# Exploiting Diversity-Oriented Chemical Synthesis for Combating Chronic Parasitic Infection

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2022 · $1,137,363

## Abstract

Summary
The overall goal of our study is to identify small molecule inhibitors with appropriate potency, selectivity, and
safety profiles to cure chronic toxoplasmosis. Toxoplasma gondii is a widespread parasite of animals that
causes opportunistic infections in humans. Although healthy individuals control the infection, they are not able
to completely eliminate it and remain chronically infected. Complications occur due to reactivation of chronic
infections in immunocompromised patients and new infections during pregnancy when the parasite can cross
the placental barrier and infect the developing fetus. It is estimated that ~ 2 billion people worldwide are
chronically infected with T. gondii and hence at risk of reactivation should their immune function decline.
Existing chemotherapy for T. gondii is only effective at suppressing acute infection, but is unable to eradicate
the chronic tissue-cyst stages. In preliminary studies, we have conducted a high throughput screen of a diverse
small molecule library of compounds and identified a number of very potent inhibitors (low nanomolar EC50) of
parasite growth in vitro. Additionally, several of these highly potent leads act on chronic stages of infection and
suppress reactivation of infection in an immunocompromised mouse model of toxoplasmosis. The active
compounds come from a diversity-oriented synthetic (DOS) library that was synthesized using modern
methods of asymmetric organic chemistry, hence they are rich in stereochemical diversity. The proposed
studies will focus on two series that display low nM potency in inhibiting T. gondii growth. We will develop
structure activity relationships based on T. gondii growth inhibition by existing analogs. We will then design and
synthesize new analogs to optimize potency, safety, metabolic, brain penetration, and pharmacokinetic
properties. Genetic and genomic approaches will be used to identify potential resistance and confirm
mechanisms of action of these leads. We will also employ animal models that we have developed for
monitoring the efficacy of compounds against reactivated toxoplasmosis. Successful achievement of these
goals will define leads for future clinical studies aimed at developing new drugs to eradicate chronic
toxoplasmosis.

## Key facts

- **NIH application ID:** 10324549
- **Project number:** 5R01AI143857-03
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Arnab Kumar Chatterjee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,137,363
- **Award type:** 5
- **Project period:** 2020-02-08 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10324549

## Citation

> US National Institutes of Health, RePORTER application 10324549, Exploiting Diversity-Oriented Chemical Synthesis for Combating Chronic Parasitic Infection (5R01AI143857-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10324549. Licensed CC0.

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