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,H NMR, andC 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. 1 13
