title: Synthesis and antimalarial effects of phenothiazine inhibitors of a Plasmodium falciparum cysteine protease.
abstract: Acridinediones have previously been shown to have potent antimalarial activity. A series of sulfur isosteres of acridinediones have been synthesized and evaluated for their inhibition of the Plasmodium falciparum cysteine protease falcipain and for their antimalarial activity. A number of these phenothiazines inhibited falcipain and demonstrated activity against cultured P. falciparum parasites at low micromolar concentrations. We propose that the compounds exerted their antimalarial effects by two mechanisms, one of which involves the inhibition of falcipain and a consequent block in parasite degradation of hemoglobin. These compounds and related phenothiazines are worthy of further study as potential antimalarial agents.
authors.affiliation: Laboratorio de Síntesis Orgánica, Facultad de Farmacia, Universidad Central de Venezuela, Caracas, Venezuela.
authors.forename: J N
authors.initials: JN
authors.lastname: Domínguez
authors.forename: S
authors.initials: S
authors.lastname: López
authors.forename: J
authors.initials: J
authors.lastname: Charris
authors.forename: L
authors.initials: L
authors.lastname: Iarruso
authors.forename: G
authors.initials: G
authors.lastname: Lobo
authors.forename: A
authors.initials: A
authors.lastname: Semenov
authors.forename: J E
authors.initials: JE
authors.lastname: Olson
authors.forename: P J
authors.initials: PJ
authors.lastname: Rosenthal
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D010640:Phenothiazines / Q000737:chemistry* / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*
chemical_list: D000962:Antimalarials; D015853:Cysteine Proteinase Inhibitors; D010640:Phenothiazines; D003546:Cysteine Endopeptidases; C099607:falcipain