Designing Triazole-Amide Hybrids for Multitarget Enzyme Inhibition: Bridging Synthesis and Computation

Ten newly designed triazole–amide conjugates featuring diverse phenyl substitutions were synthesized in good yields (74–80%), and structures were confirmed by spectral and elemental analyses. The triazole–amide conjugates were investigated for their propensity to inhibit DPPH, [Formula: see text]-amylase, [Formula: see text]-glucosidase, acetylcholinesterase, and butyrylcholinesterase. Compound 6b displayed the highest efficacy toward DPPH, [Formula: see text]AMY, and [Formula: see text]GLU (IC[Formula: see text] values of 17.62 ± 0.11, 15.22 ± 0.12, and 10.22 ± 0.81 [Formula: see text]M, respectively). This was attributed to the electronwithdrawing acetyl and bromo substituents, which induced electrondensity imbalance in the skeleton and enhanced interaction ability. Compound 6c bearing two chloro and sulfonamide substituents displayed the strongest AChE and BChE suppression (IC[Formula: see text] values of 12.72 ± 0.61 and 10.20 ± 0.12 [Formula: see text]M). The strength is attributed to electronwithdrawing chloro and SO 2 NH 2 groups, which enhance binding via H-bonding and polar interactions. Molecular docking was employed qualitatively to elucidate the binding modes of these active inhibitors, revealing favorable binding energies across the targets for 6b (−7.73 to −10.42 kcal/mol) and 6c (−7.96 to −9.73 kcal/mol). Density Functional Theory (DFT) calculations supported their electronic stability with HOMO–LUMO energy gaps ranging from 3.50 eV to 4.72 eV. Finally, ADME profiling predicted optimal physicochemical properties, high gastrointestinal absorption, and strict drug-likeness (e.g., TPSA [Formula: see text] for 6b and 6 g) for the most bioactive compounds (6b-d and 6 g) compared with standards ascorbic acid, acarbose, and galantamine, establishing them as promising multi-target lead candidates.