N‐substituted phthalazine sulfonamide derivatives as non‐classical aldose reductase inhibitors

Abstract

Aldose reductase (AR, AKR1B1; EC 1.1.1.21) is an aldo‐keto reductase that has been widely investigated as an enzyme crucially involved in the pathogenesis of several chronic complications, including nephropathy, neuropathy, retinopathy, and cataracts associated with diabetes mellitus. Although sulfonamides have been reported to possess many other biological activities, in continuation of our interest in designing and discovering potent inhibitors of AR, herein, we have evaluated the AR inhibitory potential of N‐substituted phthalazine sulfonamide derivatives 5a‐l. The biological studies revealed that all the derivatives show excellent activity against AR, with KI constants ranging from 67.73 to 495.20 nM. Among these agents, 4‐(6‐nitro‐1,4‐dioxo‐1,2,3,4‐tetrahydrophthalazine‐2‐carbonyl)benzenesulfonamide (5e) and 1,4‐dioxo‐3‐(4‐sulfamoylbenzoyl)‐1,2,3,4‐tetrahydrophthalazine‐6‐carboxylic acid (5f) showed prominent inhibitory activity with KI values of 67.73 and 148.20 nM, respectively, vs AR and were found to be more potent than epalrestat (KI = 852.50 nM), the only AR inhibitor currently used in the therapy. Moreover, molecular docking studies were also performed to rationalize binding site interactions of these sulfonamides (5a‐l) with the target enzyme AR. According to ADME‐Tox, predicts were also determined that these derivatives be ARIs displaying suitable drug‐like properties. The sulfonamides identified in this study may be used to develop lead therapeutic agents inhibiting diabetic complications.

Investigation of The Effect of Acylthiourea Derivatives on Diabetes‐Associated Enzymes

“…It has therefore attracted much attention to preventing polyol buildup by inhibiting AR to prevent retinopathy and other diabetes‐related ocular disease [58,59] . Given the critical role the AR enzyme plays in the polyol pathway and the metabolic changes associated with diabetes, its suppression is more important [60,61] . Therefore, a more profound knowledge of the study of bifunctional and acylthiourea derivatives polyol pathways enzymes inhibitory actions is necessary and would significantly improve the management of diabetes and its consequences.…”

In Vitro Inhibitory Activity and Molecular Docking Study of Selected Natural Phenolic Compounds as AR and SDH Inhibitors**

“…In silico studies were conducted employing Small‐Molecule Drug Discovery Suite 2022‐2 for Mac (Schrödinger, LLC, NY, USA), including the Maestro V13, [86] QikProp V7, [87] Protein Preparation Wizard, [88] SiteMap, [89] Receptor Grid Generation, [90] LigPrep, [91] Ligand Docking, [92] and Prime MM‐GBSA V3 [93] tools as previously reported [94,95] . Crystal structures of polyol pathway enzymes, AR (PDB ID: 4JIR; Resolution: 2.00 Å; Species: Homo sapiens) [96] and SDH (PDB ID: 1PL6; Resolution: 2.00 Å; Species: Homo sapiens) [97] were downloaded from Protein Data Bank [98] .…”

The effect of brimonidine and proparacaine on metabolic enzymes: Glucose‐6‐phosphate dehydrogenase, 6‐phosphogluconate dehydrogenase, and glutathione reductase

“…Molecular docking study was performed by tools [53] (i.e., Maestro, Protein Preparation Wizard, LigPrep, and Receptor Grid Generation) in the Schrödinger Suite 2020–2 for Mac. The 3D crystal structures of ligand‐bound NAP (PDB ID: 6E08 for G6PD) [54] and 3PG (PDB ID: 4GWK for 6PGD) [55] were retrieved from the Protein Data Bank [56] and were prepared by the Protein Preparation Wizard [57]. 3D ligand structures of brimonidine and proparacaine were sketched by ChemDraw [58] version 19.1 for Mac (PerkinElmer, Waltham, MA, USA).…”