Design, synthesis and anti‐inflammatory study of novel N‐heterocyclic substituted Aloe‐emodin derivatives. (22nd September 2020)

• Record Type: Journal Article
• Authors: Qiu, Xiang; Pei, Heying; Ni, Hengfan; Su, Zhengying; Li, Yong; Yang, Zhuang; Dou, Caixia; Chen, Lijuan; Wan, Li
• Is Part Of: Chemical biology & drug design. Volume 97:Number 2(2021)
• Page Start: 358
• Page End: 371
• Publication Date: 2020-09-22
• Subjects: Aloe‐emodin -- anti‐inflammatory -- nuclear factor‐κB -- structure modification -- ulcerative colitis; Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.13788
• Languages: English
• ISSNs: 1747-0277

Abstract

Abstract: 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 IC50 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, PGE2 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. Abstract : Aloe‐emodin is recently reported to inhibit the production of pro‐inflammatory mediators via nuclear factor‐κB pathway. Herein, we introduced aliphatic heterocycle moiety to improve its anti‐inflammatory effect in vitro and in vivo. Cytotoxicity and metabolic stability experiments with the active derivatives were also evaluated, and this study provides evidence for the application of a novel anti‐inflammatory agent.