Antidiabetic Evaluation of New Pyrimidine‐Thiazoline Hybrids Endorsed With Enzyme Kinetic Studies and Computational Analysis

The prevalence of diabetes mellitus (DM) poses a serious global health concern, given its substantial contribution to mortality rates. Millions of people worldwide are affected by this disease, which is associated with severe complications. Among the different strategies used to regulate diabetes, inhibition of carbohydrate-hydrolyzing enzymes (α-glucosidase and α-amylase) has emerged as a promising therapeutic alternative. Accordingly, the present study explored the concept of molecular hybridization for synthesizing new pyrimidine-thiazole molecular hybrids as potential α-glucosidase and α-amylase inhibitors and antioxidant agents. Among the tested hybrids, compound 8j emerged as the most potent inhibitor with 3-fold (IC₅₀ = 36.23 ± 2.41 μM) more potency than standard drug acarbose (IC₅₀ = 103.25 ± 1.45 μM) against α-glucosidase and 2-fold (IC₅₀ = 38.42 ± 1.63 μM) greater potency than acarbose (IC₅₀ = 85.00 ± 0.85 μM) against α-amylase. Compounds 8a (IC₅₀ = 37.84 μM) and 8j (IC₅₀ = 85.67 μM) displayed the strongest DPPH and NO scavenging activity, respectively, compared to ascorbic acid (IC₅₀ = 88.40 μM and 102.89 μM, respectively). In addition, kinetic studies revealed that compounds 4b, 8g, and 8j were noncompetitive inhibitors. Molecular docking studies were subsequently carried out to explore the protein-ligand interactions of these compounds. The DFT studies further explored their reactivity characteristics while the ADME/T parameters revealed them to have more drug-likeness properties than acarbose.