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

TÜRKEŞ C., Arslan M., Demir Y., Çoçaj L., Nixha A. R., BEYDEMİR Ş.

Journal of Molecular Recognition, vol.35, no.12, 2022 (SCI-Expanded) identifier identifier

  • Publication Type: Article / Article
  • Volume: 35 Issue: 12
  • Publication Date: 2022
  • Doi Number: 10.1002/jmr.2991
  • Journal Name: Journal of Molecular Recognition
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, Aerospace Database, BIOSIS, Biotechnology Research Abstracts, Chemical Abstracts Core, Communication Abstracts, EMBASE, MEDLINE, Metadex, Civil Engineering Abstracts
  • Keywords: aldose reductase, in silico study, polyol pathway
  • Bilecik Şeyh Edebali University Affiliated: No

Abstract

© 2022 John Wiley & Sons Ltd.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.