edoc

Orally active antischistosomal early leads identified from the open access malaria box

Ingram-Sieber, Katrin and Cowan, Noemi and Panic, Gordana and Vargas, Mireille and Mansour, Nuha R. and Bickle, Quentin D. and Wells, Timothy N. C. and Spangenberg, Thomas and Keiser, Jennifer. (2014) Orally active antischistosomal early leads identified from the open access malaria box. PLoS neglected tropical diseases, Vol. 8, H. 1 , e2610.

[img]
Preview
PDF - Published Version
Available under License CC BY (Attribution).

509Kb

Official URL: http://edoc.unibas.ch/dok/A6233635

Downloads: Statistics Overview

Abstract

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.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Helminth Drug Development (Keiser)
UniBasel Contributors:Vargas, Mireille and Keiser, Jennifer
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Public Library of Science
ISSN:1935-2727
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
Related URLs:
Identification Number:
Last Modified:31 Dec 2015 10:56
Deposited On:15 Aug 2014 07:16

Repository Staff Only: item control page