Nicholas A. MalmquistSandeep SundriyalJoachim CaronPatty ChenBenoit WitkowskiDidier MenardRossarin SuwanaruskLaurent ReniaFrancois NostenMaría Belén Jiménez-DíazIñigo Angulo-BarturenMaría Santos MartínezSantiago FerrerLaura M. SanzFrancisco Javier GamoSergio WittlinSandra DuffyVicky M. AveryAndrea RueckerMichael J. DelvesRobert E. SindenMatthew J. FuchterArtur ScherfInstitut Pasteur, ParisCNRS Centre National de la Recherche ScientifiqueImperial College LondonInstitut Pasteur du CambodgeAgency for Science, Technology and Research, SingaporeNuffield Department of Clinical MedicineMahidol UniversityGlaxoSmithKline plc, SpainSwiss Tropical and Public Health Institute (Swiss TPH)Universitat BaselGriffith University2018-11-232018-11-232015-02-01Antimicrobial Agents and Chemotherapy. Vol.59, No.2 (2015), 950-95910986596006648042-s2.0-84921917278https://repository.li.mahidol.ac.th/handle/20.500.14594/36520©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.Mahidol UniversityMedicineArticleSCOPUS10.1128/AAC.04419-14