Fused Imidazotriazole-Based Therapeutics: A Multidisciplinary Study Against Diabetes-Linked Enzymes Alpha-Amylase and Alpha-Glucosidase Using In Vitro and In Silico Methods

Background/Objective: The present study reports the design, synthesis, and biological evaluation of novel imidazo-triazole derivatives as potential antidiabetic agents. Methods: The novel series was synthesized by treating amino-triazole bearing carboxylic acid with substituted 2-bromo acetophenone and was biologically compared with acarbose under in vitro analysis. Results: Structure–activity relationship (SAR) analysis revealed that among these compounds, remarkable activity was shown by compound 5 (having three hydroxyl substituents) with IC₅₀ value of 6.80 ± 0.10 and 7.10 ± 0.20 µM for α-amylase and α-glucosidase in comparison to reference drug acarbose. To support experimental findings, computational investigations including molecular docking, pharmacophore modeling, molecular dynamics simulations, density functional theory (DFT), and absorption distribution metabolism excretion and toxicity (ADMET) profiling were employed. These studies confirmed the stability of ligand–protein interactions and provided insights into electronic and reactivity features governing enzyme inhibition. Conclusions: Collectively, the integration of in vitro and in silico approaches underscores the potential of novel imidazo-triazole scaffolds as promising leads for the development of safer and more effective therapeutics against diabetes mellitus.