Design, synthesis, and biological evaluation of novel Spirosulfamethoxazole-1,3,4-thiadiazole-2-carboxamide derivatives as dual COX-2/5-LOX inhibitors with promising anti-inflammatory and anti-osteoarthritic potential

  • Bioorg Chem. 2026 Sep 5:179:109986. doi: 10.1016/j.bioorg.2026.109986.
Ahmed M El-Saghier  1 ,  Fatma A M Atia  2 ,  Souhaila S Enaili  3 ,  Mounir A A Mohamed  1 ,  Ali M A Shapep  1 ,  Hanan Salah  1 ,  Noura Roushdy  4 ,  Amany M Hamed  1
Affiliations
  • 1. Chemistry Department, Faculty of Science, Sohag University, 82524 Sohag, Egypt.
  • 2. Department of Economics, College of Business, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, 11432, Riyadh, Saudi Arabia.
  • 3. Pharmaceutical Chemistry Department, Faculty of Pharmacy, University of Zawia, Al Zawia 16418, Libya.
  • 4. Department of Insurance and Risk Management, College of Business, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 11432, Riyadh, Saudi Arabia.
PMID: 42160831 DOI: 10.1016/j.bioorg.2026.109986
Abstract

Background: Inflammation and oxidative stress play pivotal roles in the pathogenesis of osteoarthritis (OA) and related degenerative disorders. In this study, a novel series of Spirosulfamethoxazole-1,3,4-thiadiazole-2-carboxamide derivatives was synthesized and systematically evaluated for their in vitro and in vivo anti-inflammatory and chondroprotective activities.

Methods: The in vitro anti-inflammatory activity was assessed using BSA protein denaturation and RBC membrane stabilization assays. The compounds were further evaluated for COX-1, COX-2, and 5-LOX inhibitory activity using celecoxib and montelukast as reference drugs. The most active derivatives (9-12) were tested in mono-iodoacetate (MIA)-induced osteoarthritis in rats to determine their in vivo efficacy. Serum levels of TNF-α, IL-1β, IL-6, CRP, COMP, MMP-3, and CTX-II were quantified to assess inflammation and cartilage degradation.

Results: All synthesized compounds exhibited potent in vitro anti-inflammatory activities, particularly Compounds 9 and 10, which showed dual inhibition of COX-2 and 5-LOX Enzymes. In the in vivo MIA model, treatment with Compounds (9-12) significantly reduced paw edema and improved weight-bearing function (p < 0.001), with Compound 9 demonstrating superior efficacy to celecoxib. Biochemical analysis revealed marked decreases in inflammatory cytokines and cartilage degradation markers, confirming strong anti-inflammatory and potential chondroprotective effects.

Conclusion: The newly synthesized Spirosulfamethoxazole-1,3,4-thiadiazole-2-carboxamide derivatives, especially Compound 9, represent promising dual COX/LOX inhibitors with potent in vivo anti-osteoarthritic and potential chondroprotective activities. These findings suggest their potential as safe and effective candidates for managing osteoarthritis and related inflammatory disorders.

Keywords
Anti-inflammatory activity; Anti-osteoarthritis; COX-2/5-LOX dual inhibition; Spirosulfamethoxazole–1,3,4-thiadiazole–2-carboxamide derivatives.
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