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

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. Compounds12rand14a-14cexhibited a higher inhibitory effect on LPS-induced nitric oxide (NO) production in RAW264.7 macrophages than Aloe-emodin did. Among them,12rshowed the most potent inhibition with an IC(50)value of 5.66 +/- 0.47 mu M. Further toxicity and pharmacokinetic studies were carried out and12rwas found to be the most active structure with low toxicity risk and good metabolic properties. It could also decrease the levels of IL-1 beta, TNF-alpha, PGE(2)and inhibit the activation of nuclear factor-kappa B signalling pathway. Importantly,12rshowed oral bioavailability of up to 55.16% and attenuated the inflammatory symptoms in an ulcerative colitis mouse model in vivo. These results indicate that12ris suitable for development as an anti-inflammatory agent.