Trypanocidal Agents that Kill Multiple Stages of the Trypanosoma cruzi Life Cycle

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Abstract. Chagas disease is a neglected tropical disease and has been designated as a research priority by NIAID and an SBIR Research Topic of Interest. Six million individuals are infected and 8,000 deaths were caused by Chagas in 2015 in mostly Central and South America by advanced forms of the disease such as Chagas hemorrhagic fever. The cost associated with Chagas disease treatment globally is estimated to be ~$7 billion. Chagas disease is caused by the parasitic protist Trypanosoma cruzi (T. cruzi) and spread by Triatominae, or "kissing bugs". While endemic in South America, it is spread to people living elsewhere due to immigration of infected patients and travel to endemic regions. No vaccine is currently available and the only drugs used to treat Chagas, the nitro aryl compounds nifurtimox and benznidazole, lose effectiveness in the chronic phase as the parasite develops resistance, and they cause limiting adverse events as well. New medications acting via novel mechanisms are urgently needed to eliminate the parasite in chronic patients suffering and dying from Chagas disease. Novel compounds synthesized at Fox Chase Chemical Diversity Center (FCCDC) have been tested at multiple collaborator sites: GSK Tres Cantos Open Lab Foundation in Tres Cantos, Spain; New York University; University Of Dundee, Scotland; and the Swiss Tropical Public Health Institute, all research facilities dedicated to curing neglected tropical diseases. The analogs tested displayed excellent activity against the T. cruzi parasite in both its replicative (amastigote) and infective (trypomastigote) forms as found in phenotypic screening assays. The compounds do not act through any known mechanism of action and display little to no toxicity to host cells, unlike the standards of care nifurtimox and benznidazole. Further, in vivo testing in a murine model for Chagas disease (NYU) confirmed potent antiparasitic activity. The lead compounds are proprietary to FCCDC and a provisional U.S. patent application has been filed. The activity seen for the series has generated great interest at the non-profit Drugs for Neglected Diseases Initiative (DNDi). DNDi evaluates many potential international collaborations each year but only selects the most promising for resource investment. Following evaluation of our project, DNDi has committed additional T. cruzi testing gratis at both the University of Dundee and the Swiss Tropical and Public Health Institute in order to evaluate potency and investigate mechanism of action. Our Aims to develop this chemotype from lead compound to preclinical candidate is (1) Optimize the potency by exploring the SAR of our novel lead using iterative medicinal chemistry synthesi, (2) characterize the biochemical properties of the compounds to optimize antiparasitic activity (NYU, DNDi), and (3) perform in vivo tests in acute and chronic Chagas disease mouse models (NYU) as well as evaluate and improve ADME properties of advanced leads as required. The goal of this program is to complete many of the studies necessary for filing an Investigational New Drug (IND) application for new agents to treat Chagas disease as monotherapy or in combination with existing agents.