title: Targeting the erythrocytic and liver stages of malaria parasites with s-triazine-based hybrids.
abstract: A diversity-oriented library of s-triazine-based hybrids was screened for activity against the chloroquine-resistant Plasmodium falciparum W2 strain. The most striking result was sub-micromolar activity against cultured erythrocytic-stage parasites of hybrid molecules containing one or two 8-aminoquinoline moieties. These compounds were not clearly toxic to human cells. The most effective blood-schizontocidal s-triazine derivatives were then screened for activity against the liver stage of malaria parasites. The s-triazine hybrid containing two 8-aminoquinoline moieties and one chlorine atom emerged as the most potent against P. berghei liver-stage infection, active in the low nanomolar region, combined with good metabolic stability in rat liver microsomes. These results indicate that s-triazine-8-aminoquinoline-based hybrids are excellent starting points for lead optimization as dual-stage antimalarials.
authors.affiliation: Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa (Portugal).
authors.forename: Catarina A B
authors.initials: CA
authors.lastname: Rodrigues
authors.forename: Raquel F M
authors.initials: RF
authors.lastname: Frade
authors.forename: Inês S
authors.initials: IS
authors.lastname: Albuquerque
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Perry
authors.forename: Jiri
authors.initials: J
authors.lastname: Gut
authors.forename: Marta
authors.initials: M
authors.lastname: Machado
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
authors.forename: Miguel
authors.initials: M
authors.lastname: Prudêncio
authors.forename: Carlos A M
authors.initials: CA
authors.lastname: Afonso
authors.forename: Rui
authors.initials: R
authors.lastname: Moreira
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D016466:CHO Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000469:parasitology*; D006801:Humans; D008099:Liver / Q000469:parasitology*; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology; D021261:Parasitic Sensitivity Tests; D010962:Plasmodium berghei / Q000187:drug effects*; D010963:Plasmodium falciparum / Q000187:drug effects*; D051381:Rats; D013329:Structure-Activity Relationship; D014227:Triazines / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000962:Antimalarials; D014227:Triazines
keywords: drug design; dual-stage antimalarials; hybrid compounds; molecular diversity; nitrogen heterocycles