Discovery and optimization of ibuprofen derivatives as the NF-κB/iNOS pathway inhibitors for the treatment of ulcerative colitis

Chao Lin; Zhong-Sheng Li; Zhan-Wei Dong; Xiao-Yi Wu; Min Ye; Ke Li; Zhen Jin; Wei Wang; You-Zhi Tang

doi:10.1016/j.bioorg.2025.108506

Discovery and optimization of ibuprofen derivatives as the NF-κB/iNOS pathway inhibitors for the treatment of ulcerative colitis

Bioorg Chem. 2025 Jul 1:161:108506. doi: 10.1016/j.bioorg.2025.108506. Epub 2025 Apr 26.

Authors

Chao Lin¹, Zhong-Sheng Li¹, Zhan-Wei Dong¹, Xiao-Yi Wu¹, Min Ye¹, Ke Li¹, Zhen Jin¹, Wei Wang², You-Zhi Tang³

Affiliations

¹ Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China.
² Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China. Electronic address: wangwei123@scau.edu.cn.
³ Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China. Electronic address: youzhitang@scau.edu.cn.

PMID: 40311243
DOI: 10.1016/j.bioorg.2025.108506

Abstract

In this study, a series of novel ibuprofen (Ibu) hybrid molecules with aminothiazole heterocycles were designed, synthesized and evaluated for their anti-inflammatory potency in vitro and in vivo. Among all these derivatives, compounds 6 and 8 effectively inhibited the production of NO (with 87 %, 79 % NO-inhibitory rates, respectively) with minimal cytotoxic effect in RAW 264.7 macrophages. Anti-inflammatory mechanism studies revealed that representative compound 6 dose-dependently inhibited pro-inflammatory cytokines by blocking the activation of NF-κB signaling pathway in LPS stimulated RAW 264.7 macrophages. In vivo experiments showed that 10 mg/kg compound 6 had a good improvement effect in DSS-induced mouse acute colitis compared to Ibu. Our findings will provide new insights into the development of new drugs with anti-inflammatory functions.

Keywords: Aminothiazole heterocycles; Anti-inflammation; Ibuprofen; NF-κB; Ulcerative colitis.

MeSH terms

Animals
Anti-Inflammatory Agents, Non-Steroidal* / chemical synthesis
Anti-Inflammatory Agents, Non-Steroidal* / chemistry
Anti-Inflammatory Agents, Non-Steroidal* / pharmacology
Anti-Inflammatory Agents, Non-Steroidal* / therapeutic use
Colitis, Ulcerative* / chemically induced
Colitis, Ulcerative* / drug therapy
Colitis, Ulcerative* / metabolism
Colitis, Ulcerative* / pathology
Dextran Sulfate
Dose-Response Relationship, Drug
Drug Discovery*
Ibuprofen* / analogs & derivatives
Ibuprofen* / chemical synthesis
Ibuprofen* / chemistry
Ibuprofen* / pharmacology
Ibuprofen* / therapeutic use
Lipopolysaccharides / antagonists & inhibitors
Lipopolysaccharides / pharmacology
Male
Mice
Molecular Structure
NF-kappa B* / antagonists & inhibitors
NF-kappa B* / metabolism
Nitric Oxide Synthase Type II* / antagonists & inhibitors
Nitric Oxide Synthase Type II* / metabolism
RAW 264.7 Cells
Signal Transduction / drug effects
Structure-Activity Relationship

Substances

NF-kappa B
Ibuprofen
Anti-Inflammatory Agents, Non-Steroidal
Nitric Oxide Synthase Type II
Lipopolysaccharides
Dextran Sulfate