Discovery and Optimization of Tambjamines as a Novel Class of Antileishmanial Agents

Leishmaniasis is a neglected tropical disease that is estimated to afflict over 12 million people. Current drugs for leishmaniasis suffer from serious deficiencies, including toxicity, high cost, modest efficacy, primarily parenteral delivery, and emergence of widespread resistance. We have discovered and developed a natural product-inspired tambjamine chemotype, known to be effective against Plasmodium spp, as a novel class of antileishmanial agents. Herein, we report in vitro and in vivo antileishmanial activities, detailed structure–activity relationships, and metabolic/pharmacokinetic profiles of a large library of tambjamines. A number of tambjamines exhibited excellent potency against both Leishmania mexicana and Leishmania donovani parasites with good safety and metabolic profiles. Notably, tambjamine 110 offered excellent potency and provided partial protection to leishmania-infected mice at 40 and/or 60 mg/kg/10 days of oral treatment. This study presents the first account of antileishmanial activity in the tambjamine family and paves the way for the generation of new oral antileishmanial drugs.利什曼病（Leishmaniasis）是一种被忽视的热带病，据估计全球有超过1200万人受其困扰。现有抗利什曼病药物存在诸多严重缺陷，包括毒性反应、成本高昂、疗效平平、主要依赖胃肠外给药，以及广泛出现的耐药性问题。本团队发现并开发了一类源自天然产物的tambjamine化学型，该类化合物此前被证实对疟原虫属（Plasmodium spp.）具有抑制活性，可作为新型抗利什曼病药剂。本文报道了一大系列tambjamine化合物的体外、体内抗利什曼病活性，详尽的构效关系（structure–activity relationships），以及代谢/药代动力学特征。多款tambjamine对墨西哥利什曼原虫（Leishmania mexicana）与杜氏利什曼原虫（Leishmania donovani）均展现出优异的抗虫活性，且具备良好的安全性与代谢特性。值得注意的是，tambjamine 110活性优异，在以40mg/kg和/或60mg/kg的剂量连续10天口服给药的方案下，可对感染利什曼原虫的小鼠提供部分保护作用。本研究首次报道了tambjamine家族化合物的抗利什曼病活性，为新型口服抗利什曼病药物的开发铺平了道路。