Design, synthesis and evaluation of ursodeoxycholic acid-cinnamic acid hybrids as potential anti-inflammatory agents by inhibiting Akt/NF-κB and MAPK signaling pathways

A series of ursodeoxycholic acid (UDCA)-cinnamic acid hybrids were designed and synthesized. The anti-inflammatory activity of these derivatives was screened through evaluating their inhibitory effects of LPS-induced nitric oxide production in RAW264.7 macrophages. The preliminary structure-activity...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2023-11, Vol.260, p.115785, Article 115785
Main Authors: Li, Xiaoxue, Hu, Yue, He, Bingxin, Li, Lingyu, Tian, Yu, Xiao, Yingjie, Shang, Hai, Zou, Zhongmei
Format: Article
Language:English
Subjects:
Akt/NF-κB and MAPK signaling pathway
Anti-inflammatory
Hybrid
Mechanism
Ursodeoxycholic acid
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Summary:A series of ursodeoxycholic acid (UDCA)-cinnamic acid hybrids were designed and synthesized. The anti-inflammatory activity of these derivatives was screened through evaluating their inhibitory effects of LPS-induced nitric oxide production in RAW264.7 macrophages. The preliminary structure-activity relationship was concluded. Among them, 2m showed the best inhibitory activity against NO (IC50 = 7.70 μM) with no significant toxicity. Further study revealed that 2m significantly decreased the levels of TNF-α, IL-1β, IL-6 and PGE2, down-regulated the expression of iNOS and COX-2. Preliminary mechanism study indicated that the anti-inflammatory activity of 2m was related to the inhibition of the Akt/NF-κB and MAPK signaling pathway. Furthermore, 2m reduced inflammation by a mouse model of LPS-induced inflammatory disease in vivo. In brief, our findings indicated that 2m might serve as a new lead compound for further development of anti-inflammatory agents. [Display omitted] •Novel ursodeoxycholic acid (UDCA)-cinnamic acid hybrids were synthesized.•Compound 2m exhibited good NO inhibitory activity, with no obvious toxicity.•Compound 2m reduced the release of TNF-α, IL-1β, IL-6 and PGE2, and downregulated the expression levels of iNOS and COX-2.•Compound 2m exerted its anti-inflammatory activity by inhibiting the Akt/NF-κB and MAPK signaling pathways.•Compound 2m exhibited in vivo anti-inflammatory efficacy in a mouse model of endotoxemia.
ISSN:0223-5234
1768-3254
1768-3254
DOI:10.1016/j.ejmech.2023.115785