Development of Novel Natural Product Inspired Antileishmanial Drugs

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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.