Development of Novel Natural Product Inspired Antileishmanial Drugs

摘要 利什曼原虫和其他动体寄生虫会导致毁灭性的疾病，折磨着数百万人，但 目前的抗利什曼药物治疗严重不足，存在毒性，难以提供， 产生抗药性，疗效不佳等。因此，人们普遍认识到迫切需要 开发新的疗法，代表着对现有药物的改进。这项提案将探索 天然产物衍生的坦巴杰明作为潜在的治疗利什曼病的新药的潜力。 坦巴杰明和结构上相关的化合物是体内疟疾寄生虫生长的有效抑制剂。 小鼠疟疾模型，其中一些在单次口服剂量时是治愈的。首字母 用106个结构不同的吡咯基吡咯亚甲基生物碱类似物进行的实验鉴定了26个丹参碱 30~100 nM EC50值对墨西哥利什曼原虫和杜氏利什曼原虫无鞭毛体生长的抑制作用 哺乳动物巨噬细胞内和体外治疗指数&gt；10，使这类化合物接近2 比目前的抗利什曼药物更有效数量级，因此有希望成为 开发新的口服生物可用药物来对抗这些寄生虫。在这个提案中，小说 将合成具有预期改进性能的坦巴杰明，用于体内疗效，包括优越的 代谢稳定性，增加了水的溶解度，改善了口服生物利用度，并降低了毒性。离体 体内药代动力学特性将被确定为新的坦巴杰明和最有希望的 将测试类似物在控制墨西哥乳杆菌引起的皮肤利什曼病和致死利什曼病方面的效果。 杜氏利什曼原虫引起的内脏利什曼病在这些疾病的小鼠模型中。总体目标是 将坦巴杰明提高到体内对利什曼原虫有活性的化合物的水平，以便 它们可以进一步开发为新的抗利什曼药物的新的、有效的、口服生物利用的线索。

SUMMARY Leishmania and other kinetoplastid parasites cause devastating diseases that afflict millions of people, yet current antileishmanial therapies are woefully inadequate, suffering from toxicity, difficulty of delivery, development of drug resistance, poor efficacy, etc. Hence, there is a widely recognized and urgent need for development of novel therapies that represent improvements over current drugs. This proposal will explore the potential of the natural product-derived tambjamines as potential novel drug leads against leishmaniasis. Tambjamines and structurally related compounds are potent inhibitors of growth of malaria parasites in vivo in murine models of malaria, with some of them being curative when delivered as a single oral dose. Initial experiments with 106 structurally diverse pyrrolylpyrromethene alkaloid analogs identified 26 tambjamines with 30-100 nM EC50 values for growth inhibition of Leishmania mexicana and L. donovani amastigotes growing inside mammalian macrophages and in vitro therapeutic indices >10, making this class of compounds almost 2 orders of magnitude more potent that current antileishmanial drugs and thus promising candidates for development of new orally bioavailable drugs for use against these parasites. In this proposal, novel tambjamines will be synthesized with expected improved properties for in vivo efficacy, including superior metabolic stability, increased aqueous solubility for improved oral bioavailability, and decreased toxicity. In vitro and in vivo pharmacokinetic properties will be determined for new tambjamines, and the most promising analogs will be tested for efficacy in controlling both cutaneous leishmaniasis induced by L. mexicana and fatal visceral leishmaniasis caused by L. donovani in murine models of these diseases. The overall objective is to advance tambjamines to the level of compounds that are active against Leishmania parasites in vivo so that they can be further developed as novel, potent, orally bioavailable leads toward new antileishmanial drugs.