Design, synthesis, enzymatic and in vivo antihyperglycemic activity evaluation of 1,3,4-oxadiazole derivatives targeting multiple pathways in type 2 diabetes

Abstract

The multifactorial and complex pathophysiology of type 2 diabetes mellitus (T2DM) requires therapeutic interventions that regulate key enzymes involved in glucose homeostasis. The study described the design of a new family of oxadiazole–tetrahydropyrimidinone hybrid compounds (18–23 and 30–36), their synthesis, and the testing of these compounds as multitarget antidiabetic agents. The in vitro enzyme inhibition was performed on four key targets: α-amylase, α-glucosidase, dipeptidyl peptidase-IV, and protein tyrosine phosphatase 1B. Among the synthesized derivatives, compound 23 exhibited excellent inhibitory activity across all four tested targets, demonstrating a balanced multitarget profile, while compounds 18 and 19 showed good to moderate activity. The in vivo antihyperglycemic activity of the chosen compounds, particularly compound 23, was proven using oral glucose tolerance tests (OGTT) and chronic studies in diabetic rat models, resulting in a significant decrease in fasting blood glucose. The docking simulations revealed favorable binding affinities with all four targets, supporting the observed multitarget behavior. Together, these results demonstrate oxadiazole–tetrahydropyrimidinone hybrids as promising scaffolds for the development of balanced multitarget antidiabetic agents with potential for synergistic glycemic control through coordinated modulation of complementary metabolic pathways, offering improved therapeutic prospects in T2DM management.