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Here, we report the discovery of a novel class of potential antimalarial compounds containing an indolizinoindolone scaffold. These novel enantiopure indolizinoindolones were synthesized, in good\u2010to\u2010excellent yields and excellent diastereoselectivities, by cyclocondensation reaction of (<jats:italic>S<\/jats:italic>)\u2010 or (<jats:italic>R<\/jats:italic>)\u2010tryptophanol and 2\u2010acyl benzoic acids, followed by intramolecular \u03b1\u2010amidoalkylation. Interestingly, we were able to synthesize for the first time 7,13b\u2010<jats:italic>cis<\/jats:italic> indolizinoindolones in a two\u2010step route. The novel compounds showed promising activity against erythrocytic stages of the human malaria parasite, <jats:italic>Plasmodium falciparum<\/jats:italic>, and liver stages of the rodent parasite <jats:italic>Plasmodium berghei<\/jats:italic>. In particular, an (<jats:italic>S<\/jats:italic>)\u2010tryptophanol\u2010derived isoindolinone was identified as a promising starting scaffold to search for novel antimalarials, combining excellent activity against both stages of the parasite\u2032s life cycle with low cytotoxicity and excellent metabolic and chemical stability in vitro.<\/jats:p>","DOI":"10.1002\/cmdc.201500429","type":"journal-article","created":{"date-parts":[[2015,11,3]],"date-time":"2015-11-03T07:03:16Z","timestamp":1446534196000},"page":"2080-2089","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["Enantiopure Indolizinoindolones with in vitro Activity against Blood\u2010 and Liver\u2010Stage Malaria Parasites"],"prefix":"10.1002","volume":"10","author":[{"given":"Nuno A. L.","family":"Pereira","sequence":"first","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa) Faculty of Pharmacy Universidade de Lisboa  Av. Prof. Gama Pinto 1649-003 Lisboa Portugal"}]},{"given":"\u00c2ngelo","family":"Monteiro","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa) Faculty of Pharmacy Universidade de Lisboa  Av. Prof. Gama Pinto 1649-003 Lisboa Portugal"}]},{"given":"Marta","family":"Machado","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Molecular Faculdade de Medicina da Universidade de Lisboa  Av. Prof. Egas Moniz 1649-028 Lisboa Portugal"}]},{"given":"Jiri","family":"Gut","sequence":"additional","affiliation":[{"name":"Department of Medicine San Francisco General Hospital University of California  San Francisco CA 94143 USA"}]},{"given":"Elies","family":"Molins","sequence":"additional","affiliation":[{"name":"Institut de Ci\u00e8ncia de Materials de Barcelona (CSIC)  Campus UAB 08193 Cerdanyola Spain"}]},{"given":"M. Jesus","family":"Perry","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa) Faculty of Pharmacy Universidade de Lisboa  Av. Prof. Gama Pinto 1649-003 Lisboa Portugal"}]},{"given":"Jorge","family":"Dourado","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa) Faculty of Pharmacy Universidade de Lisboa  Av. Prof. Gama Pinto 1649-003 Lisboa Portugal"}]},{"given":"Rui","family":"Moreira","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa) Faculty of Pharmacy Universidade de Lisboa  Av. Prof. Gama Pinto 1649-003 Lisboa Portugal"}]},{"given":"Philip J.","family":"Rosenthal","sequence":"additional","affiliation":[{"name":"Department of Medicine San Francisco General Hospital University of California  San Francisco CA 94143 USA"}]},{"given":"Miguel","family":"Prud\u00eancio","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Molecular Faculdade de Medicina da Universidade de Lisboa  Av. Prof. Egas Moniz 1649-028 Lisboa Portugal"}]},{"given":"Maria M. M.","family":"Santos","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa) Faculty of Pharmacy Universidade de Lisboa  Av. 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