Aldose reductase converts glucose to sorbitol in the polyol pathway. It is an important enzyme to prevent diabetic complications. In this study, we studied the inhibitory effects of bromophenol derivatives on aldose reductase (AR), α-glucosidase, and α-amylase enzymes. In the bromophenols series, compound 1f showed the maximum inhibition effect against AR with a K i value of 0.05 ± 0.01 μM, while compound 1d showed the lowest inhibition effect against AR with a K i value of 1.13 ± 0.99 μM. In addition, α-amylase from porcine pancreas and α-glucosidase from Saccharomyces cerevisiae were used as enzymes. In this study, all compounds were tested for the inhibition of the α-glucosidase enzyme and demonstrated efficient inhibition profiles with K i values in the range of 43.62 ± 5.28 to 144.37 ± 16.37 nM against α-glucosidase.Additionally, these compounds were tested against the α-amylase enzyme, which determined an effective inhibition profile with IC 50 values in the range of 9.63-91.47 nM. These compounds can be selective inhibitors of AR, α-glucosidase, and α-amylase enzymes as antidiabetic agents. K E Y W O R D S α-amylase, α-glucosidase, aldose reductase, bromophenol, enzyme inhibition Arch Pharm Chem Life Sci. 2018;351:e1800263.wileyonlinelibrary.com/journal/ardp AR activity was assayed according to previous studies and it measured the decrease of NADPH at 340 nm spectrophotometrically. [45,46] | Enzyme purificationEnzyme purification procedures were done according to previous studies. [47,48] | Protein determinationThe protein concentration was measured according to the Bradford method by using with Coomassie Brilliant Blue G-250. [49] 4.2.7 | SDS polyacrylamide gel electrophoresisAfter the enzyme purification, the purity degree of the enzyme was controlled according to Laemmli's method [50] by using 3-8% batch sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The electrophoresis process was carried out according to our previous papers. [51][52][53] The gel was stained with the silver staining method and photographed after staining. CONFLICT OF INTERESTThe authors declare that there are no conflicts of interest. ORCIDParham Taslimi

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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.

Carbonic anhydrase (CA) has a key role in respiration, carbon dioxide and bicarbonate transport. Acetylcholinesterase (AChE) is a serine hydrolase and mostly abundant at neuromuscular junctions and cholinergic brain synapses. Inhibitors of these enzymes could aid in illuminating the role in disease processes. In this study, we separately purified CA I and CA II from human erythrocytes. The purity of the enzymes was showed by SDS-PAGE analysis. We also investigated the inhibition of seven chalcones toward hCA I, hCA II, and AChE. The chalcones were effective inhibitors of the cytosolic CA isoforms (hCA I and hCA II) and AChE with K values in the range of 1.83-7.05 μM for hCA I, 0.59-5.50 μM for hCA II, and 0.61-86.11 μM for AChE. All compounds were showed competitive inhibition aganist both enzymes. These compounds can be a potent inhibitor of AChE enzyme and both cytosolic CA isoenzymes which are commonly used in the pharmaceutical and medical industries.