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Title: Histone methyltransferase inhibitors are orally bioavailable, fast- Acting molecules with activity against different species causing malaria in humans
Authors: Nicholas A. Malmquist
Sandeep Sundriyal
Joachim Caron
Patty Chen
Benoit Witkowski
Didier Menard
Rossarin Suwanarusk
Laurent Renia
Francois Nosten
María Belén Jiménez-Díaz
Iñigo Angulo-Barturen
María Santos Martínez
Santiago Ferrer
Laura M. Sanz
Francisco Javier Gamo
Sergio Wittlin
Sandra Duffy
Vicky M. Avery
Andrea Ruecker
Michael J. Delves
Robert E. Sinden
Matthew J. Fuchter
Artur Scherf
Institut Pasteur, Paris
CNRS Centre National de la Recherche Scientifique
Imperial College London
Institut Pasteur du Cambodge
Agency for Science, Technology and Research, Singapore
Nuffield Department of Clinical Medicine
Mahidol University
GlaxoSmithKline plc, Spain
Swiss Tropical and Public Health Institute (Swiss TPH)
Universitat Basel
Griffith University
Keywords: Medicine
Issue Date: 1-Feb-2015
Citation: Antimicrobial Agents and Chemotherapy. Vol.59, No.2 (2015), 950-959
Abstract: ©2015 American Society for Microbiology. Current antimalarials are under continuous threat due to the relentless development of drug resistance by malaria parasites. We previously reported promising in vitro parasite-killing activity with the histone methyltransferase inhibitor BIX-01294 and its analogue TM2-115. Here, we further characterize these diaminoquinazolines for in vitro and in vivo efficacy and pharmacokinetic properties to prioritize and direct compound development. BIX-01294 and TM2-115 displayed potent in vitro activity, with 50% inhibitory concentrations (IC<inf>50</inf>s) of <50 nM against drug-sensitive laboratory strains and multidrug-resistant field isolates, including artemisinin-refractory Plasmodium falciparum isolates. Activities against ex vivo clinical isolates of both P. falciparum and Plasmodium vivax were similar, with potencies of 300 to 400 nM. Sexual-stage gametocyte inhibition occurs at micromolar levels; however, mature gametocyte progression to gamete formation is inhibited at submicromolar concentrations. Parasite reduction ratio analysis confirms a high asexual-stage rate of killing. Both compounds examined displayed oral efficacy in in vivo mouse models of Plasmodium berghei and P. falciparum infection. The discovery of a rapid and broadly acting antimalarial compound class targeting blood stage infection, including transmission stage parasites, and effective against multiple malaria-causing species reveals the diaminoquinazoline scaffold to be a very promising lead for development into greatly needed novel therapies to control malaria.
ISSN: 10986596
Appears in Collections:Scopus 2011-2015

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