Design, Synthesis, and In Vitro Evaluation of Triazole-enamine Derivatives for Antidiabetic Activity: α-Amylase Inhibition and Computational Investigations

Introduction:: Diabetes mellitus is characterized by persistent hyperglycemia, often managed by inhibiting carbohydrate-digesting enzymes such as α-amylase. Triazole-containing heterocycles are promising scaffolds due to their structural versatility and hydrogen-bonding capacity. Methods:: A series of triazole derivatives (PT1–PT14) was synthesized and structurally confirmed. Molecular docking assessed interactions with α-amylase, while in vitro inhibition assays determined IC50 values (20-100 μM). ADME properties, including Lipinski’s compliance, gastrointestinal absorption, and BBB permeation, were predicted in silico. Results:: Docking showed binding affinities of –6.9 to –8.4 kcal/mol; PT13 exhibited the highest affinity (-8.4 kcal/mol) via hydrogen bonding (THR A:163), π–π stacking (TRP A:59, TYR A:62), and Pi-Alkyl interactions (LEU A:165). In vitro, PT13 was the most potent inhibitor (IC50 = 40.0 ± 0.01 μM), followed by PT14 (43.1 ± 0.25 μM), PT9 (45.4 ± 0.08 μM), PT12 (45.9 ± 0.02 μM), and PT6 (46.2 ± 0.31 μM); PT1, PT4, and PT11 were less active (>54 μM), while acarbose showed 35.5 ± 0.04 μM. ADME predictions indicated high gastrointestinal absorption, non-BBB permeation, and Lipinski compliance. Discussion:: Enhanced activity of PT13 is attributed to its fused pyrrole–pyridine heteroaryl group, facilitating hydrogen bonding, hydrophobic, and π-electron interactions. Structural modifications clearly influence binding and inhibitory potency, confirming a strong structure–activity relationship. Conclusion:: PT13 emerged as the most promising lead, combining potent α-amylase inhibition, favorable docking, and ADME properties, supporting further SAR exploration and in vivo evaluation of triazole-based antidiabetic agents.