{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T05:59:39Z","timestamp":1790488779722,"version":"4.1.0"},"reference-count":25,"publisher":"American Society for Microbiology","issue":"9","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"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":[[2015,9]]},"abstract":"ABSTRACT<\/jats:title>\n \n Chloroquine (CQ) has been the mainstay of malaria treatment for more than 60 years. However, the emergence and spread of CQ resistance now restrict its use to only a few areas where malaria is endemic. The aim of the present study was to investigate whether a novel combination of a CQ-like moiety and an imipramine-like pharmacophore can reverse CQ resistance\n ex vivo<\/jats:italic>\n . Between March to October 2011 and January to September 2013, two \u201creversed chloroquine\u201d (RCQ) compounds (PL69 and PL106) were tested against multidrug-resistant field isolates of\n Plasmodium falciparum<\/jats:named-content>\n (\n n<\/jats:italic>\n = 41) and\n Plasmodium vivax<\/jats:named-content>\n (\n n<\/jats:italic>\n = 45) in Papua, Indonesia, using a modified\n ex vivo<\/jats:italic>\n schizont maturation assay. The RCQ compounds showed high efficacy against both CQ-resistant\n P. falciparum<\/jats:named-content>\n and\n P. vivax<\/jats:named-content>\n field isolates. For\n P. falciparum<\/jats:named-content>\n , the median 50% inhibitory concentrations (IC\n 50<\/jats:sub>\n s) were 23.2 nM for PL69 and 26.6 nM for PL106, compared to 79.4 nM for unmodified CQ (\n P<\/jats:italic>\n < 0.001 and\n P<\/jats:italic>\n = 0.036, respectively). The corresponding values for\n P. vivax<\/jats:named-content>\n were 19.0, 60.0, and 60.9 nM (\n P<\/jats:italic>\n < 0.001 and\n P<\/jats:italic>\n = 0.018, respectively). There was a significant correlation between IC\n 50<\/jats:sub>\n s of CQ and PL69 (Spearman's rank correlation coefficient [\n r<\/jats:italic>\n s<\/jats:sub>\n ] = 0.727,\n P<\/jats:italic>\n < 0.001) and PL106 (\n \n r\n s<\/jats:sub>\n <\/jats:italic>\n = 0.830,\n P<\/jats:italic>\n < 0.001) in\n P. vivax<\/jats:named-content>\n but not in\n P. falciparum<\/jats:named-content>\n . Both RCQs were equally active against the ring and trophozoite stages of\n P. falciparum<\/jats:named-content>\n , but in\n P. vivax<\/jats:named-content>\n , PL69 and PL106 showed less potent activity against trophozoite stages (median IC\n 50<\/jats:sub>\n s, 130.2 and 172.5 nM) compared to ring stages (median IC\n 50<\/jats:sub>\n s, 17.6 and 91.3 nM). RCQ compounds have enhanced\n ex vivo<\/jats:italic>\n activity against CQ-resistant clinical isolates of\n P. falciparum<\/jats:named-content>\n and\n P. vivax<\/jats:named-content>\n , suggesting the potential use of reversal agents in antimalarial drug development. Interspecies differences in RCQ compound activity may indicate differences in CQ pharmacokinetics between the two\n Plasmodium<\/jats:named-content>\n species.\n <\/jats:p>","DOI":"10.1128\/aac.01048-15","type":"journal-article","created":{"date-parts":[[2015,7,7]],"date-time":"2015-07-07T02:29:57Z","timestamp":1436236197000},"page":"5721-5726","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":15,"title":["Contrasting\n Ex Vivo<\/i>\n Efficacies of \u201cReversed Chloroquine\u201d Compounds in Chloroquine-Resistant Plasmodium falciparum and P. vivax Isolates"],"prefix":"10.1128","volume":"59","author":[{"given":"Grennady","family":"Wirjanata","sequence":"first","affiliation":[{"name":"Global and Tropical Health Division, Menzies School of Health Research, Charles Darwin University, Casuarina, Darwin, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boni F.","family":"Sebayang","sequence":"additional","affiliation":[{"name":"Eijkman Institute for Molecular Biology, Jakarta, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ferryanto","family":"Chalfein","sequence":"additional","affiliation":[{"name":"Papuan Health and Community Development Foundation (PHCDF), Timika, Papua, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Prayoga","sequence":"additional","affiliation":[{"name":"Papuan Health and Community Development Foundation (PHCDF), Timika, Papua, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Handayuni","sequence":"additional","affiliation":[{"name":"Global and Tropical Health Division, Menzies School of Health Research, Charles Darwin University, Casuarina, Darwin, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rintis","family":"Noviyanti","sequence":"additional","affiliation":[{"name":"Eijkman Institute for Molecular Biology, Jakarta, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enny","family":"Kenangalem","sequence":"additional","affiliation":[{"name":"Papuan Health and Community Development Foundation (PHCDF), Timika, Papua, Indonesia"},{"name":"District Health Authority, Timika, Papua, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeanne Rini","family":"Poespoprodjo","sequence":"additional","affiliation":[{"name":"Papuan Health and Community Development Foundation (PHCDF), Timika, Papua, Indonesia"},{"name":"District Health Authority, Timika, Papua, Indonesia"},{"name":"Department of Paediatrics, Faculty of Medicine, Gadjah Mada University, Yogyakarta, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven J.","family":"Burgess","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Portland State University, Portland, Oregon, USA"},{"name":"DesignMedix, Inc., Portland, Oregon, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David H.","family":"Peyton","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Portland State University, Portland, Oregon, USA"},{"name":"DesignMedix, Inc., Portland, Oregon, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ric N.","family":"Price","sequence":"additional","affiliation":[{"name":"Global and Tropical Health Division, Menzies School of Health Research, Charles Darwin University, Casuarina, Darwin, Australia"},{"name":"Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jutta","family":"Marfurt","sequence":"additional","affiliation":[{"name":"Global and Tropical Health Division, Menzies School of Health Research, Charles Darwin University, Casuarina, Darwin, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.30875\/9f925144-en"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1086\/322858"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.17.1.235-254.2004"},{"key":"e_1_3_2_5_2","volume-title":"Guidelines for the treatment of malaria","author":"World Health Organization","year":"2010","unstructured":"World Health Organization. 2010. 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