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Título: In vivo antimalarial activity and mechanisms of action of 4-nerolidylcatechol derivatives
Autor(es): Luiz Francisco Rocha e Silva
Emerson Silva Lima
Antoniana Ursine Krettli
Wanderli Pedro Tadei
Adrian Martin Pohlit
Karla Lagos Nogueira
Ana Cristina da Silva Pinto
Alejandro Miguel Katzin
Rodrigo Antonio Ceschini Sussmann
Magno Perêa Muniz
Valter Ferreira de Andrade Neto
Francisco Célio Maia Chaves
Julia Penna Coutinho
Assunto: antimalárico
Plasmodium falciparum
Plasmodium berghei
ISSN: 1098-6596
Revista: Antimicrobial Agents and Chemotherapy
Resumo: 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.
ISSN: 1098-6596
Aparece nas coleções:Coordenação de Tecnologia e Inovação (COTI)

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