title: Antimalarial activity of new acridinone derivatives.
abstract: Malaria is one of the major threats concerning world public health. Resistance to the current antimalarial drugs has led to searches for new antimalarial compounds. Acridinone derivatives have recently demonstrated to be active against malaria parasite. We focused our attention on synthesized new acridinone derivatives, some of them resulting with high antiviral and trypanocidal activity. In this study new derivatives of 10-alyl-, 10-(3-methyl-2-butenyl)- and 10-(1,2-propadienyl)-9(10H)-acridinone were evaluated for their antimalarial activity against Plasmodium falciparum. To assess the selectivity, cytotoxicity was assessed in parallel against human MRC-5 cells. Inhibition of β-hematin formation was determined using a spectrophotometric assay. Mitochondrial bc(1) complexes were isolated from yeast and bovine heart cells to test acridinone inhibitory activity. This study resulted in the identification of three compounds with submicromolar efficacy against P. falciparum and without cytotoxic effects on human cellular line. One compound, IIa (1-fluoro-10-(3-methyl-2-butenyl)-9(10H)-acridinone), can be classified as hit for antimalarial drug development exhibiting IC(50) less than 0.2 μg/mL with SI greater than 100. In molecular tests, no relevant inhibitory activity was obtained for our compounds. The mechanism of acridinones antimalarial action remains unclear.
authors.affiliation: Departamento de Parasitología, Instituto de Medicina Tropical Pedro Kourí, Autopista Novia del Mediodía Km 6, Marianao 13, Ciudad de La Habana, Cuba. ayme@ipk.sld.cu
authors.forename: Aymé
authors.initials: A
authors.lastname: Fernández-Calienes
authors.forename: Rolando
authors.initials: R
authors.lastname: Pellón
authors.forename: Maite
authors.initials: M
authors.lastname: Docampo
authors.forename: Mirta
authors.initials: M
authors.lastname: Fascio
authors.forename: Norma
authors.initials: N
authors.lastname: D'Accorso
authors.forename: Louis
authors.initials: L
authors.lastname: Maes
authors.forename: Judith
authors.initials: J
authors.lastname: Mendiola
authors.forename: Lianet
authors.initials: L
authors.lastname: Monzote
authors.forename: Lars
authors.initials: L
authors.lastname: Gille
authors.forename: Lázara
authors.initials: L
authors.lastname: Rojas
mesh_terms: D000166:Acridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology*; D002417:Cattle; D002460:Cell Line; D004352:Drug Resistance, Microbial; D006420:Hemeproteins / Q000037:antagonists & inhibitors; D006801:Humans; D008288:Malaria / Q000188:drug therapy; D010963:Plasmodium falciparum / Q000187:drug effects; D015003:Yeasts
chemical_list: D000166:Acridines; D000962:Antimalarials; D006420:Hemeproteins; C020753:hemozoin