Compound 1a(Tanta University)

Type 2 diabetes mellitus (T2-DM) is associated with several dysfunctions and complications. In this study, different chalcones (1a-c) were synthesized through the condensation of acetylacetone with different aromatic aldehydes in a basic medium. These chalcones were then used as key synthons for the synthesis of new pyrimidine derivatives (2a-c) through a reaction with metformin (MTF). Elemental analysis and spectroscopic techniques, such as FT-IR, ¹H NMR, and ¹³C NMR were used to confirm the structures of the compounds. The compounds were then evaluated for their antidiabetic activities in vitro and in vivo. In vitro assays included glucose uptake, α-amylase, and α-glucosidase inhibition were performed. Fifty-four rats were equally divided into 9 groups: Gp1 served as a negative control; Gp2 as the T2-DM group; Gp3 was T2-DM group that were treated with MTF (100 mg/Kg); from Gp4 to Gp9 were T2-DM groups that were treated with chalcones (1a-c) and pyrimidine (2a-c) compounds (100 mg/Kg), respectively. Pharmacokinetic properties were analyzed by using the ADMET lab 2.0 web server and molecular docking studies were conducted using AutoDock Vina. Compound 1a exerted the strongest affinity with α-glucosidase, compound 2c demonstrated strong binding for dipeptidyl peptidase 4 and protein tyrosine phosphatase 1B with energy of -9.7, and -7.7 kcal/mol, respectively. The effect of MTF modified compounds demonstrated significant improvement in glucose consumption by cells, with compounds 1c and 2c had the strongest uptake activities in vitro. Significant inhibitory effects against α-amylase and α-glucosidase were recorded by 1a, 1c and 2c compounds. In vivo studies with streptozotocin-induced diabetic rats revealed 1c and 2c have shown significant antidiabetic activities.