Determination of the inhibition profiles of pyrazolyl-thiazole derivatives against aldose reductase and α-glycosidase and molecular docking studies

Abstract

Aldose reductase (AR) is the first and rate-limiting enzyme of the polyol pathway, which converts glucose to sorbitol in an NADPH-dependent reaction. α-Glycosidase breaks down starch and disaccharides to glucose. Hence, inhibition of these enzymes can be regarded a considerable approach in the treatment of diabetic complications. AR was purified from sheep liver using simple chromatographic methods. The inhibitory effects of pyrazolyl-thiazoles ((3aR,4S,7R,7aS)-2-(4-{1-[4-(4-bromophenyl)thiazol-2-yl]-5-(aryl)-4,5-dihydro-1H-pyrazol-3-yl}phenyl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione derivatives; 3a-i) on AR and α-glycosidase enzymes were investigated. All compounds showed a good inhibitory action against AR and α-glycosidase. Among these compounds, compound 3d exhibited the best inhibition profiles against AR, with a K_i value of 7.09 ± 0.19 µM, whereas compound 3e showed the lowest inhibition effects, with a K_i value of 21.89 ± 1.87 µM. Also, all compounds showed efficient inhibition profiles against α-glycosidase, with K_i values in the range of 0.43 ± 0.06 to 2.30 ± 0.48 µM, whereas the K_i value of acarbose was 12.60 ± 0.78 µM. Lastly, molecular modeling approaches were implemented to predict the binding affinities of compounds against AR and α-glycosidase. In addition, the ADME analysis of the molecules was performed.

Keywords: aldose reductase; enzyme inhibition; molecular docking; pyrazolyl-thiazole; α-glycosidase.