Discovery of novel anti-obesity agents is a challenging and promising research area. Based on our previous works, we synthesized 40 novel β-indoloquinazoline analogues by altering the skeleton and introducing preferential side chains, evaluated their lipid-lowering activity and summarized the structure-activity relationships. In combination with an evaluation of the lipid-lowering efficacies, AMP-dependent activated protein kinase (AMPK) activating ability and liver microsomal stability, compound 23 (named as IQZ23) was selected for further studies. IQZ23 exerted a high efficacy in decreasing the triglyceride level (EC₅₀ = 0.033 μM) in 3T3-L1 adipocytes. Mechanistic studies revealed the lipid-lowering activity of IQZ23 was dependent on the AMPK pathway by modulating ATP synthase activity. This activation was accompanied by mitochondrial biogenesis and oxidation capacity increased, and insulin sensitivity enhanced in pertinent cell models by various interventions. Correspondingly, IQZ23 (20 mg/kg, i.p.) treatment significantly reversed high fat and cholesterol diet (HFC)- induced body weight increases and accompanying clinical symptoms of obesity in mice but without indicative toxicity. These results indicate that IQZ23 could be a useful candidate for the treatment of obesity and related metabolic disorders.

新型抗肥胖药的发现是一个充满挑战和前途的研究领域。在之前的工作基础上，我们通过改变骨架和引入优先侧链合成了40种新颖的β-吲哚并喹唑啉类似物，评估了它们的降脂活性并总结了其构效关系。结合对降脂功效，AMP依赖性活化蛋白激酶（AMPK）活化能力和肝微粒体稳定性的评估，选择了化合物23（命名为IQZ23）进行进一步研究。IQZ23在降低甘油三酸酯水平方面具有很高的功效（EC ₅₀ = 0.033μM）在3T3-L1脂肪细胞中。机理研究表明，IQZ23的降脂活性通过调节ATP合酶活性而依赖于AMPK途径。这种激活伴随着线粒体的生物发生和氧化能力的增强，并且通过各种干预在相关细胞模型中胰岛素敏感性增强。相应地，IQZ23（20 mg / kg，ip）治疗可显着逆转高脂肪和胆固醇饮食（HFC）引起的体重增加，并伴有小鼠肥胖的临床症状，但无指示性毒性。这些结果表明，IQZ23可能是治疗肥胖症和相关代谢紊乱的有用候选药物。