{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T09:17:45Z","timestamp":1780478265364,"version":"3.54.1"},"reference-count":25,"publisher":"Wiley","issue":"22","license":[{"start":{"date-parts":[[2022,10,13]],"date-time":"2022-10-13T00:00:00Z","timestamp":1665619200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004423","name":"World Health Organization","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004423","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2022,11,18]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>New antimalarial treatments with novel mechanism of action are needed to tackle <jats:italic>Plasmodium falciparum<\/jats:italic> infections that are resistant to first\u2010line therapeutics. Here we report the exploration of MMV692140 (<jats:bold>2<\/jats:bold>) from the Pathogen Box, a collection of 400 compounds that was made available by Medicines for Malaria Venture (MMV) in 2015. Compound <jats:bold>2<\/jats:bold> was profiled in <jats:italic>in\u2005vitro<\/jats:italic> models of malaria and was found to be active against multiple life\u2010cycle stages of <jats:italic>Plasmodium<\/jats:italic> parasites. The mode of resistance, and putatively its mode of action, was identified as <jats:italic>Plasmodium falciparum<\/jats:italic> translation elongation factor 2 (<jats:italic>Pf<\/jats:italic>eEF2), which is responsible for the GTP\u2010dependent translocation of the ribosome along mRNA. The compound maintains activity against a series of drug\u2010resistant parasite strains. The structural motif of the tetrahydroquinoline (<jats:bold>2<\/jats:bold>) was explored in a chemistry program with its structure\u2010activity relationships examined, resulting in the identification of an analog with 30\u2010fold improvement of antimalarial asexual blood stage potency.<\/jats:p>","DOI":"10.1002\/cmdc.202200393","type":"journal-article","created":{"date-parts":[[2022,9,21]],"date-time":"2022-09-21T10:18:44Z","timestamp":1663755524000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Exploring a Tetrahydroquinoline Antimalarial Hit from the Medicines for Malaria Pathogen Box and Identification of its Mode of Resistance as <i>Pf<\/i>eEF2"],"prefix":"10.1002","volume":"17","author":[{"given":"Beno\u00eet","family":"Laleu","sequence":"first","affiliation":[{"name":"Medicines for Malaria Venture International Centre Cointrin  Route de Pr\u00e9-Bois 20, P.O. Box 1826 1215 Geneva 15 Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly","family":"Rubiano","sequence":"additional","affiliation":[{"name":"Department of Microbiology &amp; Immunology Columbia University Irving Medical Center  New York, NY 10032 USA"},{"name":"Current address Department of Molecular Microbiology Washington University School of Medicine  Saint Louis MO 63110 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomas","family":"Yeo","sequence":"additional","affiliation":[{"name":"Department of Microbiology &amp; Immunology Columbia University Irving Medical Center  New York, NY 10032 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Hallyburton","sequence":"additional","affiliation":[{"name":"Drug Discovery Unit Wellcome Centre for Anti-infective Research University of Dundee  Dow Street Dundee DD1 5EH UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Anderson","sequence":"additional","affiliation":[{"name":"Drug Discovery Unit Wellcome Centre for Anti-infective Research University of Dundee  Dow Street Dundee DD1 5EH UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benigno","family":"Crespo\u2010Fernandez","sequence":"additional","affiliation":[{"name":"Global Health GlaxoSmithKline R&amp;D  Tres Cantos 28760 Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco\u2010Javier","family":"Gamo","sequence":"additional","affiliation":[{"name":"Global Health GlaxoSmithKline R&amp;D  Tres Cantos 28760 Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yevgeniya","family":"Antonova\u2010Koch","sequence":"additional","affiliation":[{"name":"Department of Pediatrics School of Medicine University of California San Diego  La Jolla CA 92093 USA"},{"name":"Current address Calibr A Division of Scripps Research  11119 North Torrey Pines Road La Jola CA 92037 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela","family":"Orjuela\u2010Sanchez","sequence":"additional","affiliation":[{"name":"Department of Pediatrics School of Medicine University of California San Diego  La Jolla CA 92093 USA"},{"name":"Current address Novartis Institute for Tropical Diseases  5959 Horton Street, 8th floor Emeryville CS 94608 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergio","family":"Wittlin","sequence":"additional","affiliation":[{"name":"Swiss Tropical and Public Health Institute  Socinstrasse 57 4002 Basel Switzerland"},{"name":"University of Basel  4002 Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gouranga P.","family":"Jana","sequence":"additional","affiliation":[{"name":"TCG Lifesciences Private Limited  Block BN, Plot 7 Salt-lake Electronics Complex, Sector V Kolkata 700091 West Bengal India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bikash C.","family":"Maity","sequence":"additional","affiliation":[{"name":"TCG Lifesciences Private Limited  Block BN, Plot 7 Salt-lake Electronics Complex, Sector V Kolkata 700091 West Bengal India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elodie","family":"Chenu","sequence":"additional","affiliation":[{"name":"Medicines for Malaria Venture International Centre Cointrin  Route de Pr\u00e9-Bois 20, P.O. Box 1826 1215 Geneva 15 Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Duffy","sequence":"additional","affiliation":[{"name":"Medicines for Malaria Venture International Centre Cointrin  Route de Pr\u00e9-Bois 20, P.O. Box 1826 1215 Geneva 15 Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Sj\u00f6","sequence":"additional","affiliation":[{"name":"Medicines for Malaria Venture International Centre Cointrin  Route de Pr\u00e9-Bois 20, P.O. Box 1826 1215 Geneva 15 Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Waterson","sequence":"additional","affiliation":[{"name":"Medicines for Malaria Venture International Centre Cointrin  Route de Pr\u00e9-Bois 20, P.O. Box 1826 1215 Geneva 15 Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Winzeler","sequence":"additional","affiliation":[{"name":"Department of Pediatrics School of Medicine University of California San Diego  La Jolla CA 92093 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Guantai","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Faculty of Health Sciences University of Nairobi  00202- Nairobi Kenya"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Fidock","sequence":"additional","affiliation":[{"name":"Department of Microbiology &amp; Immunology Columbia University Irving Medical Center  New York, NY 10032 USA"},{"name":"Division of Infectious Diseases Department of Medicine Columbia University Irving Medical Center  New York, NY 10032 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3177-5522","authenticated-orcid":false,"given":"Thomas G.","family":"Hansson","sequence":"additional","affiliation":[{"name":"Medicines for Malaria Venture International Centre Cointrin  Route de Pr\u00e9-Bois 20, P.O. Box 1826 1215 Geneva 15 Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,10,13]]},"reference":[{"key":"e_1_2_8_1_1","unstructured":"WHO.World Malaria Report2021; World Health Organization2021."},{"key":"e_1_2_8_2_1","unstructured":"\u00a0"},{"key":"e_1_2_8_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0808859"},{"key":"e_1_2_8_4_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1314981"},{"key":"e_1_2_8_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature12876"},{"key":"e_1_2_8_6_1","unstructured":"\u00a0"},{"key":"e_1_2_8_7_2","unstructured":"https:\/\/www.mmv.org\/mmv-open\/pathogen-box\/about-pathogen-box;"},{"key":"e_1_2_8_8_2","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.201800755"},{"key":"e_1_2_8_9_2","unstructured":"https:\/\/www.mmv.org\/newsroom\/news\/over-5-million-compounds-screened."},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature09107"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1211936"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0030949"},{"key":"e_1_2_8_13_1","unstructured":"\u00a0"},{"key":"e_1_2_8_14_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1009384"},{"key":"e_1_2_8_15_2","unstructured":"https:\/\/www.mmv.org\/research-development\/information-scientists."},{"key":"e_1_2_8_16_1","unstructured":"All results on compounds from the 72-hour 3D7 strain assay in Table\u20052\u20134 were generated at University of Dundee except compound 35 where results was generated at TCGLS. Please see Supporting Information for details."},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature14451"},{"key":"e_1_2_8_17_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02181-19"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.exppara.2006.09.016"},{"key":"e_1_2_8_19_1","unstructured":"\u00a0"},{"key":"e_1_2_8_20_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12936-019-2724-z"},{"key":"e_1_2_8_21_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.9b00761"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aad9735"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaa6645"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.04149-14"}],"container-title":["ChemMedChem"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cmdc.202200393","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cmdc.202200393","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cmdc.202200393","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T13:46:39Z","timestamp":1760276799000},"score":1,"resource":{"primary":{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/10.1002\/cmdc.202200393"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,13]]},"references-count":25,"journal-issue":{"issue":"22","published-print":{"date-parts":[[2022,11,18]]}},"alternative-id":["10.1002\/cmdc.202200393"],"URL":"https:\/\/doi.org\/10.1002\/cmdc.202200393","archive":["Portico"],"relation":{},"ISSN":["1860-7179","1860-7187"],"issn-type":[{"value":"1860-7179","type":"print"},{"value":"1860-7187","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,13]]},"assertion":[{"value":"2022-07-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-10-13","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e202200393"}}