Discovery of novel hybrids of Morpholino-1,3,5-triazine-pyrimidine as an anti-diabetic agent in High-fat, Low-dose Streptozotocin-induced diabetes in Wistar rats: An in-vitro, in-silico and in-vivo study

Abstract

Due to their favorable safety profile, DPP-4 inhibitors are the suggested option for Type 2 Diabetes Mellitus (T2DM) for therapeutic purposes. In light of this, in this paper, we report the discovery of several novel morpholino-1,3,5-triazine-pyrimidine hybrid compounds. These compounds were synthesized via an inexpensive and simple synthetic method in high yields. The target molecules' structures have been established using FT-IR, 1H NMR, 13C NMR, mass, and elemental analyses. These compounds inhibited DPP-4 more effectively and selectively than DPP-8 and DPP-9. Compound 8c has been identified as the most effective DPP-4 inhibitor with an inhibitory concentration (IC50) of 2.9 nM. In docking analysis, compound 8c demonstrated good glide energy, and various bonded and non-bonded interactions with key DPP-4 amino acid residues of the S1/S2 site, including Tyr666, Val656, Tyr547, Gly632, Asn710, etc. Furthermore, the effect of compound 8c was also studied on high-fat, low-dose streptozotocin (STZ)-induced diabetes in Wistar rats to determine its anti-diabetic performance. Compound 8c has been shown to considerably improve the insulin level, lipid profile, and anti-oxidant status of diabetic Wistar rats in a dose-dependent manner, with no toxicity. Our findings imply that new morpholino-pyrimidine 1,3,5-triazine hybrid compounds could serve as potential lead for anti-diabetic drug discovery.