Functionalized thiazole and thiophene compounds as aldose reductase inhibitors: from rational design to biological and in silico evaluation

Novel thiazole and thiophene derivatives were developed as Aldose Reductase (ALR2) inhibitors with intrinsic antioxidant activity to address diabetic complications associated with the polyol pathway. A series of compounds 3, 4a-c, 8, 9a-b, 10, 12 and 13a-c were evaluated for in vitro ALR2 inhibitory activity, particularly congeners 8 and 10 demonstrated potent inhibition with IC₅₀ values of 1.965 ± 0.185 and 2.135 ± 0.168 μM, respectively, comparable to the reference epalrestat (IC₅₀ = 2.726 ± 0.292 μM). Based on the more favorable docking results, derivative 8 was further evaluated in STZ-induced diabetic mice at 10 mg/kg (i.p.) for 15 days. Treatment attenuated oxidative stress, as evidenced by reduced malondialdehyde (MDA) levels and enhanced antioxidant enzyme activities, including SOD, CAT, and GPx compared with diabetic controls (p < 0.05). In addition, treatment significantly improved the serum lipid parameters by reducing total Cholesterol (TC), triglycerides (TG), and LDL-C levels, while increasing HDL-C levels (p < 0.05). Furthermore, hepatic and renal biochemical markers, together with histopathological examination, demonstrated protective effects of compound 8 against diabetes-associated tissue damage. Molecular docking studies suggested favorable binding interactions of compound 8 to key ALR2 active site residues, particularly Trp111, while MD simulations further supported the stability of the ALR2-8 complex. Hence, the combined biological and computational results establish compound 8 as an auspicious ALR2 candidate inhibitor with potential in vivo antioxidant activity for further development.