{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T21:11:00Z","timestamp":1789852260664,"version":"4.0.1"},"reference-count":41,"publisher":"American Chemical Society (ACS)","issue":"21","license":[{"start":{"date-parts":[[2015,8,22]],"date-time":"2015-08-22T00:00:00Z","timestamp":1440201600000},"content-version":"vor","delay-in-days":365,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_termsofuse.html"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,11,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The continued proliferation of malaria throughout temperate and tropical regions of the world has promoted a push for more efficacious treatments to combat the disease. Unfortunately, more recent remedies such as artemisinin combination therapies have been rendered less effective due to developing parasite resistance, and new drugs are required that target the parasite in the liver to support the disease elimination efforts. Research was initiated to revisit antimalarials developed in the 1940s and 1960s that were deemed unsuitable for use as therapeutic agents as a result of poor understanding of both physicochemical properties and parasitology. Structure\u2013activity and structure\u2013property relationship studies were conducted to generate a set of compounds with the general 6-chloro-7-methoxy-2-methyl-4(1H)-quinolone scaffold which were substituted at the 3-position with a variety of phenyl moieties possessing various properties. Extensive physicochemical evaluation of the quinolone series was carried out to downselect the most promising 4(1H)-quinolones, 7, 62, 66, and 67, which possessed low-nanomolar EC50 values against W2 and TM90-C2B as well as improved microsomal stability. Additionally, in vivo Thompson test results using Plasmodium berghei in mice showed that these 4(1H)-quinolones were efficacious for the reduction of parasitemia at &amp;gt;99% after 6 days.<\/jats:p>","DOI":"10.1021\/jm500942v","type":"journal-article","created":{"date-parts":[[2014,8,22]],"date-time":"2014-08-22T10:07:20Z","timestamp":1408702040000},"page":"8860-8879","source":"Crossref","is-referenced-by-count":39,"title":["Orally Bioavailable 6-Chloro-7-methoxy-4(1\n                    <i>H<\/i>\n                    )-quinolones Efficacious against Multiple Stages\nof\n                    <i>Plasmodium<\/i>"],"prefix":"10.1021","volume":"57","author":[{"given":"R. Matthew","family":"Cross","sequence":"first","affiliation":[{"name":"University of South Florida , , CHE 205, 4202 East Fowler Avenue , , ,","place":["Tampa, Florida, United States, 33620"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David L.","family":"Flanigan","sequence":"additional","affiliation":[{"name":"University of South Florida , , CHE 205, 4202 East Fowler Avenue , , ,","place":["Tampa, Florida, United States, 33620"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrii","family":"Monastyrskyi","sequence":"additional","affiliation":[{"name":"University of South Florida , , CHE 205, 4202 East Fowler Avenue , , ,","place":["Tampa, Florida, United States, 33620"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexis N.","family":"LaCrue","sequence":"additional","affiliation":[{"name":"University of South Florida , , 3720 Spectrum Boulevard, Suite 304 , , ,","place":["Tampa, Florida, United States, 33612"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabia\u0301n E.","family":"Sa\u0301enz","sequence":"additional","affiliation":[{"name":"University of South Florida , , 3720 Spectrum Boulevard, Suite 304 , , ,","place":["Tampa, Florida, United States, 33612"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordany R.","family":"Maignan","sequence":"additional","affiliation":[{"name":"University of South Florida , , CHE 205, 4202 East Fowler Avenue , , ,","place":["Tampa, Florida, United States, 33620"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tina S.","family":"Mutka","sequence":"additional","affiliation":[{"name":"University of South Florida , , 3720 Spectrum Boulevard, Suite 304 , , ,","place":["Tampa, Florida, United States, 33612"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen L.","family":"White","sequence":"additional","affiliation":[{"name":"Monash University , , , ,","place":["Parkville, Victoria, Australia, 3052"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David M.","family":"Shackleford","sequence":"additional","affiliation":[{"name":"Monash University , , , ,","place":["Parkville, Victoria, Australia, 3052"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Bathurst","sequence":"additional","affiliation":[{"name":"Medicines for Malaria Venture , 20, route de Pre\u0301-Bois , P.O. Box 1826, 15,","place":["Geneva, Switzerland, 1215"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank R","family":"Fronczek","sequence":"additional","affiliation":[{"name":"Louisiana State University , , , ,","place":["Baton Rouge, Louisiana, United States, 70803"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lukasz","family":"Wojtas","sequence":"additional","affiliation":[{"name":"University of South Florida , , CHE 205, 4202 East Fowler Avenue , , ,","place":["Tampa, Florida, United States, 33620"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wayne C.","family":"Guida","sequence":"additional","affiliation":[{"name":"University of South Florida , , CHE 205, 4202 East Fowler Avenue , , ,","place":["Tampa, Florida, United States, 33620"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan A.","family":"Charman","sequence":"additional","affiliation":[{"name":"Monash University , , , ,","place":["Parkville, Victoria, Australia, 3052"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy N.","family":"Burrows","sequence":"additional","affiliation":[{"name":"Medicines for Malaria Venture , 20, route de Pre\u0301-Bois , P.O. Box 1826, 15,","place":["Geneva, Switzerland, 1215"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis E.","family":"Kyle","sequence":"additional","affiliation":[{"name":"University of South Florida , , 3720 Spectrum Boulevard, Suite 304 , , ,","place":["Tampa, Florida, United States, 33612"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roman","family":"Manetsch","sequence":"additional","affiliation":[{"name":"University of South Florida , , CHE 205, 4202 East Fowler Avenue , , ,","place":["Tampa, Florida, United States, 33620"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2014,8,22]]},"reference":[{"key":"2026090305335725500_cit1","doi-asserted-by":"crossref","first-page":"1266","DOI":"10.1172\/JCI33996","article-title":"Malaria:\nprogress, perils, and prospects\nfor eradication","volume":"118","author":"Greenwood","year":"2008","journal-title":"J. Clin. Invest."},{"key":"2026090305335725500_cit2","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1038\/nature03342","article-title":"The global\ndistribution of clinical episodes of Plasmodium falciparum malaria","volume":"434","author":"Snow","year":"2005","journal-title":"Nature"},{"key":"2026090305335725500_cit3","unstructured":"World Malaria Report\n2012; World Health Organization, 2013."},{"key":"2026090305335725500_cit4","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1056\/NEJMoa0808859","article-title":"Artemisinin\nresistance in Plasmodium\nfalciparum malaria","volume":"361","author":"Dondorp","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"2026090305335725500_cit5","first-page":"54","article-title":"Artemisinin and derivatives\nin the treatment of uncomplicated\nmalaria","volume":"58","author":"White","year":"1998","journal-title":"Med. Trop. (Mars.)"},{"key":"2026090305335725500_cit6","doi-asserted-by":"crossref","first-page":"2619","DOI":"10.1056\/NEJMc0805011","article-title":"Artemisinin\nResistance in Cambodia 1 Study, C. Evidence of artemisinin-resistant\nmalaria in western Cambodia","volume":"359","author":"Noedl","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"2026090305335725500_cit7","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1038\/nature12845","article-title":"Malaria:\nResistance nailed","volume":"505","author":"Plowe","year":"2014","journal-title":"Nature"},{"key":"2026090305335725500_cit8","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1038\/nature12876","article-title":"A molecular marker\nof artemisinin-resistant Plasmodium\nfalciparum malaria","volume":"505","author":"Ariey","year":"2014","journal-title":"Nature"},{"key":"2026090305335725500_cit9","doi-asserted-by":"crossref","first-page":"479","DOI":"10.2174\/156802606776743147","article-title":"A medicinal\nchemistry perspective on 4-aminoquinoline antimalarial drugs","volume":"6","author":"O\u2019Neill","year":"2006","journal-title":"Curr. Top. Med. Chem."},{"key":"2026090305335725500_cit10","first-page":"235","article-title":"Novel Quinoline Antimalarials","volume-title":"Antimalarial Chemotherapy","author":"Stocks","year":"2001"},{"key":"2026090305335725500_cit11","doi-asserted-by":"crossref","first-page":"3685","DOI":"10.1021\/jm100057h","article-title":"Development of a new generation of\n4-aminoquinoline antimalarial compounds using predictive pharmacokinetic\nand toxicology models","volume":"53","author":"Ray","year":"2010","journal-title":"J. Med. Chem."},{"key":"2026090305335725500_cit12","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1038\/nature02779","article-title":"Identification\nof an antimalarial synthetic trioxolane drug development candidate","volume":"430","author":"Vennerstrom","year":"2004","journal-title":"Nature"},{"key":"2026090305335725500_cit13","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1002\/cber.19480810103","article-title":"U\u0308ber einen neuen, gegen Vogelmalaria\nwirksamen Verbindungstypus","volume":"81","author":"Salzer","year":"1948","journal-title":"Chem. Ber."},{"key":"2026090305335725500_cit14","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1021\/jm00248a030","article-title":"4(1H)-quinolones.\n2. Antimalarial effect of some 2-methyl-3-(1\u2032-alkenyl)-or-3-alkyl-4(1H)-quinolones","volume":"17","author":"Casey","year":"1974","journal-title":"J. Med. Chem."},{"key":"2026090305335725500_cit15","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1002\/jhet.5570090242","article-title":"Synthesis of Some 2-Methyl-3-(2\u2032-Alkenyl)-4(1h)Quinolones","volume":"9","author":"Casey","year":"1972","journal-title":"J. Heterocycl. Chem."},{"key":"2026090305335725500_cit16","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1016\/0035-9203(90)90066-N","article-title":"Quinoline esters as potential antimalarial drugs: effect\non relapses of Plasmodium cynomolgi infections in monkeys","volume":"84","author":"Puri","year":"1990","journal-title":"Trans. R. Soc. Trop. Med. Hyg."},{"key":"2026090305335725500_cit17","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1080\/00034983.1970.11686683","article-title":"The antimalarial activity of some quinolone esters","volume":"64","author":"Ryley","year":"1970","journal-title":"Ann. Trop. Med. Parasitol."},{"key":"2026090305335725500_cit18","doi-asserted-by":"crossref","first-page":"5214","DOI":"10.1016\/j.bmcl.2011.07.044","article-title":"Potent antimalarial\n4-pyridones with improved physico-chemical properties","volume":"21","author":"Bueno","year":"2011","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"2026090305335725500_cit19","doi-asserted-by":"crossref","first-page":"2845","DOI":"10.1021\/jm0705760","article-title":"Synthesis and structure-activity\nrelationships of 4-pyridones as potential antimalarials","volume":"51","author":"Yeates","year":"2008","journal-title":"J. Med. Chem."},{"key":"2026090305335725500_cit20","doi-asserted-by":"crossref","first-page":"7076","DOI":"10.1021\/jm1007903","article-title":"Endochin optimization: structure-activity and structure-property\nrelationship studies of 3-substituted 2-methyl-4(1H)-quinolones with\nantimalarial activity","volume":"53","author":"Cross","year":"2010","journal-title":"J. Med. Chem."},{"key":"2026090305335725500_cit21","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1016\/j.exppara.2010.10.016","article-title":"Optimization of\nendochin-like quinolones for antimalarial\nactivity","volume":"127","author":"Winter","year":"2011","journal-title":"Exp. Parasitol."},{"key":"2026090305335725500_cit22","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.3005029","article-title":"Quinolone-3-diarylethers:\na new class of antimalarial drug","volume":"5","author":"Nilsen","year":"2013","journal-title":"Sci. Transl.\nMed."},{"key":"2026090305335725500_cit23","doi-asserted-by":"crossref","first-page":"1831","DOI":"10.1021\/jm201179h","article-title":"Identification,\ndesign and biological evaluation of\nbisaryl quinolones targeting Plasmodium falciparum type II NADH:quinone\noxidoreductase (PfNDH2)","volume":"55","author":"Pidathala","year":"2012","journal-title":"J. Med. Chem."},{"key":"2026090305335725500_cit24","doi-asserted-by":"crossref","first-page":"8298","DOI":"10.1073\/pnas.1205651109","article-title":"Generation of quinolone\nantimalarials targeting the Plasmodium falciparum mitochondrial respiratory\nchain for the treatment and prophylaxis of malaria","volume":"109","author":"Biagini","year":"2012","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2026090305335725500_cit25","doi-asserted-by":"crossref","first-page":"8321","DOI":"10.1021\/jm200718m","article-title":"Synthesis, antimalarial activity, and structure-activity\nrelationship of 7-(2-phenoxyethoxy)-4(1H)-quinolones","volume":"54","author":"Cross","year":"2011","journal-title":"J. Med. Chem."},{"key":"2026090305335725500_cit26","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1039\/C1MD00183C","article-title":"The development of quinolone esters\nas novel antimalarial agents targeting the Plasmodium falciparum bc(1)\nprotein complex","volume":"3","author":"Cowley","year":"2012","journal-title":"MedChemComm"},{"key":"2026090305335725500_cit27","doi-asserted-by":"crossref","first-page":"4205","DOI":"10.1021\/jm201642z","article-title":"Lead optimization of 3-carboxyl-4(1H)-quinolones\nto deliver orally bioavailable antimalarials","volume":"55","author":"Zhang","year":"2012","journal-title":"J. Med. Chem."},{"key":"2026090305335725500_cit28","doi-asserted-by":"crossref","first-page":"4399","DOI":"10.1021\/jm200015a","article-title":"Optimization of 1,2,3,4-tetrahydroacridin-9(10H)-ones\nas antimalarials utilizing structure-activity and structure-property\nrelationships","volume":"54","author":"Cross","year":"2011","journal-title":"J. Med. Chem."},{"key":"2026090305335725500_cit29","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1038\/nature07937","article-title":"Discovery\nof dual\nfunction acridones as a new antimalarial chemotype","volume":"459","author":"Kelly","year":"2009","journal-title":"Nature"},{"key":"2026090305335725500_cit30","doi-asserted-by":"crossref","first-page":"3818","DOI":"10.1021\/jm500147k","article-title":"Discovery,\nSynthesis, and Optimization of Antimalarial 4(1H)-Quinolone-3-Diarylethers","volume":"57","author":"Nilsen","year":"2014","journal-title":"J. Med. Chem."},{"key":"2026090305335725500_cit31","doi-asserted-by":"crossref","first-page":"8654","DOI":"10.1021\/jo1014504","article-title":"Divergent route to access structurally diverse 4-quinolones\nvia mono or sequential cross-couplings","volume":"75","author":"Cross","year":"2010","journal-title":"J. Org.\nChem."},{"key":"2026090305335725500_cit32","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1128\/AAC.16.6.710","article-title":"Quantitative assessment\nof antimalarial activity in vitro by a semiautomated microdilution\ntechnique","volume":"16","author":"Desjardins","year":"1979","journal-title":"Antimicrob. Agents Chemother."},{"key":"2026090305335725500_cit33","doi-asserted-by":"crossref","first-page":"62","DOI":"10.4269\/ajtmh.1996.54.62","article-title":"Clinical studies\nof atovaquone, alone or in combination\nwith other antimalarial drugs, for treatment of acute uncomplicated\nmalaria in Thailand","volume":"54","author":"Looareesuwan","year":"1996","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"2026090305335725500_cit34","first-page":"61","article-title":"In vitro strategies\nfor circumventing antimalarial drug resistance","volume":"313","author":"Milhous","year":"1989","journal-title":"Prog. Clin. Biol. Res."},{"key":"2026090305335725500_cit35","doi-asserted-by":"crossref","first-page":"2311","DOI":"10.4155\/fmc.12.177","article-title":"Exploration\nof 4(IH)-pyridones as a novel family of potent antimalarial inhibitors\nof the plasmodial cytochrome bcl","volume":"4","author":"Bueno","year":"2012","journal-title":"Future Med.\nChem."},{"key":"2026090305335725500_cit36","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1002\/cmdc.201000485","article-title":"Revealing\natropisomer axial chirality in drug discovery","volume":"6","author":"LaPlante","year":"2011","journal-title":"ChemMedChem"},{"key":"2026090305335725500_cit37","doi-asserted-by":"crossref","first-page":"7005","DOI":"10.1021\/jm200584g","article-title":"Assessing atropisomer\naxial chirality in drug discovery and development","volume":"54","author":"LaPlante","year":"2011","journal-title":"J. Med. Chem."},{"key":"2026090305335725500_cit38","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1021\/jm101356p","article-title":"Improvement in aqueous solubility in small molecule\ndrug discovery programs by disruption of molecular planarity and symmetry","volume":"54","author":"Ishikawa","year":"2011","journal-title":"J. Med. Chem."},{"key":"2026090305335725500_cit39","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1128\/AAC.00793-12","article-title":"4(1H)-Quinolones\nwith liver stage activity against Plasmodium berghei","volume":"57","author":"Lacrue","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"2026090305335725500_cit40","doi-asserted-by":"crossref","first-page":"6187","DOI":"10.1128\/AAC.00492-13","article-title":"4-(1H)-Quinolones and 1,2,3,4-tetrahydroacridin-9(10H)-ones\nprevent the transmission of Plasmodium falciparum to Anopheles freeborni","volume":"57","author":"Saenz","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"2026090305335725500_cit41","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1002\/jps.20012","article-title":"Evaluation\nof the protein binding ratio of drugs by a micro-scale ultracentrifugation\nmethod","volume":"93","author":"Nakai","year":"2004","journal-title":"J. Pharm. Sci."}],"container-title":["Journal of Medicinal Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/jm500942v","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jmcmar\/article-pdf\/57\/21\/8860\/12876857\/jm500942v.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jmcmar\/article-pdf\/57\/21\/8860\/12876857\/jm500942v.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T09:34:09Z","timestamp":1788428049000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jmcmar\/article\/57\/21\/8860\/1300535\/Orally-Bioavailable-6-Chloro-7-methoxy-4-1H"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,8,22]]},"references-count":41,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2014,8,22]]},"published-print":{"date-parts":[[2014,11,13]]}},"URL":"https:\/\/doi.org\/10.1021\/jm500942v","relation":{},"ISSN":["0022-2623","1520-4804"],"issn-type":[{"value":"0022-2623","type":"print"},{"value":"1520-4804","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,8,22]]}}}