Spiropyrrolizine derivatives as multitarget antidiabetic agents in obese type 2 diabetes: integrated in silico , in vitro , and in vivo evaluation of DPP-4 inhibition and hepatic enzyme modulation

Aims Obesity-associated type 2 diabetes (OB-T2D) remains a major clinical challenge due to insulin resistance and the limited efficacy of current dipeptidyl peptidase-4 (DPP-4) inhibitors in addressing metabolic dysfunction. This study aimed to explore spiropyrrolizine and spiropyrrolothiazole derivatives as multitarget antidiabetic agents.Materials and methods A series of spiropyrrolizine/spiropyrrolothiazole derivatives (4a – i) were synthesized via a one-pot multicomponent reaction5 and screened in vitro for their dipeptidyl peptidase-4 inhibitory activity. The most active compound (4d) was further studied by molecular docking and evaluated in obese type 2 diabetic rats for its in vivo efficacy on dipeptidyl peptidase-4 activity, hepatic enzyme modulation, and metabolic control.Results Among the tested compounds, spiropyrrolizine 4d showed the highest inhibitory activity, comparable to sitagliptin. In vivo, compound 4d reduced serum dipeptidyl peptidase-4 activity, improved hepatic metabolic enzyme activities, and decreased blood glucose and body weight. In silico analyses supported favorable drug-like properties.Conclusion Spiropyrrolizine 4d emerges as a promising multitarget antidiabetic candidate for OB-T2D management.