title: In vivo antimalarial activity and mechanisms of action of 4-nerolidylcatechol derivatives.
abstract: 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)-(3)H]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.
authors: National Institute for Amazon Research, Manaus, Amazonas, Brazil Federal University of Amazonas, Manaus, Amazonas, Brazil Center North University, Manaus, Amazonas, Brazil.
authors: Luiz Francisco
authors: LF
authors: Rocha e Silva
authors: National Institute for Amazon Research, Manaus, Amazonas, Brazil Federal University of Amazonas, Manaus, Amazonas, Brazil.
authors: Karla Lagos
authors: KL
authors: Nogueira
authors: National Institute for Amazon Research, Manaus, Amazonas, Brazil.
authors: Ana Cristina da Silva
authors: AC
authors: Pinto
authors: Department of Parasitology, Institute of Biomedical Science, University of São Paulo, São Paulo, São Paulo, Brazil.
authors: Alejandro Miguel
authors: AM
authors: Katzin
authors: Department of Parasitology, Institute of Biomedical Science, University of São Paulo, São Paulo, São Paulo, Brazil.
authors: Rodrigo A C
authors: RA
authors: Sussmann
authors: National Institute for Amazon Research, Manaus, Amazonas, Brazil.
authors: Magno Perêa
authors: MP
authors: Muniz
authors: Laboratory of Malaria and Toxoplasmosis Biology-Rio Grande do Norte Federal University, Natal, Rio Grande do Norte, Brazil.
authors: Valter Ferreira
authors: VF
authors: de Andrade Neto
authors: EMBRAPA Amazônia Ocidental, Manaus, Amazonas, Brazil.
authors: Francisco Célio Maia
authors: FC
authors: Chaves
authors: René Rachou Research Center-Fiocruz, Belo Horizonte, Minas Gerais, Brazil Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors: Julia Penna
authors: JP
authors: Coutinho
authors: School of Pharmaceutical Sciences, Federal University of Amazonas, Manaus, Amazonas, Brazil.
authors: Emerson Silva
authors: ES
authors: Lima
authors: René Rachou Research Center-Fiocruz, Belo Horizonte, Minas Gerais, Brazil Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors: Antoniana Ursine
authors: AU
authors: Krettli
authors: National Institute for Amazon Research, Manaus, Amazonas, Brazil.
authors: Wanderli Pedro
authors: WP
authors: Tadei
authors: National Institute for Amazon Research, Manaus, Amazonas, Brazil ampohlit@inpa.gov.br.
authors: Adrian Martin
authors: http://orcid.org/0000-0002-6793-3759
authors: AM
authors: Pohlit
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002396:Catechols / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010962:Plasmodium berghei / Q000187:drug effects / Q000472:pathogenicity; D010963:Plasmodium falciparum / Q000187:drug effects / Q000472:pathogenicity; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C110583:4-nerolidylcatechol; D000962:Antimalarials; D002396:Catechols