{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T12:54:26Z","timestamp":1762865666094},"reference-count":36,"publisher":"American Society for Microbiology","issue":"9","license":[{"start":{"date-parts":[[2010,9,1]],"date-time":"2010-09-01T00:00:00Z","timestamp":1283299200000},"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":[[2010,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Malaria is a global health problem that causes significant mortality and morbidity, with more than 1 million deaths per year caused by\n            <jats:italic>Plasmodium falciparum<\/jats:italic>\n            . Most antimalarial drugs face decreased efficacy due to the emergence of resistant parasites, which necessitates the discovery of new drugs. To identify new antimalarials, we developed an automated 384-well plate screening assay using\n            <jats:italic>P. falciparum<\/jats:italic>\n            parasites that stably express cytoplasmic firefly luciferase. After initial optimization, we tested two different types of compound libraries: known bioactive collections (Library of Pharmacologically Active Compounds [LOPAC] and the library from the National Institute of Neurological Disorders and Stroke [NINDS]) and a library of uncharacterized compounds (ChemBridge). A total of 12,320 compounds were screened at 5.5 \u03bcM. Selecting only compounds that reduced parasite growth by 85% resulted in 33 hits from the combined bioactive collection and 130 hits from the ChemBridge library. Fifteen novel drug-like compounds from the bioactive collection were found to be active against\n            <jats:italic>P. falciparum<\/jats:italic>\n            . Twelve new chemical scaffolds were found from the ChemBridge hits, the most potent of which was a series based on the 1,4-naphthoquinone scaffold, which is structurally similar to the FDA-approved antimalarial atovaquone. However, in contrast to atovaquone, which acts to inhibit the\n            <jats:italic>bc<\/jats:italic>\n            <jats:sub>1<\/jats:sub>\n            complex and block the electron transport chain in parasite mitochondria, we have determined that our new 1,4-napthoquinones act in a novel, non-\n            <jats:italic>bc<\/jats:italic>\n            <jats:sub>1<\/jats:sub>\n            -dependent mechanism and remain potent against atovaquone- and chloroquine-resistant parasites. Ultimately, this study may provide new probes to understand the molecular details of the malaria life cycle and to identify new antimalarials.\n          <\/jats:p>","DOI":"10.1128\/aac.00431-10","type":"journal-article","created":{"date-parts":[[2010,6,15]],"date-time":"2010-06-15T04:11:20Z","timestamp":1276575080000},"page":"3597-3604","update-policy":"http:\/\/dx.doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":40,"title":["Discovery of Potent Small-Molecule Inhibitors of Multidrug-Resistant\n            <i>Plasmodium falciparum<\/i>\n            Using a Novel Miniaturized High-Throughput Luciferase-Based Assay"],"prefix":"10.1128","volume":"54","author":[{"given":"Edinson","family":"Lucumi","sequence":"first","affiliation":[{"name":"Department of Chemical and Biomolecular Engineering &amp; Penn Center for Molecular Discovery"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claire","family":"Darling","sequence":"additional","affiliation":[{"name":"Department of Pharmacology"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyunil","family":"Jo","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania 19104"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew D.","family":"Napper","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biomolecular Engineering &amp; Penn Center for Molecular Discovery"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rajesh","family":"Chandramohanadas","sequence":"additional","affiliation":[{"name":"Department of Pharmacology"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicholas","family":"Fisher","sequence":"additional","affiliation":[{"name":"Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, United Kingdom L3 5QA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alison E.","family":"Shone","sequence":"additional","affiliation":[{"name":"Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, United Kingdom L3 5QA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huiyan","family":"Jing","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biomolecular Engineering &amp; Penn Center for Molecular Discovery"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen A.","family":"Ward","sequence":"additional","affiliation":[{"name":"Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, United Kingdom L3 5QA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giancarlo A.","family":"Biagini","sequence":"additional","affiliation":[{"name":"Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, United Kingdom L3 5QA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William F.","family":"DeGrado","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania 19104"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Scott L.","family":"Diamond","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biomolecular Engineering &amp; 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