Multitarget Inhibition of Diabetic Enzymes by Thiazole Carboxylic Acids: Experimental and Computational Approaches

Abstract

Diabetes mellitus is a complex metabolic disorder characterized by chronic hyperglycemia, which results from either insulin resistance or insufficient insulin secretion, and is closely associated with numerous microvascular and macrovascular complications. The polyol pathway plays a central role in the onset and progression of diabetic complications, primarily through the actions of two key enzymes: aldose reductase (ALR2) and sorbitol dehydrogenase (SDH), which catalyze critical steps in glucose metabolism under hyperglycemic conditions. In this study, ALR2 and SDH enzymes were purified from sheep kidney tissue, while α-glycosidase was commercially sourced, to evaluate the inhibitory effects of nine novel thiazole-based carboxylic acid derivatives. In vitro enzymatic assays demonstrated that the synthesized compounds exerted potent inhibitory effects on the target enzymes at micromolar concentrations. Notably, compound 5 showed the most pronounced inhibition of ALR2 (K<inf>i</inf>: 0.556 ± 0.102 μM), compound 3 was the most potent inhibitor of SDH (K<inf>i</inf>: 1.890 ± 0.136 μM), and compound 7 exhibited the strongest activity against α-Glu (K<inf>i</inf>: 0.292 ± 0.047 μM). Furthermore, in silico ADMET profiling revealed that the most active compounds possess favorable pharmacokinetic properties, including high gastrointestinal absorption, acceptable solubility, and compliance with key drug-likeness criteria. Additionally, the cytotoxic potential of the most active compounds (3, 5, 6, and 7) was evaluated using the MTT assay on healthy L929 fibroblast cells to assess their safety profiles. These results were corroborated by molecular docking that also revealed the favorable binding interaction in the active sites of the target enzymes. Taken together, the prepared thiazole derivatives are potential lead compounds for discovery of novel antidiabetic drugs for the treatment of diabetes via inhibition of the key enzymes of glucose metabolism. © 2025 Elsevier B.V.