Design, synthesis and structure activity relationship of fructose-1, 6 bisphosphatase inhibitors

Fructose 1, 6-bisphosphatase (FBPase) plays a critical role in hepatic gluconeogenesis and represents an important therapeutic target for the treatment of type 2 diabetes mellitus. In the present study, a series of novel pyranopyrimidine derivatives ( PP01 – PP13 ) were rationally designed and synthesized as potential non phosphorus FBPase inhibitors using a multicomponent synthetic strategy. The synthesized compounds were evaluated for in vitro FBPase inhibitory activity and supported by molecular docking studies to understand their binding interactions within the enzyme active site. Several derivatives displayed significant enzyme inhibition, with compounds PP01 , PP04 , PP06 and PP12 showing IC 50 values ranging from 0.046 to 0.082 µM. Docking analysis suggested favourable hydrogen bonding and hydrophobic interactions with key residues including Thr31, Cys179, Leu30 and Lys23, supporting the observed biological activity. Among the series, PP01 demonstrated the most balanced pharmacological profile and was further evaluated for in vivo antihyperglycemic activity in streptozotocin induced diabetic rats at oral doses of 100 and 150 mg/kg for 28 days. Treatment with PP01 resulted in a significant reduction in blood glucose levels compared with the diabetic control group, indicating notable antihyperglycemic potential. Overall, these findings identify pyranopyrimidine derivatives as promising scaffolds for the development of non-phosphorus based FBPase inhibitors and provide a useful framework for further medicinal chemistry optimization toward novel antidiabetic agents.