Neolignans from leaves of Nectandra leucantha (Lauraceae) display in vitro antitrypanosomal activity via plasma membrane and mitochondrial damages

Autor(es):Mostrar menos -

Grecco, Simone S. ^{[1, 2, 3]} ; Costa-Silva, Thais A. ^[2] ; Jerz, Gerold ^[1] ; de Sousa, Fernanda S. ^[4] ; Londero, Vinicius S. ^[4] ; Galuppo, Mariana K. ^[5] ; Lima, Marta L. ^{[6, 5]} ; Neves, Bruno J. ^{[7, 8]} ; Andrade, Carolina H. ^[7] ; Tempone, Andre G. ^[5] ; Lago, Joao Henrique G. ^[2]

Afiliação do(s) autor(es)

^[1] Tech Univ Carolo Wilhelmina Braunschweig, Inst Food Chem, D-38106 Braunschweig - Germany

^[2] Fed Univ ABC, Ctr Nat Sci & Humanities, BR-09210180 Santo Andre, SP - Brazil

^[3] Anhanguera Univ Sao Paulo, Biotechnol & Innovat Hlth Program, BR-05145200 Sao Paulo - Brazil

^[4] Univ Fed Sao Paulo, Inst Environm Chem & Pharmaceut Sci, BR-09972270 Diadema, SP - Brazil

^[5] Adolfo Lutz Inst, Ctr Parasitol & Mycol, BR-01246902 Sao Paulo - Brazil

^[6] Univ Sao Paulo, Inst Med Trop Sao Paulo, BR-05403000 Sao Paulo - Brazil

^[7] Univ Fed Goias, Fac Pharm, Lab Mol Modeling & Drug Design, LabMol, BR-74605170 Goiania, Go - Brazil

^[8] Unievangel Univ Ctr, Postgrad Program Soc Technol & Environm, BR-75083515 Anapolis, Go - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Chemico-Biological Interactions; v. 277, p. 55-61, NOV 1 2017.
• Citações Web of Science: 8

Resumo

Chagas disease is a neglected tropical disease, caused by the protozoan parasite Trypanosoma cruzi, which affects more than eight million people in Tropical and Subtropical countries especially in Latin America. Current treatment is limited to nifurtimox and benznidazole, both with reduced effectiveness and high toxicity. In this work, the n-hexane extract from leaves of Nectandra leucantha (Lauraceae) displayed in vitro antitrypanosomal activity against T. cruzi. Using several chromatographic steps, four related neolignans were isolated and chemically characterized as dehydrodieugenol B (1), 1-(8-propenyl)-3-{[}3'-methoxy-1'-(8-propenyl)-phenoxy]-4,5dimethoxybenz ene (2), 1-{[}(7S)-hydroxy-8-propenyl]-3-{[}3'-methoxy-1'-(8'-propenyl)-phenoxy]- 4hydroxy-5-methoxybenzene (3), and 1-{[}(7S)-hydroxy-8-propenyl]-3-{[}3'-methoxy-1'-(8'-propenyl)-phenoxy]- 4,5-dimethoxybenzene (4). These compounds were tested against intracellular amastigotes and extracellular trypomastigotes of T. cruzi and for mammalian cytotoxicity. Neolignan 4 showed the higher selectivity index (SI) against trypomastigotes (>5) and amastigotes (>13) of T. cruzi. The investigation of the mechanism of action demonstrated that neolignan 4 caused substantial alteration of the plasma membrane permeability, together with mitochondrial dysfunctions in trypomastigote forms. In silico studies of pharmacokinetics and toxicity (ADMET) properties predicted that all compounds were non-mutagenic, non-carcinogenic, non-genotoxic, weak hERG blockers, with acceptable volume of distribution (1.66-3.32 L/kg), and low rodent oral toxicity (LD50 810-e2200 mg/kg). Considering some clinical events of cerebral Chagas disease, the compounds also demonstrated favorable properties, such as blood-brain barrier penetration. Unfavorable properties were also predicted as high promiscuity for P450 isoforms, high plasma protein binding affinity (>91%), and moderate-to-low oral bioavailability. Finally, none of the isolated neolignans was predicted as interference compounds (PAINS). Considering the promising chemical and biological properties of the isolated neolignans, these compounds could be used as starting points to develop new lead compounds for Chagas disease. (C) 2017 Elsevier B.V. All rights reserved. (AU)

• Processo FAPESP: 15/50075-2 - Brazilian biodiversity as a source for novel drug scaffolds against neglected protozoan diseases
• Beneficiário: André Gustavo Tempone Cardoso
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 15/11936-2 - Emprego da quimiodiversidade de espécies vegetais de áreas remanescentes da Mata Atlântica do Estado de São Paulo na seleção de protótipos biologicamente ativos
• Beneficiário: João Henrique Ghilardi Lago
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 13/50228-8 - Componentes da biodiversidade, e seus caracteres metabólicos, de ilhas do Brasil: uma abordagem integrada
• Beneficiário: Roberto Gomes de Souza Berlinck
• Modalidade de apoio: Auxílio à Pesquisa - Programa BIOTA - Temático