Design, synthesis, and combined computational and experimental evaluation of novel 1,2,4-triazole Schiff base hybrids as potent dual inhibitors of urease and α-glucosidase

Dual inhibition of urease and α-glucosidase offers a unified approach to gastric and metabolic disorders. Two new 1,2,4-triazole – Schiff base hybrids (5a, 5b) were designed, synthesized, and spectroscopically verified. Frontier orbitals and electronic descriptors were computed at the B3LYP/6–311++G(d,p) level. Enzyme inhibition was quantified in vitro and rationalized by in-silico docking. Both ligands were potent urease inhibitors: 5a IC50 = 18.63 ± 1.47 μg/mL and 5b IC50 = 16.94 ± 1.09 μg/mL; 5b approached thiourea (14.42 ± 1.13 μg/mL) and surpassed acetohydroxamic acid (19.35 ± 0.94 μg/mL). Against α-glucosidase, 5b showed strong activity (IC50 = 13.78 ± 0.89 μg/mL), comparable to acarbose (11.08 ± 0.85 μg/mL), whereas 5a was moderate (19.66 ± 2.08 μg/mL). Docking corroborated these trends, indicating higher urease affinities for 5a (−7.0 kcal/mol) and 5b (−7.6 kcal/mol) than thiourea (−3.3 kcal/mol), and favorable α-glucosidase binding (−6.2/−6.5 kcal/mol) relative to acarbose (−5.3 kcal/mol). Interaction analyses revealed hydrogen-bond networks, π–π stacking, π–cation/anion contacts, and hydrophobic stabilization; phenolic substituents in 5b reinforced active-site complementarity. By integrating spectroscopy, quantum-chemical characterization, enzyme assays, and docking, this work identifies 5a and especially 5b as multifunctional scaffolds for dual urease and α-glucosidase inhibition with potential utility against Helicobacter pylori–associated gastric disease and type 2 diabetes.