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Open AccessArticle

Design, Synthesis and Investigation of the Potential Anti-Inflammatory Activity of 7-O-Amide Hesperetin Derivatives

by Yilong Zhang 1,2,3,†, Yan Zheng 1,2,3,†, Wen Shi 1,2,3, Yahui Guo 1,2, Tao Xu 1,2,3, Zeng Li 1,2,3, Cheng Huang 1,2,3,* and Jun Li 1,2,3,*
1
The Key Laboratory of Major Autoimmune Diseases, Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China
2
The Key laboratory of Anti-Inflammatory Immune Medicines, Ministry of Education, Hefei 230032, China
3
Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei 230032, China
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this paper.
Molecules 2019, 24(20), 3663; https://doi.org/10.3390/molecules24203663
Received: 14 August 2019 / Revised: 8 September 2019 / Accepted: 1 October 2019 / Published: 11 October 2019
(This article belongs to the Section Medicinal Chemistry)
To develop new anti-inflammatory agents, a series of 7-O-amide hesperetin derivatives was designed, synthesized and evaluated for anti-inflammatory activity using RAW264.7 cells. All compounds showed inhibitory effect on LPS-induced NO production. Among them, 7-O-(2-(Propylamino)-2-oxoethyl)hesperetin (4d) and 7-O-(2-(Cyclopentylamino)-2-oxoethyl)hesperetin (4k) with hydrophobic side chains exhibited the most potent NO inhibitory activity (IC50 = 19.32 and 16.63 μM, respectively), showing stronger inhibitory effect on the production of pro- inflammatory cytokines tumor necrosis factor (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) than indomethacin and celecoxib at 10 μM. The structure-activity relationships (SARs) suggested that the 7-O-amide unit was buried in a medium-sized hydrophobic cavity of the bound receptor. Furthermore, compound 4d could also significantly suppress the expression of inducible nitric oxide synthase enzymes (iNOS) and cyclooxygenase-2 (COX-2), through the nuclear factor-kappa B (NF-κB) signaling pathway. View Full-Text
Keywords: hesperetin derivatives; synthesis; inflammatory; NF-κB; structure-activity relationships. hesperetin derivatives; synthesis; inflammatory; NF-κB; structure-activity relationships.
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Zhang, Y.; Zheng, Y.; Shi, W.; Guo, Y.; Xu, T.; Li, Z.; Huang, C.; Li, J. Design, Synthesis and Investigation of the Potential Anti-Inflammatory Activity of 7-O-Amide Hesperetin Derivatives. Molecules 2019, 24, 3663.

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