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

> **NIH NIH R44** · FOX CHASE CHEMICAL DIVERSITY CENTER, INC · 2024 · $1,000,000

## Abstract

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. T...

## Key facts

- **NIH application ID:** 10824271
- **Project number:** 5R44AI152788-04
- **Recipient organization:** FOX CHASE CHEMICAL DIVERSITY CENTER, INC
- **Principal Investigator:** Mark E McDonnell
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,000,000
- **Award type:** 5
- **Project period:** 2020-07-20 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10824271

## Citation

> US National Institutes of Health, RePORTER application 10824271, Trypanocidal Agents that Kill Multiple Stages of the Trypanosoma cruzi Life Cycle (5R44AI152788-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10824271. Licensed CC0.

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