2. Academic Validation
  3. Structural modification based on the diclofenac scaffold: Achieving reduced colitis side effects through COX-2/NLRP3 selective inhibition

Structural modification based on the diclofenac scaffold: Achieving reduced colitis side effects through COX-2/NLRP3 selective inhibition

  • Eur J Med Chem. 2024 Feb 17:268:116257. doi: 10.1016/j.ejmech.2024.116257.
Zhiran Ju 1,  Junde Xu 1,  Keshuang Tang 1,  Fener Chen 2
Affiliations

Affiliations

  • 1 Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, 310014, China.
  • 2 Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, 310014, China; Engineering Center of Catalysis and Synthesis for Chiral Molecules, Fudan University, Shanghai, 200433, China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai, 200433, China. Electronic address: [email protected].
PMID: 38382390 DOI: 10.1016/j.ejmech.2024.116257
Abstract

COX-2/NLPR3-targeted therapy might be beneficial for the inflammation diseases. To discover novel anti-inflammatory compounds with favorable safety profiles, three new series of non-carboxylic diclofenac analogues bearing various ring systems, such as oxadiazoles 4a-4w, triazoles 6a-6m, and cyclic imides 7a and 7b, were synthesized. The synthesized analogues were evaluated for their inhibitory activity against COX-2 Enzyme. Among them, compound 6k exhibited potent selective COX-2 inhibition (IC50 = 1.53 μM; selectivity ((IC50 (COX-1)/IC50(COX-2) = 17.19). Treatment with compound 6k effectively suppressed the NF-κB/NLRP3 signaling pathway, resulting in reduced expression of pro-inflammatory factors. The in vivo ulcerative colitis assay demonstrated that compound 6k significantly ameliorated histological damages and showed strong protection against DSS-induced acute colitis. The collected results indicated that compound 6k displays anti-inflammatory activity through COX-2/NLRP3 inhibition. Therefore, compound 6k represents a promising candidate for further development as a new lead compound with reduced colitis side effects.

Keywords

Anti-inflammatory; COX-2; Diclofenac; NLRP3; Ulcerative colitis.

Figures
Products