{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T15:40:23Z","timestamp":1791560423972,"version":"4.3.4"},"reference-count":34,"publisher":"National Academy of Sciences","issue":"39","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2012,9,25]]},"abstract":"<jats:p>\n                    <jats:italic>Toxoplasma gondii<\/jats:italic>\n                    is a widely distributed protozoan pathogen that causes devastating ocular and central nervous system disease. We show that the endochin-like quinolone (ELQ) class of compounds contains extremely potent inhibitors of\n                    <jats:italic>T. gondii<\/jats:italic>\n                    growth in vitro and is effective against acute and latent toxoplasmosis in mice. We screened 50 ELQs against\n                    <jats:italic>T. gondii<\/jats:italic>\n                    and selected two lead compounds, ELQ-271 and ELQ-316, for evaluation. ELQ-271 and ELQ-316, have in vitro IC\n                    <jats:sub>50<\/jats:sub>\n                    values of 0.1 nM and 0.007 nM, respectively. ELQ-271 and ELQ-316 have ED\n                    <jats:sub>50<\/jats:sub>\n                    values of 0.14 mg\/kg and 0.08 mg\/kg when administered orally to mice with acute toxoplasmosis. Moreover, ELQ-271 and ELQ-316 are highly active against the cyst form of\n                    <jats:italic>T. gondii<\/jats:italic>\n                    in mice at low doses, reducing cyst burden by 76\u201388% after 16 d of treatment. To investigate the ELQ mechanism of action against\n                    <jats:italic>T. gondii<\/jats:italic>\n                    , we demonstrate that endochin and ELQ-271 inhibit cytochrome\n                    <jats:italic>c<\/jats:italic>\n                    reduction by the\n                    <jats:italic>T. gondii<\/jats:italic>\n                    cytochrome\n                    <jats:italic>bc<\/jats:italic>\n                    <jats:sub>1<\/jats:sub>\n                    complex at 8 nM and 31 nM, respectively. We also show that ELQ-271 inhibits the\n                    <jats:italic>Saccharomyces cerevisiae<\/jats:italic>\n                    cytochrome\n                    <jats:italic>bc<\/jats:italic>\n                    <jats:sub>1<\/jats:sub>\n                    complex, and an M221Q amino acid substitution in the Q\n                    <jats:sub>i<\/jats:sub>\n                    site of the protein leads to &gt;100-fold resistance. We conclude that ELQ-271 and ELQ-316 are orally bioavailable drugs that are effective against acute and latent toxoplasmosis, likely acting as inhibitors of the Q\n                    <jats:sub>i<\/jats:sub>\n                    site of the\n                    <jats:italic>T. gondii<\/jats:italic>\n                    cytochrome\n                    <jats:italic>bc<\/jats:italic>\n                    <jats:sub>1<\/jats:sub>\n                    complex.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1208069109","type":"journal-article","created":{"date-parts":[[2012,9,11]],"date-time":"2012-09-11T02:04:27Z","timestamp":1347329067000},"page":"15936-15941","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":192,"title":["Endochin-like quinolones are highly efficacious against acute and latent experimental toxoplasmosis"],"prefix":"10.1073","volume":"109","author":[{"given":"J. Stone","family":"Doggett","sequence":"first","affiliation":[{"name":"Division of Infectious Diseases and"},{"name":"Veterans Administration Medical Center, Portland, OR 97239;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron","family":"Nilsen","sequence":"additional","affiliation":[{"name":"Veterans Administration Medical Center, Portland, OR 97239;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isaac","family":"Forquer","sequence":"additional","affiliation":[{"name":"Veterans Administration Medical Center, Portland, OR 97239;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith W.","family":"Wegmann","sequence":"additional","affiliation":[{"name":"Veterans Administration Medical Center, Portland, OR 97239;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorraine","family":"Jones-Brando","sequence":"additional","affiliation":[{"name":"Stanley Division of Developmental Neurovirology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert H.","family":"Yolken","sequence":"additional","affiliation":[{"name":"Stanley Division of Developmental Neurovirology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Bord\u00f3n","sequence":"additional","affiliation":[{"name":"Stanley Division of Developmental Neurovirology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan A.","family":"Charman","sequence":"additional","affiliation":[{"name":"Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kasiram","family":"Katneni","sequence":"additional","affiliation":[{"name":"Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tracey","family":"Schultz","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy N.","family":"Burrows","sequence":"additional","affiliation":[{"name":"Medicines for Malaria Venture, Geneva 15, Switzerland; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Hinrichs","sequence":"additional","affiliation":[{"name":"Veterans Administration Medical Center, Portland, OR 97239;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brigitte","family":"Meunier","sequence":"additional","affiliation":[{"name":"Centre de G\u00e9n\u00e9tique Mol\u00e9culaire, Unit\u00e9 Propre de Recherche 3404, Centre National de la Recherche Scientifique, Gif-sur-Yvette 91198, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vern B.","family":"Carruthers","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael K.","family":"Riscoe","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR 97239;"},{"name":"Veterans Administration Medical Center, Portland, OR 97239;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2012,9,10]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.4269\/ajtmh.2007.77.405"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1097\/IIO.0b013e3181d26bf4"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/bmt.2010.102"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199212033272306"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1097\/00005792-199207000-00005"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1002\/cber.19480810103"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.4269\/ajtmh.1951.s1-31.12"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.exppara.2010.10.016"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.exppara.2007.10.016"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.47.31040"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-6851(00)00184-5"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molbiopara.2005.12.002"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pt.2007.08.004"},{"key":"e_1_3_3_14_2","doi-asserted-by":"crossref","unstructured":"C Vallieres et al. 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