Diclofenac and eugenol hybrid with enhanced anti-inflammatory activity through activating HO-1 and inhibiting NF-κB pathway in vitro and in vivo

  • Eur J Med Chem. 2023 Nov 5;259:115669. doi: 10.1016/j.ejmech.2023.115669.
Wei Wang  1 ,  Shou-Kai Wang  1 ,  Qi Wang  1 ,  Zhe Zhang  1 ,  Bo Li  1 ,  Zi-Dan Zhou  1 ,  Jian-Feng Zhang  1 ,  Chao Lin  1 ,  Ting-Xiao Chen  1 ,  Zhen Jin  1 ,  You-Zhi Tang  2
Affiliations
  • 1. Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China; Guangdong Laboratory for Lingnan Modern Agriculture, 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; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, 510642, China. Electronic address: [email protected].
PMID: 37517204 DOI: 10.1016/j.ejmech.2023.115669
Abstract

A series of diclofenac hybrid molecules were synthesized and evaluated for their NO-inhibitory ability in LPS-induced RAW 264.7 macrophage cells. Among them, compound 1 showed the highest NO-inhibitory ability (approximately 66%) and no significant cytotoxicity. Compound 1 exhibited superior NF-κB-inhibitory ability compared to diclofenac through the activation of Nrf2/HO-1 signaling pathway in RAW 264.7. 20 mg/kg compound 1 resulted in remarkable colitis improvement in dextran sulfate sodium (DSS)-induced mice model by up-regulating HO-1 and down-regulating phosphorylation level of NF-κB p65. Moreover, 50 mg/kg dose of compound 1 showed a lower ulcerogenic potential compared to diclofenac in rats. The diclofenac-eugenol hybrid (compound 1) may serve as a novel anti-inflammatory agent based on its role in inhibiting the NF-κB signaling pathway and activating HO-1 expression with no toxicity in vitro and in vivo.

Keywords
Anti-inflammation; Diclofenac-eugenol hybrid; Gastric ulcer; Heme oxygenase-1; NF-κB p65; Ulcerative colitis.
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