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            <funder>S.S. acknowledges the European Commission for a Marie Curie International Incoming Fellowship (agreement no. 299857). L.R. was supported by funding from the Singapore Immunology Network (SIgN) and the Horizontal Programme on Infectious Diseases under the Agency for Science, Technology and Research (A*STAR, Singapore). The Shoklo Malaria Research Unit is part of the Mahidol Oxford University Research Unit, supported by the Wellcome Trust of Great Britain. V.M.A. acknowledges support from the Australian Research Council (LP120200557). A.S. acknowledges support from the European Research Council.</funder>
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              <p>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 (IC50s) of &lt;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.</p>
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              <org type="consortium">We thank Xavier Ding and Brice Campo of the Medicines for Malaria Venture for helpful discussions and aid in coordinating some of the collaborative efforts. We thank Jolanda Kamber for assistance in performing the P. berghei in vivo assay and Christoph Siethoff (Swiss BioQuant) for the determination of compound levels in P. berghei-infected mice. We are also grateful to the Therapeutic Efficacy, Pharmacology, and Laboratory Animal Science groups at GSK Tres Cantos Medicines Development Campus for assistance. We thank L. D. Shultz and The Jackson Laboratory for providing access to nonobese diabetic SCID IL-2Rγcnull mice through their collaboration with GSK Tres Cantos Medicines Development Campus. We are indebted to Susan A. Charman of Monash University for critically reviewing the manuscript.</org>
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