Unlocking the antidiabetic potential of novel pyrazole-triazole hybrids through synthesis, dual α-amylase/α-glucosidase inhibition, multiscale biological evaluation, and molecular dynamics studies

Abstract

This study aimed to design potent antidiabetic agents based on a pyrazole-linked carbohydrazide scaffold. Eighteen derivatives of substituted pyrazole-carbohydrazide linked to further pyrazole 8a–i or 1,2,3-triazolo-pyrazole 12a–i were synthesized. All synthesized compounds were evaluated for their inhibitory activity against α-amylase and α-glucosidase. Between them, compounds 8g, 12d, and 12e revealed potent inhibition for α-amylase (IC₅₀ = 8.48 ± 0.04–30.54 ± 0.03 µM) along with appreciable α-glucosidase at 25 µM. Subsequently, the promising candidates 8g, 12d, and 12e were assessed in vivo studies using glucose intolerance and alloxan-induced diabetic models. The selected compounds showed a substantial improvement in blood glucose control with high potency compared to the standard therapy. Compound 8g exhibited the strongest antihyperglycemic effect, reducing blood glucose levels by 38.76% in the alloxan-induced diabetic rat model and maintaining significant glucose-lowering activity for up to 4 hours in the oral glucose tolerance test. Safety assessment, including cytotoxicity evaluation on normal cell line Wi-38 cells and subacute toxicity studies in mice, revealed that compounds 8g, 12d, and 12e exhibited no observable toxicity in mice, with all hepatic, renal, and cardiac biomarkers remaining within normal limits. These compounds would stand out as potential antidiabetic agents. Furthermore, molecular docking, integrated with molecular dynamics, showed strong binding affinities with key amino acids.