their bioactivity, the antioxidant properties of the complexes were investigated using both experimental and computational approaches. The DPPH free radical scavenging assay provided empirical evidence of antioxidant efficacy, while Density Functional Theory (DFT) offered mechanistic insights into their electron‐donating capabilities. The hydrogen atom transfer (HAT) mechanism was used to elucidate the underlying principles of the antioxidant power. Additionally, molecular docking study shedding light on potential pathways through which these compounds may mitigate hepatic damage. Besides, quantitative structure–activity relationship (QSAR) modeling suggested that the complexes hold therapeutic promise beyond hepatoprotection, particularly as candidates for ovarian cancer treatment. The strong concordance between experimental results and theoretical predictions underscores the therapeutic relevance of Mn‐APAP complexes and highlights their potential in reducing hepatotoxicity and their applicability in combating oxidative stress‐associated pathologies.