Premium
Design, synthesis and anti‐inflammatory study of novel N‐heterocyclic substituted Aloe‐emodin derivatives
Author(s) -
Qiu Xiang,
Pei Heying,
Ni Hengfan,
Su Zhengying,
Li Yong,
Yang Zhuang,
Dou Caixia,
Chen Lijuan,
Wan Li
Publication year - 2021
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13788
Subject(s) - chemistry , aloe emodin , emodin , in vivo , bioavailability , pharmacology , nitric oxide , piperazine , toxicity , anti inflammatory , in vitro , pharmacokinetics , stereochemistry , biochemistry , medicine , biology , organic chemistry , microbiology and biotechnology
A novel series of Aloe‐emodin derivatives containing N‐heterocyclic moieties was designed and synthesized. The structure‐activity relationship studies (SARs) indicated that the replacement of hydroxyethyl and benzhydryl piperazine groups could improve efficacy. Compounds 12r and 14a – 14c exhibited a higher inhibitory effect on LPS‐induced nitric oxide (NO) production in RAW264.7 macrophages than Aloe‐emodin did. Among them, 12r showed the most potent inhibition with an IC 50 value of 5.66 ± 0.47 μM. Further toxicity and pharmacokinetic studies were carried out and 12r was found to be the most active structure with low toxicity risk and good metabolic properties. It could also decrease the levels of IL‐1β, TNF‐α, PGE 2 and inhibit the activation of nuclear factor‐κB signalling pathway. Importantly, 12r showed oral bioavailability of up to 55.16% and attenuated the inflammatory symptoms in an ulcerative colitis mouse model in vivo. These results indicate that 12r is suitable for development as an anti‐inflammatory agent.