Novel phthalide derivatives: Synthesis and anti-inflammatory activity in vitro and in vivo

  • Eur J Med Chem. 2020 Nov 15;206:112722. doi: 10.1016/j.ejmech.2020.112722.
Liu Zeng Chen  1 ,  Jing Wu  1 ,  Kang Li  1 ,  Qian Qian Wu  1 ,  Rui Chen  1 ,  Xin Hua Liu  2 ,  Ban Feng Ruan  3
Affiliations
  • 1. School of Pharmacy, Anhui Medical University, Hefei, 230032, PR China.
  • 2. School of Pharmacy, Anhui Medical University, Hefei, 230032, PR China. Electronic address: [email protected].
  • 3. Key Lab of Biofabrication of Anhui Higher Education, Hefei University, Hefei, 230601, PR China. Electronic address: [email protected].
PMID: 32823004 DOI: 10.1016/j.ejmech.2020.112722
Abstract

Phthalide is a promising chemical scaffold and has been proved to show potent anti-inflammatory efficacy. In this study, three series, total of 31 novel phthalide derivatives were designed and synthesized, their anti-inflammatory activities were screened in vitro and in vivo. The anti-inflammatory activity of all the compounds were screened on LPS induced NO production to evaluating their inhibitory effects. Structure-activity relationship has been concluded, and finally 3-((4-((4-fluorobenzyl)oxy)phenyl)(hydroxy)methyl)-5,7-dimethoxyisobenzofuran-1 (3H)-one (compound 9o) was found to be the active one with low toxicity, which showed 95.23% inhibitory rate at 10 μM with IC50 value of 0.76 μM against LPS-induced NO over expression. Preliminary mechanism studies indicated that compound 9o activated Nrf2/HO-1 signaling pathway via accumulation ROS and blocks the NF-κB/MAPK signaling pathway. The in vivo anti-inflammatory activity shown that compound 9o had obvious therapeutic effect against the adjuvant-induced rat arthritis model.

Keywords
Anti-inflammatory; Design; Phthalide derivatives; Synthesis.
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