An extensive research on aldose reductase inhibitory effects of new 4H-1,2,4-triazole derivatives

Abstract

Aldose reductase (AR) is a key enzyme, which triggers the excessive accumulation of sorbitol in insulin independent tissues leading to severe diabetes-induced microvascular complications. Substantial evidence has proven that AR inhibition is a well-established strategy to attenuate these complications. In the current work, new 2-[(4-amino-5-aryl-4H-1,2,4-triazol-3-yl)thio]-N-(thiazol/benzothiazol-2-yl)acetamides (1–18) were synthesized and evaluated for their inhibitory capacities on AR. 2-[(4-Amino-5-(4-methylphenyl)-4H-1,2,4-triazol-3-yl)thio]-N-(5-nitrothiazol-2-yl)acetamide (12) and 2-[(4-amino-5-(3-pyridyl)-4H-1,2,4-triazol-3-yl)thio]-N-(6-nitrobenzothiazol-2-yl)acetamide (17) were identified as the most effective AR inhibitors in this series with the Ki values of 0.04 ± 0.01 µM and 0.08 ± 0.02 µM, respectively as compared to quercetin (Ki = 5.66 ± 0.66 μM). These two compounds displayed competitive AR inhibition. MTT assay, a tetrazolium-based cell viability assay, was performed to determine the cytotoxic effects of compounds 1–18 on L929 mouse fibroblast (healthy) cell line. Compounds 1–18, except for compounds 10, 13, 14, 15 and 16, were found nontoxic against healthy cells. Besides, molecular docking studies were fundamentally in agreement with the biological data with regard to essential π-π interactions with Trp219, Phe122 and Trp111 residues in the active site of AR. Eventually, in vitro and in silico assays ascertain that in particular compounds 12 and 17 will attract a great notice as drug-like AR inhibitors for further investigations related to amelioration of long-term diabetic complications.