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No antimalarials have been shown to target the brief extracellular merozoite form of blood-stage malaria. We studied a panel of 12 drugs, 10 of which have been used extensively clinically, for their invasion, schizont rupture, and growth-inhibitory activity using high-throughput flow cytometry and new approaches for the study of merozoite invasion and early intraerythrocytic development. Not surprisingly, given reported mechanisms of action, none of the drugs inhibited merozoite invasion<jats:italic>in vitro<\/jats:italic>. Pretreatment of erythrocytes with drugs suggested that halofantrine, lumefantrine, piperaquine, amodiaquine, and mefloquine diffuse into and remain within the erythrocyte and inhibit downstream growth of parasites. Studying the inhibitory activity of the drugs on intraerythrocytic development, schizont rupture, and reinvasion enabled several different inhibitory phenotypes to be defined. All drugs inhibited parasite replication when added at ring stages, but only artesunate, artemisinin, cycloheximide, and trichostatin A appeared to have substantial activity against ring stages, whereas the other drugs acted later during intraerythrocytic development. When drugs were added to late schizonts, only artemisinin, cycloheximide, and trichostatin A were able to inhibit rupture and subsequent replication. Flow cytometry proved valuable for<jats:italic>in vitro<\/jats:italic>assays of antimalarial activity, with the free merozoite population acting as a clear marker for parasite growth inhibition. These studies have important implications for further understanding the mechanisms of action of antimalarials, studying and evaluating drug resistance, and developing new antimalarials.<\/jats:p>","DOI":"10.1128\/aac.01881-12","type":"journal-article","created":{"date-parts":[[2013,1,15]],"date-time":"2013-01-15T04:53:42Z","timestamp":1358225622000},"page":"1455-1467","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":141,"title":["Defining the Timing of Action of Antimalarial Drugs against Plasmodium falciparum"],"prefix":"10.1128","volume":"57","author":[{"given":"Danny W.","family":"Wilson","sequence":"first","affiliation":[{"name":"Infection and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia"},{"name":"Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Langer","sequence":"additional","affiliation":[{"name":"Infection and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia"},{"name":"Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher D.","family":"Goodman","sequence":"additional","affiliation":[{"name":"Plant Cell Biology Research Centre, School of Botany, University of Melbourne, Parkville, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geoffrey I.","family":"McFadden","sequence":"additional","affiliation":[{"name":"Plant Cell Biology Research Centre, School of Botany, University of Melbourne, Parkville, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James G.","family":"Beeson","sequence":"additional","affiliation":[{"name":"Infection and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia"},{"name":"Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, Victoria, Australia"},{"name":"Department of Microbiology, Monash University, Clayton, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.30875\/65678d0b-en"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-2952(01)00878-4"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.drup.2004.07.001"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj3390363"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(86)90473-9"},{"key":"e_1_3_3_7_2","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/S0026-895X(25)14644-0","article-title":"Plasmodium berghei dihydrofolate reductase. 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