Development of non-acidic 4-methylbenzenesulfonate-based aldose reductase inhibitors; Design, Synthesis, Biological evaluation and in-silicostudies

• Published in: Bioorganic chemistry 2024-10, Vol.151, p.107666, Article 107666
• Main Authors: Said, Gehad E., Metwally, Heba M., Abdel-Latif, Ehab, Elnagar, Mohamed R., Ibrahim, Hany S., Ibrahim, Marwa A.
• Format: Article
• Language: English
• Subjects: Aldehyde Reductase - antagonists & inhibitors; Aldehyde Reductase - metabolism; Aldose reductase enzyme; Animals; Benzenesulfonates - chemical synthesis; Benzenesulfonates - chemistry; Benzenesulfonates - pharmacology; Diabetes; Diabetes Mellitus, Experimental - chemically induced; Diabetes Mellitus, Experimental - drug therapy; Dose-Response Relationship, Drug; Drug Design; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Hypoglycemic Agents - chemical synthesis; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - pharmacology; Male; Mice; Molecular Docking Simulation; Molecular Structure; Phenyl sulfonate; Simulation studies; Structure-Activity Relationship; Thiazole
• ISSN: 0045-2068; 1090-2120; 1090-2120
• DOI: 10.1016/j.bioorg.2024.107666

[Display omitted] •A series of non-acidic 4-methylbenzenesulfonate-based ALR2 inhibitors were designed.•Molecular docking was utilized for virtual screening to identify suitable candidates.•Seventeen new compounds were chosen for synthesis and biological evaluation.•In vivo studies were conducted for the most active compound 10a to assess the efficacy. Design and virtual screening of a set of non-acidic 4-methyl-4-phenyl-benzenesulfonate-based aldose reductase 2 inhibitors had been developed followed by chemical synthesis. Based on the results, the synthesized compounds 2, 4a,b, 7a-c, 9a-c, 10a-c, 11b,c and 14a-c inhibited the ALR2 enzymatic activity in a submicromolar range (99.29–417 nM) and among them, the derivatives 2, 9b, 10a and 14b were able to inhibit ALR2 by IC50 of 160.40, 165.20, 99.29 and 120.6 nM, respectively. Moreover, kinetic analyses using Lineweaver–Burk plot revealed that the most active candidate 10a inhibited ALR2 potently via a non-competitive mechanism. In vivo studies showed that 10 mg/kg of compound 10a significantly lowered blood glucose levels in alloxan-induced diabetic mice by 46.10 %. Moreover, compound 10a showed no toxicity up to a concentration of 50 mg/kg and had no adverse effects on liver and kidney functions. It significantly increased levels of GSH and SOD while decreasing MDA levels, thereby mitigating oxidative stress associated with diabetes and potentially attenuating diabetic complications. Furthermore, the binding mode of compound 10a was confirmed through MD simulation. Noteworthy, compounds 2 and 14b showed moderate antimicrobial activity against the two fungi Aspergillus fumigatus and Aspergillus niger. Finally, we report the thiazole derivative 10a as a new promising non-acidic aldose reductase inhibitor that may be beneficial in treating diabetic complications.