Development of Novel Indole-Based Bifunctional Aldose Reductase Inhibitors/Antioxidants as Promising Drugs for the Treatment of Diabetic Complications

Aldose reductase (AR, ALR2), the first enzyme of the polyol pathway, is implicated in the pathophysiology of diabetic complications. Aldose reductase inhibitors (ARIs) thus present a promising therapeutic approach to treat a wide array of diabetic complications. Moreover, a therapeutic potential of ARIs in the treatment of chronic inflammation-related pathologies and several genetic metabolic disorders has been recently indicated. Substituted indoles are an interesting group of compounds with a plethora of biological activities. This article reviews a series of indole-based bifunctional aldose reductase inhibitors/antioxidants (ARIs/AOs) developed during recent years. Experimental results obtained in in vitro, ex vivo, and in vivo models of diabetic complications are presented. Structure–activity relationships with respect to carboxymethyl pharmacophore regioisomerization and core scaffold modification are discussed along with the criteria of ‘drug-likeness”. Novel promising structures of putative multifunctional ARIs/AOs are designed.

Isatin Derivatives as a New Class of Aldose Reductase Inhibitors With Antioxidant Activity

In this work, isatin was employed as the scaffold to design aldose reductase inhibitors with antioxidant activity. Most of the isatin derivatives were proved to be excellent in the inhibition of aldose reductase (ALR2) with IC 50 values at submicromolar level, and (E)-2-(5-(4-methoxystyryl)-2,3-dioxoindolin-1-yl) acetic acid (9g) was identified as the most effective with an IC 50 value of 0.015 μM. Moreover, compounds 9a-h with styryl side chains at the C5 position of isatin showed potent antioxidant activity. Particularly, the phenolic compound 9h demonstrated similar antioxidant activity with the well-known antioxidant Trolox. Structure-activity relationship and molecular docking studies showed that the acetic acid group at N1 and C5 p-hydroxystyryl side chain were the key structures to increase the aldose reductase inhibitory activity and antioxidant activity.

In Silico Screening of Sesquiterpene Lactones as Aldose Reductase Inhibitors

Aldose reductase, a key enzyme of the polyol pathway catalyses NADPH-dependent reduction of glucose to sorbitol. Increased activity of this enzyme is considered a major factor contributing to the development of diabetic complications hence could be an important target in the treatment of these complications. In this work, a database of sesquiterpenes was prepared and screened for their drug-like properties based on the Lipinski’s rule of 5. The co-crystallised structure of aldose reductase was obtained from the Protein Databank and prepared for docking. In silico docking experiments was performed on Autodock tools using 198 sesquiterpene lactones that passed screening, and compounds with the lowest binding energy and favourable binding interactions were selected for molecular docking simulation. Six of the best ranking compounds selected had binding energies ranging from–11.96 Kcal/mol to -9.45 Kcal/mol and were comparable to the energy of the standard inhibitor Idd594 used in the study. They also show good complementarity in their binding to the residues of the binding pocket. The results suggest that dehydrooopodin (1), 11(S),13-dihydrolactucopicrin (2), and Chrysanin (3) offered potential inhibitory activities toward aldose reductase and may serve as lead compounds for in vivo validation as aldose reductase inhibitors. Keywords: Sesquiterpene lactones, Aldose reductase, Binding energy, Molecular docking, Autodock