Novel triazole-based piperidine DPP-4 inhibitors with potent anti-diabetic activity: design, synthesis, and biological evaluation

Dipeptidyl peptidase type 4 (DPP-4) inhibitors are well-established antidiabetic agents that exert their effects through modulation of incretin hormones and improvement of glucose homeostasis. In this study, a new series of 1H-1,2,4-triazol-5-yl piperidine derivatives was designed, synthesized, and evaluated for their inhibitory activity against the DPP-4 enzyme. Among the synthesized compounds, 6 h , 6 m , and 6n showed the most pronounced DPP-4 inhibition, with IC₅₀ values of 80.46, 89.97, and 506.62 nM, respectively. In-silico selectivity studies demonstrated a preferential binding affinity of the designed compounds toward DPP-4 over DPP-8 and DPP-9, suggesting a reduced risk of off-target effects. In-vivo evaluation revealed that compound 6 h significantly improved glucose tolerance in NMRI mice in an oral glucose tolerance test (OGTT) at a dose of 10 mg/kg. Furthermore, repeated administration of compound 6 h for 14 days led to a marked reduction in fasting blood glucose levels in a high-fat diet/streptozotocin-induced type 2 diabetic Wistar rat model, showing an antihyperglycemic effect comparable to that of the reference drug sitagliptin.