{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T09:26:22Z","timestamp":1787045182188,"version":"build-2736575974"},"reference-count":18,"publisher":"American Chemical Society (ACS)","issue":"7","license":[{"start":{"date-parts":[[2020,5,5]],"date-time":"2020-05-05T00:00:00Z","timestamp":1588636800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2020,5,5]],"date-time":"2020-05-05T00:00:00Z","timestamp":1588636800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2020,5,5]],"date-time":"2020-05-05T00:00:00Z","timestamp":1588636800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI105106"],"award-info":[{"award-number":["AI105106"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,7,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The emergence of artemisinin resistance, combined with certain suboptimal properties of ozonide agents arterolane and artefenomel, has necessitated the search for new drug candidates in the endoperoxide class. Our group has focused on trioxolane analogues with substitution patterns not previously explored. Here, we describe the enantioselective synthesis of analogues bearing a trans-3\u2033 carbamate side chain and find these to be superior, both in vitro and in vivo, to the previously reported amides. We identified multiple analogues that surpass the oral efficacy of arterolane in the Plasmodium berghei model while exhibiting drug-like properties (logD, solubility, metabolic stability) similar or superior to next-generation clinical candidates like E209 and OZ609. While the preclinical assessment of new analogues is still underway, current data suggest the potential of this chemotype as a likely source of future drug candidates from the endoperoxide class.<\/jats:p>","DOI":"10.1021\/acsinfecdis.0c00064","type":"journal-article","created":{"date-parts":[[2020,5,5]],"date-time":"2020-05-05T14:14:32Z","timestamp":1588688072000},"page":"1827-1835","source":"Crossref","is-referenced-by-count":27,"title":["Antimalarial Trioxolanes with Superior Drug-Like Properties\nand In Vivo Efficacy"],"prefix":"10.1021","volume":"6","author":[{"given":"Brian\nR.","family":"Blank","sequence":"first","affiliation":[{"name":"University of California, San Francisco , , 600 16th Street , , ,","place":["San Francisco, California, United States, 94143"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan L.","family":"Gonciarz","sequence":"additional","affiliation":[{"name":"University of California, San Francisco , , 600 16th Street , , ,","place":["San Francisco, California, United States, 94143"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Poulami","family":"Talukder","sequence":"additional","affiliation":[{"name":"University of California, San Francisco , , 600 16th Street , , ,","place":["San Francisco, California, United States, 94143"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiri","family":"Gut","sequence":"additional","affiliation":[{"name":"University of California , , , ,","place":["San\nFrancisco, California, United States, 94143"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Legac","sequence":"additional","affiliation":[{"name":"University of California , , , ,","place":["San\nFrancisco, California, United States, 94143"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip J.","family":"Rosenthal","sequence":"additional","affiliation":[{"name":"University of California , , , ,","place":["San\nFrancisco, California, United States, 94143"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1240-2846","authenticated-orcid":true,"given":"Adam R.","family":"Renslo","sequence":"additional","affiliation":[{"name":"University of California, San Francisco , , 600 16th Street , , ,","place":["San Francisco, California, United States, 94143"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2020,5,5]]},"reference":[{"key":"2026081722182840300_cit1","unstructured":"World Malaria Report\n2019 (2019), World Health\nOrganization, Geneva,\nSwitzerland."},{"key":"2026081722182840300_cit2","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1016\/S1473-3099(15)00487-9","article-title":"Dihydroartemisinin\u2013Piperaquine\nResistance in Plasmodium Falciparum Malaria in Cambodia: A Multisite\nProspective Cohort Study","volume":"16","author":"Amaratunga","year":"2016","journal-title":"Lancet Infect. Dis."},{"key":"2026081722182840300_cit3","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1126\/science.aax4735","article-title":"A Kelch13-defined\nendocytosis pathway mediates artemisinin\nresistance in malaria parasites","volume":"367","author":"Birnbaum","year":"2020","journal-title":"Science"},{"key":"2026081722182840300_cit4","doi-asserted-by":"publisher","first-page":"4400","DOI":"10.1073\/pnas.1015762108","article-title":"Synthetic\nozonide drug candidate OZ439 offers new hope for a single-dose cure\nof uncomplicated malaria","volume":"108","author":"Charman","year":"2011","journal-title":"Proc. Natl. Acad.\nSci. U. S. A."},{"key":"2026081722182840300_cit5","doi-asserted-by":"publisher","first-page":"e00172","DOI":"10.1128\/mBio.00172-17","article-title":"Plasmodium falciparum K13 Mutations\nDifferentially Impact Ozonide Susceptibility and Parasite Fitness\nIn Vitro","volume":"8","author":"Straimer","year":"2017","journal-title":"mBio"},{"key":"2026081722182840300_cit6","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1186\/s12936-017-1696-0","article-title":"In vitro activity of anti-malarial\nozonides against an artemisinin-resistant isolate","volume":"16","author":"Baumga\u0308rtner","year":"2017","journal-title":"Malar. J."},{"key":"2026081722182840300_cit7","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1186\/s12936-019-3056-8","article-title":"Anti-malarial ozonides OZ439 and\nOZ609 tested at clinically\nrelevant compound exposure parameters in a novel ring-stage survival\nassay","volume":"18","author":"Walz","year":"2019","journal-title":"Malar. J."},{"key":"2026081722182840300_cit8","doi-asserted-by":"publisher","first-page":"3535","DOI":"10.1021\/acs.molpharmaceut.8b00541","article-title":"Interactions of\nArtefenomel (OZ439)\nwith Milk during Digestion: Insights into Digestion-Driven Solubilization\nand Polymorphic Transformations","volume":"15","author":"Salim","year":"2018","journal-title":"Mol. Pharmaceutics"},{"key":"2026081722182840300_cit9","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1016\/S1473-3099(15)00320-5","article-title":"Antimalarial\nActivity of Artefenomel\n(OZ439), a Novel Synthetic Antimalarial Endoperoxide, in Patients\nwith Plasmodium Falciparum and Plasmodium Vivax Malaria: An Open-Label\nPhase 2 Trial","volume":"16","author":"Phyo","year":"2016","journal-title":"Lancet Infect. Dis."},{"key":"2026081722182840300_cit10","doi-asserted-by":"publisher","first-page":"15159","DOI":"10.1038\/ncomms15159","article-title":"A tetraoxane-based antimalarial drug candidate that\novercomes PfK13-C580Y dependent artemisinin resistance","volume":"8","author":"O\u2019Neill","year":"2017","journal-title":"Nat. Commun."},{"key":"2026081722182840300_cit11","doi-asserted-by":"publisher","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":"2026081722182840300_cit12","doi-asserted-by":"publisher","first-page":"2945","DOI":"10.1002\/jps.20958","article-title":"Iron-Mediated Degradation\nKinetics of Substituted Dispiro-1,2,4-Trioxolane Antimalarials","volume":"96","author":"Creek","year":"2007","journal-title":"J. Pharm. Sci."},{"key":"2026081722182840300_cit13","doi-asserted-by":"publisher","first-page":"6400","DOI":"10.1021\/acs.jmedchem.7b00699","article-title":"Enantioselective Synthesis and in\nVivo Evaluation of Regioisomeric Analogues of the Antmalarial Arterolane","volume":"60","author":"Blank","year":"2017","journal-title":"J. Med. Chem."},{"key":"2026081722182840300_cit14","doi-asserted-by":"publisher","first-page":"5776","DOI":"10.1021\/ol5028392","article-title":"Efficient and stereocontrolled\nsynthesis\nof 1,2,4-trioxolanes useful for ferrous iron-dependent drug delivery","volume":"16","author":"Fontaine","year":"2014","journal-title":"Org. Lett."},{"key":"2026081722182840300_cit15","doi-asserted-by":"publisher","first-page":"6577","DOI":"10.1039\/b914207j","article-title":"Catalytic enantioselective boron conjugate addition to cyclic carbonyl\ncompounds: a new approach to cyclic \u03b2-hydroxy carbonyls","author":"Feng","year":"2009","journal-title":"Chem. Commun."},{"key":"2026081722182840300_cit16","doi-asserted-by":"publisher","first-page":"4384","DOI":"10.1073\/pnas.0307720101","article-title":"Gene disruption\nconfirms a critical role for the cysteine\nprotease falcipain-2 in hemoglobin hydrolysis by Plasmodium falciparum","volume":"101","author":"Sijwali","year":"2004","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2026081722182840300_cit17","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12936-019-3075-5","article-title":"An in vitro\ntoolbox\nto accelerate anti-malarial drug discovery and development","volume":"19","author":"Charman","year":"2020","journal-title":"Malar. J."},{"key":"2026081722182840300_cit18","doi-asserted-by":"publisher","first-page":"2654","DOI":"10.1021\/acs.jmedchem.6b01586","article-title":"Structure-Activity\nRelationship of the Antimalarial Ozonide Artefenomel (OZ439)","volume":"60","author":"Dong","year":"2017","journal-title":"J. Med. Chem."}],"container-title":["ACS Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsinfecdis.0c00064","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article-pdf\/6\/7\/1827\/6373279\/id0c00064.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article-pdf\/6\/7\/1827\/6373279\/id0c00064.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T08:35:23Z","timestamp":1787042123000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article\/6\/7\/1827\/618214\/Antimalarial-Trioxolanes-with-Superior-Drug-Like"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,5]]},"references-count":18,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2020,5,5]]},"published-print":{"date-parts":[[2020,7,10]]}},"URL":"https:\/\/doi.org\/10.1021\/acsinfecdis.0c00064","relation":{},"ISSN":["2373-8227"],"issn-type":[{"value":"2373-8227","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,5,5]]}}}