Pereira, Nuno A. L.Monteiro, ÂngeloMachado, MartaGut, JiriMolins, EliesPerry, Maria JesusDourado, JorgeMoreira, RuiRosenthal, Philip J.Prudêncio, MiguelSantos, Maria M. M.2022-02-112022-02-112015ChemMedChem. 2015 Dec;10(12):2080-20891860-7179http://hdl.handle.net/10451/51232© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, WeinheimMalaria continues to be a major cause of morbidity and mortality to this day, and resistance to drugs like chloroquine has led to an urgent need to discover novel chemical entities aimed at new targets. 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-to-excellent yields and excellent diastereoselectivities, by cyclocondensation reaction of (S)- or (R)-tryptophanol and 2-acyl benzoic acids, followed by intramolecular α-amidoalkylation. Interestingly, we were able to synthesize for the first time 7,13b-cis indolizinoindolones in a two-step route. The novel compounds showed promising activity against erythrocytic stages of the human malaria parasite, Plasmodium falciparum, and liver stages of the rodent parasite Plasmodium berghei. In particular, an (S)-tryptophanol-derived isoindolinone was identified as a promising starting scaffold to search for novel antimalarials, combining excellent activity against both stages of the parasite's life cycle with low cytotoxicity and excellent metabolic and chemical stability in vitro.engDiastereoselectivityDrug designDual-stage antimalarialsMalariaNitrogen heterocyclesjournal article10.1002/cmdc.2015004291860-7187