title: Enantiopure Indolizinoindolones with in vitro Activity against Blood- and Liver-Stage Malaria Parasites.
abstract: 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.
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisboa, Portugal.
authors.forename: Nuno A L
authors.initials: NA
authors.lastname: Pereira
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisboa, Portugal.
authors.forename: Ângelo
authors.initials: Â
authors.lastname: Monteiro
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028, Lisboa, Portugal.
authors.forename: Marta
authors.initials: M
authors.lastname: Machado
authors.affiliation: Department of Medicine, San Francisco General Hospital, University of California, San Francisco, CA, 94143, USA.
authors.forename: Jiri
authors.initials: J
authors.lastname: Gut
authors.affiliation: Institut de Ciència de Materials de Barcelona (CSIC), Campus UAB, 08193, Cerdanyola, Spain.
authors.forename: Elies
authors.initials: E
authors.lastname: Molins
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisboa, Portugal.
authors.forename: M Jesus
authors.initials: MJ
authors.lastname: Perry
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisboa, Portugal.
authors.forename: Jorge
authors.initials: J
authors.lastname: Dourado
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisboa, Portugal.
authors.forename: Rui
authors.initials: R
authors.lastname: Moreira
authors.affiliation: Department of Medicine, San Francisco General Hospital, University of California, San Francisco, CA, 94143, USA.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028, Lisboa, Portugal. mprudencio@medicina.ulisboa.pt.
authors.forename: Miguel
authors.initials: M
authors.lastname: Prudêncio
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisboa, Portugal. mariasantos@ff.ulisboa.pt.
authors.forename: Maria M M
authors.initials: MM
authors.lastname: Santos
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D004912:Erythrocytes / Q000469:parasitology; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology; D008018:Life Cycle Stages / Q000187:drug effects; D051379:Mice; D008968:Molecular Conformation; D010962:Plasmodium berghei / Q000187:drug effects / Q000254:growth & development / Q000302:isolation & purification; D010963:Plasmodium falciparum / Q000187:drug effects / Q000254:growth & development / Q000302:isolation & purification; D013237:Stereoisomerism
chemical_list: D000962:Antimalarials; D007211:Indoles
keywords: diastereoselectivity; drug design; dual-stage antimalarials; malaria; nitrogen heterocycles