# Optimization of Antischistosomal Chemotypes

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2021 · $642,039

## Abstract

Schistosomiasis is a tropical parasitic disease caused by infections with flukes of the genus Schistosoma, 
affecting as many as 200 million individuals worldwide, with 779 million living at risk of infection. A new drug for 
schistosomiasis is urgently needed as praziquantel is currently the drug of last resort and the development of 
resistance cannot be ignored, particularly in view of its large-­scale use in many endemic. Our long-­term goal is 
to discover a new orally active single-­dose antischistosomal drug with activities against all parasite stages and 
with a novel mechanism of action. The objective of this proposal is to identify one or more antischistosomal 
drug development candidates. To accomplish this objective, we will optimize four promising antischistosomal 
chemotypes. We will also continue our investigation into the host-­mediated antischistosomal mode of action of 
aryl hydantoin drug candidate AR102. We propose four specific aims: 1) to synthesize and characterize target 
compounds; 2) to assess pharmacokinetic properties and antischistosomal activity of target compounds; 3) to 
further profile selected target compounds using more rigorous assays; and 4) to investigate the mode of action 
of drug candidate AR102. Compound design will be informed by existing SAR and will maximize structural 
diversity guided by prospective in silico physicochemical profiling. Based on iterative feedback from 
physicochemical profiling, in vitro ADME, and cytotoxicity (SA 1), ex vivo and in vivo antischistosomal activity 
and in vivo ADME (SA 2 and 3), new structural hypotheses will arise, and we will synthesize additional target 
compounds. Target compounds will progress through the various assays using clearly defined progression 
criteria. We suggest that this proposed research is innovative for several reasons First, the aryl hydantoins and 
ozonides have proven in vivo antischistosomal efficacy, but have very low ex vivo (in vitro) activity, the reverse 
of the usual situation where lead compounds have in vitro but no in vivo activity. Second, the azonine keto 
lactam chemotype and backup tricyclic imidazolidin-­4-­one compound series are examples of relatively rare 
medium-­ring compounds (8 to 11 atoms). Third, we seek to demarcate the unique host-­mediated mode of 
action of antischistosomal drug candidate AR102. The expected outcome from this work is to identify one or 
more antischistosomal drug development candidates effective against all parasite stages. For antischistosomal 
drug candidate AR102, we will define its host-­mediated antischistosomal mode of action. This proposed 
research is significant because a new drug would be important in the chemotherapy of drug-­resistant 
schistosomiasis and likely be valuable in integrated control programs to curb this parasitic disease.

## Key facts

- **NIH application ID:** 10128355
- **Project number:** 5R01AI116723-07
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Jonathan L Vennerstrom
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $642,039
- **Award type:** 5
- **Project period:** 2015-02-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10128355

## Citation

> US National Institutes of Health, RePORTER application 10128355, Optimization of Antischistosomal Chemotypes (5R01AI116723-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10128355. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*