Design, Synthesis, DFT‐Based Characterization, Molecular Docking, and ADMET Evaluation of a Novel Mannich Base Derivative

ABSTRACT In this study, a new Mannich base derivative, 1‐(4‐piperidine carboxamid‐1‐yl‐methyl)‐3‐methyl‐4‐(3‐hydroxy‐4‐methoxybenzylideneamino)‐4,5‐dihydro‐1 H ‐1,2,4‐triazol‐5‐one ( PHMT ), was synthesized and characterized using IR, 1 H‐NMR, and 1 3 C‐NMR spectroscopic techniques. Experimental results were supported by theoretical calculations performed using density functional theory (DFT) with the B3PW91 and B3LYP/6‐311G(d,p) methods. Molecular electrostatic potential (MEP) maps identified the electrophilic and nucleophilic regions of PHMT, while HOMO–LUMO analysis provided insights into its chemical reactivity and stability. Natural bond orbital (NBO) analysis revealed hyperconjugative interactions influencing intramolecular charge transfer and molecular stability, and Mulliken charge distribution identified reactive sites. The calculated dipole moment, polarizability, and first‐order hyperpolarizability values indicate that PHMT possesses promising nonlinear optical (NLO) properties. Molecular docking studies demonstrated strong interactions between PHMT and the 6W75 (RdRp) and 7BV2 (main protease (Mpro/3CLpro)), enzymes, with binding energies of –7.80 and ‐8.50 kcal/mol, respectively. ADMETlab 2.0 analysis showed that PHMT complies with Lipinski's rule of five and exhibits high predicted oral bioavailability. Overall, these findings suggest that PHMT is a biologically active and pharmacologically promising compound with potential applications in drug discovery and development.