Discovery of imeglimin-inspired novel 1,3,5-triazine derivatives as antidiabetic agents in streptozotocin-induced diabetes in Wistar rats via inhibition of DPP-4

Abstract

Novel 1,3,5-triazine derivatives bearing oxazine have been synthesized and tested for their ability to inhibit a panel of dipeptidyl peptidase (DPP)-4, 8, and 9 enzymes. In a comparative inhibitory assay, the molecules showed potent inhibition of DPP-4 ranging from IC₅₀ of 4.2 ± 0.30–260.5 ± 0.42 nM, with no activity against DPP-8 and DPP-9. Among the tested series, compound 8c demonstrated the strongest DPP-4 inhibitory activity with an IC₅₀ of 4.2 ± 0.30 nM. It also showed the greatest binding affinity during docking studies with DPP-4 with a docking score of −8.956 and a glide energy of −78.546 kcal mol⁻¹ and was found oriented in the S1 and S2 pockets of the DPP-4 active site, which is composed of the catalytic triad Ser 630, Asp 710, and His 740. The in vivo pharmacological assay revealed that compound 8c in a dose-dependent manner improved the insulin level, body weight, antioxidants, and HDL, and reduced the levels of blood glucose, LDL, and VLDL in streptozotocin-induced diabetes in Wistar rats. Our study demonstrated the discovery and development of novel 1,3,5-triazine derivatives bearing oxazine as a novel class of anti-diabetic agents via inhibition of DPP-4.