期刊
CHEMMEDCHEM
卷 10, 期 12, 页码 2080-2089出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201500429
关键词
diastereoselectivity; drug design; dual-stage antimalarials; malaria; nitrogen heterocycles
资金
- Fundacao para a Ciencia e a Tecnologia (FCT) through iMed.ULisboa [UID/DTP/04138/2013]
- European Social Fund for the IF Program [IF/00732/2013]
- [PTDC/QUI-QUI/111664/2009]
- [PTDC/SAU-MIC/117060/2010]
- Fundação para a Ciência e a Tecnologia [PTDC/SAU-MIC/117060/2010, UID/DTP/04138/2013, PTDC/QUI-QUI/111664/2009] Funding Source: FCT
Malaria 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 -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 parasites life cycle with low cytotoxicity and excellent metabolic and chemical stability in vitro.
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