Hybrids of Benzenesulfonamide Oxadiazole Derivatives with Dual CA II and COX-2 Inhibitory Activity Demonstrating Antiglaucoma and Anti-inflammatory Action: Synthesis, In Silico Insights, and In Vitro and In Vivo Bioevaluation

  • J Med Chem. 2026 Jul 23;69(14):17243-17259. doi: 10.1021/acs.jmedchem.6c01117.
Manal Abdel Fattah Ezzat  1 ,  Emad M Seif  2 ,  Husam Nassar  3 ,  Alessandro Bonardi  4 ,  Marta Ferraroni  5 ,  Ahmed A Attia  6 ,  Yomna T T Khater  7 ,  Rabab Ahmed Rasheed  8 ,  Omnia A M Abd El-Ghafar  9 ,  Heba Abdelrasheed Allam  1 ,  Andrea Angeli  10 ,  Matthias Schmidt  3 ,  Claudiu T Supuran  4 ,  Hany S Ibrahim  3  11
Affiliations
  • 1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt.
  • 2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, October University for Modern Sciences and Arts University (MSA), Giza 12451, Egypt.
  • 3. Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, Halle (Saale) 06120, Germany.
  • 4. Department NEUROFARBA─Pharmaceutical and Nutraceutical Section, University of Firenze, Via Ugo Schiff 6, Sesto Fiorentino I-50019, Firenze, Italy.
  • 5. Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia 3-13, Sesto Fiorentino I-50019, Italy.
  • 6. Mansoura Ophthalmic Centre, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt.
  • 7. Medical Experimental Research Center, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt.
  • 8. Department of Medical Histology and Cell Biology, School of Medicine, Badya University, Giza 12573, Egypt.
  • 9. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Nahda University, Beni-Suef 62764, Egypt.
  • 10. NEUROFARBA Department, Sezione di Scienze Farmaceutiche, University of Florence, Via Ugo Schiff 6, Sesto Fiorentino 50019, Florence, Italy.
  • 11. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo 11829, Egypt.
PMID: 42387821 DOI: 10.1021/acs.jmedchem.6c01117
Abstract

In this study, new sulfonamide derivatives 5a-g and 10a-e were designed, synthesized, and biologically evaluated for their anti-inflammatory activity. In vitro COX inhibitory assays were performed, and among the synthesized compounds, 5b and 5d emerged as the most promising leads, combining COX-2 inhibition with remarkable selectivity (COX-2 IC50 = 0.13 and 0.05 μM, SI = 9.25 and 12.02, respectively) and hCA II inhibition (Ki = 39.1 nM and 62.6 nM, respectively) with a high selectivity index over hCA I (SI = 933.8 and 704.2, respectively). In vivo evaluations confirmed that compounds 5b and 5d (50 mg/kg) possess promising analgesic and anti-inflammatory effects, with rapid onset, sustained duration of action, and a reduced ulcerogenic liability, indicating an improved gastrointestinal safety profile. Additionally, 5b showed significant and sustained IOP-lowering effects in antiglaucoma animal models. Computational studies and X-ray crystallography were performed as a proof of concept.

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