Design, synthesis and anti‐inflammatory study of novel N‐heterocyclic substituted Aloe‐emodin derivatives

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.

Synergy between machine learning and natural products cheminformatics: Application to the lead discovery of anthraquinone derivatives

“…It must be noted that compound (1) presented in Figure 6, with N ‐heterocyclic moiety on the methyl group at C‐3, exerts an anti‐inflammatory power illustrated by inhibiting the LPS‐induced nitric oxide production in RAW264.7 macrophages and nuclear factor‐kappa B signaling pathway, such as COX‐2, and decreasing the levels of IL‐1β, TNF‐α, and PGE 2 (Qiu et al, 2021). Furthermore, the pyrazole‐linked aloe‐emodin derivative, such as compound (2), showed significant early and late apoptosis induction for breast cancer cell lines with high selectivity and low toxicity compared with other standard anticancer agents and anthraquinone derivative, Doxorubicin (Kumar et al, 2021).…”

Design, synthesis, and biological evaluation of morpholinopyrimidine derivatives as anti-inflammatory agents

“…Based on the literature found it as an anti-inammatory agent. 28,29 Similarly, six-membered aromatic heterocyclic motif pyrimidine underlined in several natural and synthetic bioactive small molecules. There are several studies which utilizes pyrimidine for the development of library of pharmacologically active agents.…”

Emodin in cardiovascular disease: The role and therapeutic potential

“…Emodin, 1,3,8-trihydroxy-6-methylanthracene-9,10-dione (the structure of emodin is shown in Figure 1), is an anthraquinone compound extracted from rhubarb, with a molecular formula of C 15 H 10 O 5 . Emodin is a tricyclic planar structure with multiple modification sites: a hydroxyl group at position 3, an anthraquinone ring mainly at positions 2 and 4, and a methyl group at position 6 (Ghimire et al, 2015;Qiu et al, 2021). It is used abroad as a light laxative (Li et al, 2008).…”