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Type 2 diabetes mellitus is a vast growing progressive disease that almost affects one person among every twelve globally. Regardless the availability of wide variety of oral hypoglycemics, only one-third of patients achieves proper glycemic control. With the advantage of the low risk of hypoglycemia, DPP-IV attracted the attention of medicinal chemists as a new target for oral hypoglycemics. In this report, a lead compound 1, with antipyrine scaffold, was obtained, and its binding mode was calculated. Several derivatives with bridged nitrogenous heterocycles have been synthesized via multicomponent reaction under controlled microwave heating conditions. The antidiabetic activity versus DPP-IV protein was evaluated and compared with sitagliptin. Compounds with smaller- or medium-sized nitrogenous bridges were comparable with sitagliptin in terms of DPP-IV inhibitory activity, potentially via targeting Glu203 and Glu204. The oral hypoglycemic activities of compounds with submicromolar IC50 values were further evaluated using diabetic mouse model.

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