Bridging the gap with amide linkers: rational design, synthesis, and multi-target evaluation of sulfonamide/acetamide-NSAID hybrids as dual COX-2/5-LOX inhibitors

  • Future Med Chem. 2026 Jan;18(2):131-148. doi: 10.1080/17568919.2025.2605716.
Triveena M Ramsis  1 ,  Shaimaa Hussein  2 ,  Moustafa S Abusaif  3  4 ,  Ahmed Ragab  3  5 ,  Yousry A Ammar  3 ,  Omaima Ali  6  7 ,  Arafa Musa  8 ,  Asmaa S Elzaitony  9 ,  Mona M Kamal  9 ,  Mohammad M Al-Sanea  10 ,  Eman A Fayed  11
Affiliations
  • 1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Sinai University, Ismailia, Egypt.
  • 2. Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Saudi Arabia.
  • 3. Department of Chemistry, Faculty of Science (Boys), Al-Azhar University, Nasr City, Egypt.
  • 4. Polymer Institute of the Slovak Academy of Sciences PSAS, Bratislava, Slovak Republic.
  • 5. Chemistry Department, Faculty of Science, Galala University, Suez, Egypt.
  • 6. Small Animal Clinical Sciences Department, College of Veterinary Medicine, University of Florida, Gainesville, USA.
  • 7. General Division for Biological Control and Research, Egyptian Drug Authority, Cairo, Egypt.
  • 8. Department of Pharmacognosy, College of Pharmacy, Jouf University, Sakaka, Saudi Arabia.
  • 9. Pharmacology and Toxicology Department, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt.
  • 10. Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Saudi Arabia.
  • 11. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt.
PMID: 41492228 DOI: 10.1080/17568919.2025.2605716
Abstract

Aim: Novel hybrids of ibuprofen and naproxen were designed as dual COX-2/5-LOX inhibitors to create safer anti-inflammatory drugs.

Materials and methods: The prodrugs were developed through a hybridization molecular approach; their potency against COX-1, COX-2, and 5-LOX was assessed, alongside measurements of PGE2 levels, NO scavenging, and mTOR and Nrf2 protein expression. Molecular docking was used to predict binding interactions.

Results: Hybrids 9 and 10 showed excellent COX-2 inhibition with IC50 values of 3.3 and 2.0 µM, respectively, and high selectivity indices (SI) of 20.7 and 17.2. Both hybrids also demonstrated substantial 5-LOX inhibition with IC50 values of 3.1 and 4.2 µM.

Conclusion: The new hybrids exhibit strong COX-2/5-LOX inhibition, suggesting their structural framework is crucial for developing safer anti-inflammatory drugs.

Keywords
COX-1/COX-2/5-LOX; NO scavenging capacity; NSAIDs; Naproxen; PGE2; adamantane; hybrids; ibuprofen; nrf2 and mTOR; sulfonamides.
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