Design, synthesis, and evaluation of carboxylic acid-substituted celecoxib isosteres as potential anti-inflammatory agents

  • Eur J Med Chem. 2025 Mar 15:286:117286. doi: 10.1016/j.ejmech.2025.117286.
Zi-Jie Song  1 ,  Xiao-Fei Wu  1 ,  Zhi-Ya Zhou  1 ,  Jing-Jing Zhang  1 ,  Yan-Yan Pan  2 ,  Xue Dong  1 ,  Xuan Pang  1 ,  Ya-Ping Xie  1 ,  Juan Sun  3 ,  Yu Zhang  4 ,  Jie Qin  5
Affiliations
  • 1. School of Life Sciences and Medicine, Shandong University of Technology, Zibo, 255049, PR China.
  • 2. Qilu Medical University, Zibo, 255300, PR China.
  • 3. School of Biological & Chemical Engineering, Zhejiang University of Science and Technology, Hangzhou, 310023, PR China. Electronic address: [email protected].
  • 4. School of Life Sciences and Medicine, Shandong University of Technology, Zibo, 255049, PR China. Electronic address: [email protected].
  • 5. School of Life Sciences and Medicine, Shandong University of Technology, Zibo, 255049, PR China. Electronic address: [email protected].
PMID: 39854941 DOI: 10.1016/j.ejmech.2025.117286
Abstract

A library comprising twenty-four isosteric derivatives of celecoxib substituted with carboxylic acid (labeled as 5a-5x), was synthesized and characterized through 1H NMR, 13C NMR, HRMS, and elemental analysis. Molecular docking studies revealed that all compounds successfully docked into the binding pocket of COX-2, and the introduction of carboxyl group enhances the interaction between the derivatives and COX-2. The compounds were further evaluated for cell toxicity, and in vitro anti-inflammatory activity. Notably, compound 5l exhibited significant inhibition of both COX-2 and NO release in vitro in comparison to the standard compound, displaying the highest selectivity towards the COX-2 enzyme (SI = 295.9) in comparison to celecoxib (SI = 261.3). 5l also exhibited the most potent anti-inflammatory activity and safety (ulcer index = 5.2) in vivo comparable to celecoxib at the same concentration. Through the molecular modeling and dynamics analysis, it was observed that compound 5l effectively stabilized within the active binding site of COX-2 through strong hydrogen bond interactions, and through the ADMET studies investigated the physiochemical properties and drug-likeliness behavior of compound 5l. In conclusion, compound 5l demonstrated to be a potential selective COX-2 anti-inflammatory candidate with reduced gastrointestinal risks.

Keywords
Anti-inflammatory activity; Carboxylic acid; Celecoxib isosteric derivative; Molecular docking; Selective COX-2 inhibitor.
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