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

Harvard | Vancouver

Geary, TG, Ingram-Sieber, K, Cowan, N, Panic, G, Vargas, M, Mansour, N, Bickle, Q, Wells, TNC, Spangenberg, T and Keiser, J. 2014. Orally Active Antischistosomal Early Leads Identified from the Open Access Malaria Box. [Online]. Figshare. Available from: 10.1371/journal.pntd.0002610

Export Citation

Sharing

Description

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 next generation drugs. We 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. Promising 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. The 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.

Published in a 3rd party system Date: 2014
Data capture method:
Mode of data capture
Experiment
Data Creators(s): Geary, TG, Ingram-Sieber, K, Cowan, N, Panic, G, Vargas, M, Mansour, N, Bickle, Q, Wells, TNC, Spangenberg, T and Keiser, J
LSHTM Faculty/Department: Faculty of Infectious and Tropical Diseases > Dept of Immunology and Infection
Participating Institutions: Study consortium

Files

Data

Resources

Actions

Edit Item Edit Item (admin only)