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https://www.arca.fiocruz.br/handle/icict/12568
IN VIVO ANTIMALARIAL ACTIVITY AND MECHANISMS OF ACTION OF 4-NEROLIDYLCATECHOL DERIVATIVES
Author
Silva, Luiz Francisco Rocha e
Nogueira, Karla Lagos
Pinto, Ana Cristina da Silva
Katzin, Alejandro Miguel
Sussmann, Rodrigo A. C.
Muniz, Magno Perêa
Neto, Valter Ferreira de Andrade
Chaves, Francisco Célio Maia
Coutinho, Julia Penna
Lima, Emerson Silva
Krettli, Antoniana Ursine
Tadei, Wanderli Pedro
Pohlit, Adrian Martin
Nogueira, Karla Lagos
Pinto, Ana Cristina da Silva
Katzin, Alejandro Miguel
Sussmann, Rodrigo A. C.
Muniz, Magno Perêa
Neto, Valter Ferreira de Andrade
Chaves, Francisco Célio Maia
Coutinho, Julia Penna
Lima, Emerson Silva
Krettli, Antoniana Ursine
Tadei, Wanderli Pedro
Pohlit, Adrian Martin
Affilliation
Instituto Nacional Para Pesquisa da Amazonia. Manaus, AM, Brasil/Universidade Federal da Amazonas. Manaus, AM, Brasil/Universidade Centro Norte. Manaus, AM, Brasil
Instituto Nacional Para Pesquisa da Amazonia. Manaus, AM, Brasil/Universidade Federal da Amazonas. Manaus, AM, Brasil
Instituto Nacional Para Pesquisa da Amazonia. Manaus, AM, Brasil
Universidade de São Paulo. Instituto de Ciencias Biomedicas. Departamento de Parasitologia. São Paulo, SP, Brasil
Universidade de São Paulo. Instituto de Ciencias Biomedicas. Departamento de Parasitologia. São Paulo, SP, Brasil
Instituto Nacional Para Pesquisa da Amazonia. Manaus, AM, Brasil
Universidade Federal do Rio Grande do Norte. Laboratorio de Malaria e Biologia da Toxoplasmose. Natal, RN, Brasil
Empresa Brasileira de Pesquisa Agricola Amazônia Ocidental. Manaus, AM, Brasil
Fundação Oswaldo Cruz. Centro de Pesquisa Rene Rachou. Belo Horizonte, MG, Brasil/Universidade Federal de Minas Gerais. Escola de Farmacia. Belo Horizonte, MG, Brasil
Universidade Federal da Amazonas. Manaus, AM, Brasil
Fundação Oswaldo Cruz. Centro de Pesquisa Rene Rachou. Belo Horizonte, MG, Brasil/Universidade Federal de Minas Gerais. Escola de Farmacia. Belo Horizonte, MG, Brasil
Instituto Nacional Para Pesquisa da Amazonia. Manaus, AM, Brasil
Universidade Federal da Amazonas. Manaus, AM, Brasil
Instituto Nacional Para Pesquisa da Amazonia. Manaus, AM, Brasil/Universidade Federal da Amazonas. Manaus, AM, Brasil
Instituto Nacional Para Pesquisa da Amazonia. Manaus, AM, Brasil
Universidade de São Paulo. Instituto de Ciencias Biomedicas. Departamento de Parasitologia. São Paulo, SP, Brasil
Universidade de São Paulo. Instituto de Ciencias Biomedicas. Departamento de Parasitologia. São Paulo, SP, Brasil
Instituto Nacional Para Pesquisa da Amazonia. Manaus, AM, Brasil
Universidade Federal do Rio Grande do Norte. Laboratorio de Malaria e Biologia da Toxoplasmose. Natal, RN, Brasil
Empresa Brasileira de Pesquisa Agricola Amazônia Ocidental. Manaus, AM, Brasil
Fundação Oswaldo Cruz. Centro de Pesquisa Rene Rachou. Belo Horizonte, MG, Brasil/Universidade Federal de Minas Gerais. Escola de Farmacia. Belo Horizonte, MG, Brasil
Universidade Federal da Amazonas. Manaus, AM, Brasil
Fundação Oswaldo Cruz. Centro de Pesquisa Rene Rachou. Belo Horizonte, MG, Brasil/Universidade Federal de Minas Gerais. Escola de Farmacia. Belo Horizonte, MG, Brasil
Instituto Nacional Para Pesquisa da Amazonia. Manaus, AM, Brasil
Universidade Federal da Amazonas. Manaus, AM, Brasil
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 vivoantimalarial 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 vitroprotein 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 vivoresult 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.
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