Orally Active Antischistosomal Early Leads Identified from the Open Access Malaria Box

Timothy G Geary,Katrin Ingram-Sieber,Jennifer Keiser,Quentin D Bickle,Mireille Vargas,Noemi Cowan,Gordana Panic,Thomas Spangenberg,Timothy N C Wells,Nuha R Mansour

doi:10.1371/journal.pntd.0002610

Abstract

BackgroundWorldwide hundreds of millions of schistosomiasis patients rely on treatment with a single drug, praziquantel. Therapeutic limitations and the threat of praziquantel resistance underline the need to discover and develop next generation drugs.MethodologyWe studied the antischistosomal properties of the Medicines for Malaria Venture (MMV) malaria box containing 200 diverse drug-like and 200 probe-like compounds with confirmed in vitro activity against Plasmodium falciparum. Compounds were tested against schistosomula and adult Schistosoma mansoni in vitro. Based on in vitro performance, available pharmacokinetic profiles and toxicity data, selected compounds were investigated in vivo.Principal FindingsPromising antischistosomal activity (IC50: 1.4–9.5 µM) was observed for 34 compounds against schistosomula. Three compounds presented IC50 values between 0.8 and 1.3 µM against adult S. mansoni. Two promising early leads were identified, namely a N,N′-diarylurea and a 2,3-dianilinoquinoxaline. Treatment of S. mansoni infected mice with a single oral 400 mg/kg dose of these drugs resulted in significant worm burden reductions of 52.5% and 40.8%, respectively.Conclusions/SignificanceThe two candidates identified by investigating the MMV malaria box are characterized by good pharmacokinetic profiles, low cytotoxic potential and easy chemistry and therefore offer an excellent starting point for antischistosomal drug discovery and development.

Highlights

With hundreds of millions of people living at risk of infection and 207 million people infected with schistosomes worldwide, schistosomiasis is one of the most devastating parasitic diseases in tropical countries and remains a major public health problem, especially in Sub-Saharan Africa [1,2]
To discover new chemical scaffolds for the treatment of schistosomiasis, we investigated the Medicines for Malaria Venture malaria box containing 200 diverse drug-like and 200 probe-like compounds with known antimalarial activity against Schistosoma mansoni
We identified two entirely new chemical scaffolds: the N,N9-diarylurea and 2,3-dianilinoquinoxaline derivatives with antischistosomal in vitro activity in the sub micromolar range and significant activity in the mouse model

Summary

Introduction

With hundreds of millions of people living at risk of infection and 207 million people infected with schistosomes worldwide, schistosomiasis is one of the most devastating parasitic diseases in tropical countries and remains a major public health problem, especially in Sub-Saharan Africa [1,2]. Praziquantel, discovered in the 1970’s, is the only drug available for the treatment of schistosomiasis [7,8,9]. Despite many benefits of praziquantel, most notably its high efficacy and excellent tolerability, the drug has major drawbacks, most importantly its inefficacy against juvenile schistosomes [10,11]. The increasing administration of praziquantel to millions of people annually [12] results in high drug pressure, and drug-resistant parasites are likely to evolve [13]. Worldwide hundreds of millions of schistosomiasis patients rely on treatment with a single drug, praziquantel. Therapeutic limitations and the threat of praziquantel resistance underline the need to discover and develop generation drugs

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