{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T02:31:04Z","timestamp":1791340264569,"version":"4.3.1"},"reference-count":39,"publisher":"American Society for Microbiology","issue":"2","license":[{"start":{"date-parts":[[2015,2,1]],"date-time":"2015-02-01T00:00:00Z","timestamp":1422748800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2015,2]]},"abstract":"ABSTRACT<\/jats:title>\n \n Current antimalarials are under continuous threat due to the relentless development of drug resistance by malaria parasites. We previously reported promising\n in vitro<\/jats:italic>\n parasite-killing activity with the histone methyltransferase inhibitor BIX-01294 and its analogue TM2-115. Here, we further characterize these diaminoquinazolines for\n in vitro<\/jats:italic>\n and\n in vivo<\/jats:italic>\n efficacy and pharmacokinetic properties to prioritize and direct compound development. BIX-01294 and TM2-115 displayed potent\n in vitro<\/jats:italic>\n activity, with 50% inhibitory concentrations (IC\n 50<\/jats:sub>\n s) of <50 nM against drug-sensitive laboratory strains and multidrug-resistant field isolates, including artemisinin-refractory\n Plasmodium falciparum<\/jats:named-content>\n isolates. Activities against\n ex vivo<\/jats:italic>\n clinical isolates of both\n P. falciparum<\/jats:named-content>\n and\n Plasmodium vivax<\/jats:named-content>\n 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\n in vivo<\/jats:italic>\n mouse models of\n Plasmodium berghei<\/jats:named-content>\n and\n P. falciparum<\/jats:named-content>\n 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.\n <\/jats:p>","DOI":"10.1128\/aac.04419-14","type":"journal-article","created":{"date-parts":[[2014,11,25]],"date-time":"2014-11-25T04:28:59Z","timestamp":1416889739000},"page":"950-959","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":64,"title":["Histone Methyltransferase Inhibitors Are Orally Bioavailable, Fast-Acting Molecules with Activity against Different Species Causing Malaria in Humans"],"prefix":"10.1128","volume":"59","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2822-8245","authenticated-orcid":false,"given":"Nicholas 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