In vitro studies of potent aldose reductase inhibitors: Synthesis, characterization, biological evaluation and docking analysis of rhodanine-3-hippuric acid derivatives

• Published in: Bioorganic chemistry 2020-04, Vol.97, p.103640-103640, Article 103640
• Main Authors: Celestina, Stephen Kumar, Sundaram, Kaveri, Ravi, Subban
• Format: Article
• Language: English
• Subjects: Aldehyde Reductase - antagonists & inhibitors; Aldehyde Reductase - chemistry; Aldehyde Reductase - metabolism; Aldose reductase; Drug Design; Drug Discovery; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Hippurates - chemistry; Hippurates - pharmacology; Humans; Molecular docking; Molecular Docking Simulation; Pyrazole pharmacophore; Rhodanine - analogs & derivatives; Rhodanine - pharmacology; Rhodanine-3-hippuric acid; Structure-Activity Relationship
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2020.103640

[Display omitted] •Novel rhodanine-3-hippuric acid derivatives were synthesized.•In vitro aldose reductase inhibitory activity was carried out for the synthesized compounds.•Compounds 6g and 6e are found to be more active and the IC50 values are 0.04 µM and 0.06 µM.•All the compounds are well occupied in the receptor cavity. Inhibitors of aldose reductase are rate-limiting enzymes and could play a key role to prevent the complications of diabetes. In our attempt to develop novel inhibitors of aldose reductase, the derivatives of rhodanine-3-hippuric acid-pyrazole hybrid were synthesized and characterised by spectral data. The biological studies reveal that all the compounds show an excellent activity against ALR2 with IC50 values ranging from 0.04 to 1.36 µM. Among these the synthesised compounds 6a-m, 6g and 6e showed specific inhibitory activity with IC50 values of 0.04 and 0.06 µM respectively against ALR2 and found to be more potent than epalrestat (IC50 = 0.87 μM), the only aldose reductase inhibitor currently used in the therapy. Molecular docking analysis using the AR-NADP+ complex as a receptor was performed with all the synthesized compounds. All the compounds exhibit a well-defined binding mode within the AR active site, similarly to previous described AR inhibitors, with the anion head group bound to the catalytic center, blocking thus its activity. By forming hydrogen bonds with Tyr48 and His110 of the protein from ALR2 (PDB ID: 2FZD), the compounds 6g and 6e interrupt the proton donation mechanism, which is necessary for the catalytic activity of ALR2.