# Development of thiophen-2-yl-phenylpyrimidines for treatment of schistosomiasis

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $237,000

## Abstract

ABSTRACT
Schistosomiasis is a disease of poverty that infects over 200 million people worldwide and places another 700
million at risk. Current treatment and control of the disease rely on just one drug, praziquantel (PZQ) - a
precarious situation should drug resistance emerge. Furthermore, the therapeutic profile of PZQ is not ideal. The
World Health Organization has therefore declared schistosomiasis a disease for which new therapies are urgently
needed. Microtubules (MTs) are essential components of the cytoskeleton in all eukaryotic cells. MT-targeting
drugs, which include MT-stabilizing and -destabilizing compounds, form a cornerstone of cancer chemotherapy;
in addition, studies suggest that such compounds may be useful to treat parasitic infections, including
schistosomiasis. Accordingly, we phenotypically screened a library of >300 MT-stabilizing agents with generally
favorable drug-like properties for anti-schistosomal activity. We identified different members of the
phenylpyrimidine (PP) class that exhibited marked bioactivity. Further exploration of the structure activity
relationships (SARs) of the most promising compounds identified a series of novel thiophen-2-yl-
phenylpyrimidine (TPP) derivatives that produce a potent and long-lasting paralysis of Schistosoma mansoni at
compound concentrations that do not elicit MT changes or cytotoxicity in mammalian cells. In light of these in
vitro results, these TPPs hold promise as candidate anti-schistosomal agents.
The next critical step in the evaluation and development of these compounds as candidate treatments for
schistosomiasis is to demonstrate the tolerability and in vivo efficacy of one or more TPP candidates. Towards
this end, we propose two aims:
(1) Complete structure activity/property relationship studies (SAR/SPR) of 30-50 TPPs through their design,
synthesis and in vitro phenotypic evaluation vs. S. mansoni. This will be followed up with pharmacokinetic (PK)
analysis of the most promising compounds (3–6) that meet all pre-defined selection criteria for in vitro anti-
schistosomal activity, selectivity and “drug-like” physicochemical properties.
(2) After the resynthesis of the top 1-3 performing compounds, define their maximum tolerated doses in vivo
and subsequently determine their efficacy in a mouse model of S. mansoni infection.
The proposed project will provide evidence of a correlation between in vitro and in vivo anti-schistosomal
activity, and identify one or more lead structures for future studies that will focus specifically on lead
optimization and an understanding of the mechanism of action.

## Key facts

- **NIH application ID:** 10371822
- **Project number:** 1R21AI156554-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Carlo Ballatore
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $237,000
- **Award type:** 1
- **Project period:** 2021-09-23 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10371822

## Citation

> US National Institutes of Health, RePORTER application 10371822, Development of thiophen-2-yl-phenylpyrimidines for treatment of schistosomiasis (1R21AI156554-01A1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10371822. Licensed CC0.

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