Design, Synthesis, and Biological Evaluation of a New Imidazole–Pyrazole–Triazole Hybrid: Antidiabetic, and Molecular Docking Studies

ABSTRACT A novel series of imidazole–pyrazole ‐ 1,2,3‐triazole hybrids ( 7a–b and 8c–j ) were synthesized and evaluated for their in vitro antidiabetic potential through inhibition of the aldose reductase (AR) enzyme. Sorbinil was used as the standard reference inhibitor (IC 50 = 2.01 ± 0.31 µM). Several hybrids exhibited superior inhibitory activity, particularly the fluoro‐substituted analogue 7a , the methoxy derivative 7b , and the methyl analogue 8c , with IC 50 values of 1.20 ± 0.39, 1.88 ± 0.19, and 1.93 ± 0.23 µM, respectively. The trimethoxy analogue 8h also demonstrated potent activity (IC 50 = 2.19 ± 0.36 µM), comparable to Sorbinil . Molecular docking studies were performed using the AR crystal structure (PDB ID: 1PWM), and the docking protocol was validated by re‐docking the co‐crystallized ligand Fidarestat (RMSD = 1.18 Å). All synthesized hybrids showed stronger binding affinities (–13.8—16.3 kcal/mol) compared to Sorbinil (–11.2 kcal/mol). Notably, compound 8c displayed the highest docking score (–16.3 kcal/mol) and formed key stabilizing interactions, including π–π stacking with Trp219 and π‐cation interactions with Leu301 and Ser302. The favorable binding energies and interaction profiles strongly correlate with the observed in vitro activities, highlighting these hybrids as promising AR inhibitors for antidiabetic drug development.