1,3-Substituted β-Carboline Derivatives as Potent Chemotherapy for the Treatment of Cystic Echinococcosis,Journal of Medicinal Chemistry

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1,3-Substituted β-Carboline Derivatives as Potent Chemotherapy for the Treatment of Cystic Echinococcosis
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-12-09 , DOI: 10.1021/acs.jmedchem.3c01326
Bei Chen ₁ , Jianbing Wu ₂ , Zhengsheng Yan ₂ , Hongmei Wu ₃ , Huijing Gao ₁ , Yun Liu ₃ , Jun Zhao ₁ , Jianhua Wang ₁ , Jianhua Yang ₁ , Yihua Zhang ₂ , Jingxuan Pan ₄ , Yong Ling ₃ , Hao Wen ₁ , Zhangjian Huang _{1,

2}

Affiliation

Echinococcosis is a global public health issue that generally occurs in areas with developed animal husbandry. In search of safe and effective therapeutic agents against echinococcosis, we designed and synthesized new 1,3-substituted β-carboline derivatives based on harmine. Among them, compounds 1a, 1c, and 1e displayed potent inhibitory activity against Echinococcus granulosus in vitro, significantly better than albendazole and harmine. The morphological detection revealed that 1a, 1c, and 1e significantly changed the ultrastructure of Echinococcus granulosus protoscolices (PSCs). Furthermore, pharmacokinetic studies suggested that 1a possessed a better metabolic property. Encouragingly, 1a exhibited a highest cyst inhibition rate as 76.8% in vivo and did not display neurotoxicity in mice. Further mechanistic research illustrated that 1a has the potential to induce autophagy in PSCs, which may be responsible for the therapeutic effect of the drugs. Together, 1a could be a promising therapeutic agent against echinococcosis, warranting further study.

中文翻译：

1,3-取代的β-咔啉衍生物作为治疗囊型包虫病的有效化疗药物

包虫病是一个全球性的公共卫生问题，普遍发生在畜牧业发达的地区。为了寻找安全有效的包虫病治疗药物，我们设计并合成了基于去氢骆驼蓬碱的新型1,3-取代β-咔啉衍生物。其中，化合物1a 、 1c 、 1e在体外对细粒棘球蚴具有较强的抑制活性，明显优于阿苯达唑和去氢骆驼蓬碱。形态学检测显示， 1a 、 1c 、 1e显着改变了细粒棘球绦虫原头节（PSC）的超微结构。此外，药代动力学研究表明1a具有更好的代谢特性。令人鼓舞的是， 1a在体内表现出最高的包囊抑制率，达到76.8%，并且在小鼠中没有表现出神经毒性。进一步的机制研究表明， 1a有可能诱导 PSC 发生自噬，这可能是药物产生治疗效果的原因。总之， 1a可能是一种很有前景的包虫病治疗剂，值得进一步研究。

更新日期：2023-12-09

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