In vivo antimalarial activity and mechanisms of action of 4-nerolidylcatechol derivatives

• Autor(a) principal: Silva, Luiz Francisco Rocha e
• Data de Publicação: 2015
• Outros Autores: Nogueira, Karla Lagos, Pinto, Ana Cristina da Silva, Katzin, Alejandro Miguel, Sussmann, Rodrigo Antonio Ceschini, Muniz, Magno Perêa, Andrade Neto, Valter Ferreira de, Chaves, Francisco Célio Maia, Coutinho, Julia Penna, Lima, Emerson Silva, Krettli, Antoniana Ursine, Tadei, Wanderli Pedro, Pohlita, Adrian Martin
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Institucional do INPA
• Texto Completo: https://repositorio.inpa.gov.br/handle/1/15896
• topic: 1,2 O,o Diacetyl 4 Nerolidylcatechol; 2 O Benzyl 4 Nerolidylcatechol; Antimalarial Agent; Catechol Derivative; Chloroquine; Dolichol; Hemozoin; Isoprenoid; Menatetrenone; Natural Product; Quinine Sulfate; Ubiquinone; Unclassified Drug; 4 Nerolidylcatechol; Antimalarial Agent; Catechol Derivative; Adult; Animals Experiment; Animals Model; Antimalarial Activity; Biosynthesis; Blood; Controlled Study; Female; In Vitro Study; In Vivo Study; Malaria; Metabolite; Mouse; Nonhuman; Plasma; Plasmodium Berghei; Plasmodium Falciparum; Priority Journal; Protein Synthesis; Animals; Bagg Albino Mouse; Drug Effects; Malaria, Falciparum; Metabolism; Pathogenicity; Electrophoresis, Polyacrylamide Gel; Reverse Transcription Polymerase Chain Reaction; Animal; Antimalarials; Catechols; Electrophoresis, Polyacrylamide Gel; Female; Malaria, Falciparum; Mice; Mice, Inbred Balb C; Plasmodium Berghei; Plasmodium Falciparum; Reverse Transcriptase Polymerase Chain Reaction

4-Nerolidylcatechol (1) is an abundant antiplasmodial metabolite that is isolated from Piper peltatum roots. O-Acylation or O-alkylation of compound 1 provides derivatives exhibiting improved stability and significant in vitro antiplasmodial activity. The aim of this work was to study the in vitro inhibition of hemozoin formation, inhibition of isoprenoid biosynthesis in Plasmodium falciparum cultures, and in vivo antimalarial activity of several 4-nerolidylcatechol derivatives. 1,2-O,O-Diacetyl-4-nerolidylcatechol (2) inhibited in vitro hemozoin formation by up to 50%. In metabolic labeling studies using [1-(n)-3H]geranylgeranyl pyrophosphate, diester 2 significantly inhibited the biosynthesis of isoprenoid metabolites ubiquinone 8, menaquinone 4, and dolichol 12 in cultures of P. falciparum 3D7. Similarly, 2-O-benzyl-4-nerolidylcatechol (3) significantly inhibited the biosynthesis of dolichol 12. P. falciparum in vitro protein synthesis was not affected by compounds 2 or 3. At oral doses of 50 mg per kg of body weight per day, compound 2 suppressed Plasmodium berghei NK65 in infected BALB/c mice by 44%. This in vivo result for derivative 2 represents marked improvement over that obtained previously for natural product 1. Compound 2 was not detected in mouse blood 1 h after oral ingestion or in mixtures with mouse blood/blood plasma in vitro. However, it was detected after in vitro contact with human blood or blood plasma. Derivatives of 4-nerolidylcatechol exhibit parasite-specific modes of action, such as inhibition of isoprenoid biosynthesis and inhibition of hemozoin formation, and they therefore merit further investigation for their antimalarial potential. Copyright © 2015, American Society for Microbiology. All Rights Reserved.