Coumarin-based multimodal dual-target ligands for MAOB and 5-HT2CR: DFT analysis, QED scoring, molecular docking, and narcosis evaluation

Abstract Monoamine oxidase B (MAO-B) and the 5-HT₂C receptor are important targets in the treatment of neurological disorders, motivating the search for dual-target ligands with multimodal activity. In this study, a series of hydroxylated coumarin-benzamide derivatives (CmBH1–CmBH10) was investigated to evaluate their electronic properties and pharmacological potential. Density Functional Theory (DFT) calculations were employed to assess molecular stability and reactivity, while molecular electrostatic potential maps were used to identify key interaction sites. In addition, molecular docking and quantitative estimate of drug-likeness (QED) analyses were performed to explore binding affinity and drug-like properties. The HOMO–LUMO energy gaps ranged from 4.3 to 4.6 eV, indicating overall stability, with CmBH2 and CmBH9 showing greater electronic softness and potential reactivity. Electrostatic potential maps revealed nucleophilic regions at the coumarin and amide carbonyl groups, and σ-hole regions in chlorinated derivatives, suggesting possible halogen bonding. Docking results indicated preferential binding to MAO-B over 5-HT₂C, with CmBH9 exhibiting the most favorable interaction profile and evidence of π–π stacking potential. Overall, CmBH9 emerged as a promising lead compound, combining favorable electronic properties, binding affinity, and drug-likeness, supporting its potential as a dual-target ligand and warranting further experimental validation.