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

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

  • Bioorg Chem. 2024 Oct:151:107666. doi: 10.1016/j.bioorg.2024.107666.
Gehad E Said 1,  Heba M Metwally 2,  Ehab Abdel-Latif 3,  Mohamed R Elnagar 4,  Hany S Ibrahim 5,  Marwa A Ibrahim 6
Affiliations

Affiliations

  • 1 Department of Chemistry, Faculty of Science, Mansoura University, 35516 Mansoura, Egypt. Electronic address: gehadsaid@mans.edu.eg.
  • 2 Department of Chemistry, Faculty of Science, Mansoura University, 35516 Mansoura, Egypt. Electronic address: hebama@mans.edu.eg.
  • 3 Department of Chemistry, Faculty of Science, Mansoura University, 35516 Mansoura, Egypt.
  • 4 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt; Department of Pharmacology, College of Pharmacy, The Islamic University, Najaf, 54001, Iraq.
  • 5 Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, 06120 Halle (Saale), Germany; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo 11829, Egypt.
  • 6 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt. Electronic address: marwa.abdelaziz@pharma.cu.edu.eg.
PMID: 39067420 DOI: 10.1016/j.bioorg.2024.107666
Abstract

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.

Keywords

Aldose reductase enzyme; Diabetes; Phenyl sulfonate; Simulation studies; Thiazole.

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