{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T21:08:13Z","timestamp":1768770493196,"version":"3.49.0"},"reference-count":40,"publisher":"American Society for Microbiology","issue":"2","license":[{"start":{"date-parts":[[2014,2,1]],"date-time":"2014-02-01T00:00:00Z","timestamp":1391212800000},"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":[[2014,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Quinine and other cinchona-derived alkaloids, although recently supplanted by the artemisinins (ARTs), continue to be important for treatment of severe malaria. Quinine and quinidine have narrow therapeutic indices, and a safer quinine analog is desirable, particularly with the continued threat of antimalarial drug resistance. Hydroxyethylapoquinine (HEAQ), used at 8 g a day for dosing in humans in the 1930s and halving mortality from bacterial pneumonias, was shown to cure bird malaria in the 1940s and was also reported as treatment for human malaria cases. Here we describe synthesis of HEAQ and its novel stereoisomer hydroxyethylapoquinidine (HEAQD) along with two intermediates, hydroxyethylquinine (HEQ) and hydroxyethylquinidine (HEQD), and demonstrate comparable but elevated antimalarial 50% inhibitory concentrations (IC\n            <jats:sub>50<\/jats:sub>\n            ) of 100 to 200 nM against\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Plasmodium falciparum<\/jats:named-content>\n            quinine-sensitive strain 3D7 (IC\n            <jats:sub>50<\/jats:sub>\n            , 56 nM). Only HEAQD demonstrated activity against quinine-tolerant\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">P. falciparum<\/jats:named-content>\n            strains Dd2 and INDO with IC\n            <jats:sub>50<\/jats:sub>\n            s of 300 to 700 nM. HEQD had activity only against Dd2 with an IC\n            <jats:sub>50<\/jats:sub>\n            of 313 nM. In the lethal mouse malaria model\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Plasmodium berghei<\/jats:named-content>\n            ANKA, only HEQD had activity at 20 mg\/kg of body weight comparable to that of the parent quinine or quinidine drugs measured by parasite inhibition and 30-day survival. In addition, HEQ, HEQD, and HEAQ (IC\n            <jats:sub>50<\/jats:sub>\n            \u2265 90 \u03bcM) have little to no human ether-\u00e0-go-go-related gene (hERG) channel inhibition expressed in CHO cells compared to HEAQD, quinine, and quinidine (hERG IC\n            <jats:sub>50<\/jats:sub>\n            s of 27, 42, and 4 \u03bcM, respectively). HEQD more closely resembled quinine\n            <jats:italic>in vitro<\/jats:italic>\n            and\n            <jats:italic>in vivo<\/jats:italic>\n            for\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Plasmodium<\/jats:named-content>\n            inhibition and demonstrated little hERG channel inhibition, suggesting that further optimization and preclinical studies are warranted for this molecule.\n          <\/jats:p>","DOI":"10.1128\/aac.01704-13","type":"journal-article","created":{"date-parts":[[2013,11,19]],"date-time":"2013-11-19T04:59:32Z","timestamp":1384837172000},"page":"820-827","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":20,"title":["Antimalarial Efficacy of Hydroxyethylapoquinine (SN-119) and Its Derivatives"],"prefix":"10.1128","volume":"58","author":[{"given":"Natalie G.","family":"Sanders","sequence":"first","affiliation":[{"name":"W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David J.","family":"Meyers","sequence":"additional","affiliation":[{"name":"Johns Hopkins University School of Medicine, Department of Pharmacology and Molecular Sciences, Baltimore, Maryland, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David J.","family":"Sullivan","sequence":"additional","affiliation":[{"name":"W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","volume-title":"World malaria report","author":"WHO","year":"2012","unstructured":"WHO. 17 December 2012, posting date. World malaria report. WHO, Geneva, Switzerland. http:\/\/www.who.int\/malaria\/publications\/world_malaria_report_2012\/en\/."},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(12)60034-8"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1186\/1475-2875-10-116"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1097\/QCO.0b013e32834cd3ed"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.4103\/0255-0857.83906"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1186\/1475-2875-9-247"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1186\/1475-2875-10-144"},{"key":"e_1_3_2_9_2","first-page":"45","volume-title":"Treatment and prevention of malaria","author":"Sullivan DJ","year":"2012","unstructured":"SullivanDJ. 2012. Cinchona alkaloids: quinine and quinidine, p 45\u201368. In StainesHMKrishnaS (ed), Treatment and prevention of malaria. Springer Basel AG, Basel, Switzerland."},{"key":"e_1_3_2_10_2","volume-title":"Guidelines for the treatment of malaria","author":"WHO","year":"2010","unstructured":"WHO. 9 March 2010, posting date. Guidelines for the treatment of malaria, 2nd ed. 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