当前位置： SCI文献检索 > EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > Indolyl-isoxazolidines attenuate LPS-stimulated pro-inflammatory cytokines and increase survival in a mouse model of sepsis: Identification of potent lead.

Indolyl-isoxazolidines attenuate LPS-stimulated pro-inflammatory cytokines and increase survival in a mouse model of sepsis: Identification of potent lead.

Abstract：

:A library of indolyl-isoxazolidines (6-9) has been synthesized by regio- and stereoselective microwave irradiated 1,3-dipolar cycloadditions of C-(3-indolyl)-N-phenylnitrone (2') with variedly substituted dipolarophiles (3'-5') and screened for their anti-inflammatory activities through inhibition of pro-inflammatory cytokines such as TNF-α and IL-6. Amongst the evaluated compounds (6-9), bicyclic isoxazolidine (9a) was found to exhibit significant inhibitory potential against LPS induced human IL-6 and TNF-α in THP-1 cells. Compound 9a was further assessed for in vivo analgesic and anti-inflammatory activities via acetic acid induced writhing and carrageenan induced paw edema models in mice, respectively. The results showed that compound possesses potent anti-inflammatory-analgesic activity comparable to indomethacin and did not show toxicity up to a 2000 mg kg-1 dose as evidenced by histopathological studies. Consequently, the most active compound 9a was also evaluated against LPS-induced septic death and exhibited a significant protection in in vivo mouse model. Taken all together, the results suggest that the compound 9a is able to attenuate pro-inflammatory cytokines such as IL-6 and TNF-α; accelerate resolution of inflammation, and also increased survival rate of septic mice. Therefore, these "lead" isoxazolidines can be used as promising candidate for further analgesic/anti-inflammatory drug design and development.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Singh G,Singh G,Bhatti R,Gupta M,Kumar A,Sharma A,Singh Ishar MP

doi

10.1016/j.ejmech.2018.04.004

subject

Has Abstract

pub_date

2018-06-10 00:00:00

pages

56-64

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(18)30331-3

journal_volume

153

pub_type

杂志文章

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