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.

中文翻译：

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作为一类新型抗利什曼药物的 Tambijamines 的发现和优化


利什曼病是一种被忽视的热带疾病，估计有超过 1200 万人受到影响。目前治疗利什曼病的药物存在严重缺陷，包括毒性、成本高、功效有限、主要是胃肠外给药以及出现广泛的耐药性。我们发现并开发了一种受天然产品启发的坦巴贾明化学型，已知对疟原虫属有效，是一类新型的抗利什曼病药物。在此，我们报告了大型坦巴杰明库的体外和体内抗利什曼活性、详细的结构-活性关系以及代谢/药代动力学特征。许多坦巴明对墨西哥利什曼原虫和杜氏利什曼原虫寄生虫表现出优异的效力，并且具有良好的安全性和代谢特征。值得注意的是，tambajamine 110 具有出色的效力，并以 40 和/或 60 mg/kg/10 天的口服治疗剂量为感染利什曼原虫的小鼠提供部分保护。这项研究首次阐述了坦巴明家族的抗伊利什曼病活性，并为新型口服抗伊利什曼病药物的产生铺平了道路。