Development of Novel -Acylhydrazone Derivatives with High Anti-obesity Activity and Improved Safety by Exploring the Pharmaceutical Properties of Aldehyde Group

The discovery of effective and safe antiobesity agents remains a challenging yet promising field. Our previous studies identified Bouchardatine derivatives as potential antiobesity agents. However, the 8a-aldehyde moiety rendered them unsuitable for drug development. In this study, we designed two series of novel derivatives to modify this structural feature. Through a structure-activity relationship study, we elucidated the role of the 8a-aldehyde group in toxicity induction. We identified compound , featuring an 8a--acylhydrazone moiety, which exhibited significant lipid-lowering activity and reduced toxicity. Compound shares a similar lipid-lowering mechanism with our lead compound , but demonstrates improved pharmacokinetic properties and safety profile. Both oral and injectable administration of significantly reduced body weight gain and ameliorated metabolic syndrome in diet-induced obese mice. Our findings identify as a promising antiobesity agent and highlight the potential of substituting the aldehyde group with an -acylhydrazone to enhance drug-like properties.