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Enantiopure Indolizinoindolones with in vitro Activity against Blood‐ and Liver‐Stage Malaria Parasites
Author(s) -
Pereira Nuno A. L.,
Monteiro Ângelo,
Machado Marta,
Gut Jiri,
Molins Elies,
Perry M. Jesus,
Dourado Jorge,
Moreira Rui,
Rosenthal Philip J.,
Prudêncio Miguel,
Santos Maria M. M.
Publication year - 2015
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201500429
Subject(s) - enantiopure drug , malaria , plasmodium falciparum , plasmodium berghei , parasite hosting , in vitro , cytotoxicity , biology , plasmodium (life cycle) , metabolic stability , chloroquine , pharmacology , chemistry , biochemistry , combinatorial chemistry , immunology , enantioselective synthesis , world wide web , computer science , catalysis
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 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.