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

Autor: Grecco SS; Center of Natural Sciences and Humanities, Federal University of ABC, Santo Andre, SP, 09210-180, Brazil; Institute of Food Chemistry, Technische Universität Braunschweig, Braunschweig, 38106, Germany; Biotechnology and Innovation in Health Program, Anhanguera University of São Paulo, São Paulo, SP, 05145-200, Brazil., Costa-Silva TA; Center of Natural Sciences and Humanities, Federal University of ABC, Santo Andre, SP, 09210-180, Brazil., Jerz G; Institute of Food Chemistry, Technische Universität Braunschweig, Braunschweig, 38106, Germany., de Sousa FS; Institute of Environmental, Chemical and Pharmaceutical Sciences, Federal University of São Paulo, Diadema, SP, 09972-270, Brazil., Londero VS; Institute of Environmental, Chemical and Pharmaceutical Sciences, Federal University of São Paulo, Diadema, SP, 09972-270, Brazil., Galuppo MK; Centre for Parasitology and Mycology, Instituto Adolfo Lutz, São Paulo, SP, 01246-902, Brazil., Lima ML; Centre for Parasitology and Mycology, Instituto Adolfo Lutz, São Paulo, SP, 01246-902, Brazil; Instituto de Medicina Tropical de São Paulo, Universidade de São Paulo, São Paulo, SP, 05403-000, Brazil., Neves BJ; LabMol, Laboratory for Molecular Modeling and Drug Design, Faculty of Pharmacy, Federal University of Goias, Goiânia, GO, 74605-170, Brazil; Postgraduate Program in Society, Technology and Environment, Unievangelica University Center, Anápolis, GO, 75083-515, Brazil., Andrade CH; LabMol, Laboratory for Molecular Modeling and Drug Design, Faculty of Pharmacy, Federal University of Goias, Goiânia, GO, 74605-170, Brazil., Tempone AG; Centre for Parasitology and Mycology, Instituto Adolfo Lutz, São Paulo, SP, 01246-902, Brazil., Lago JHG; Center of Natural Sciences and Humanities, Federal University of ABC, Santo Andre, SP, 09210-180, Brazil. Electronic address: joao.lago@ufabc.edu.br.
Jazyk: angličtina
Zdroj: Chemico-biological interactions [Chem Biol Interact] 2017 Nov 01; Vol. 277, pp. 55-61. Date of Electronic Publication: 2017 Aug 31.
DOI: 10.1016/j.cbi.2017.08.017
Abstrakt: 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]-4,5-dimethoxybenzene (2), 1-[(7S)-hydroxy-8-propenyl]-3-[3'-methoxy-1'-(8'-propenyl)-phenoxy]-4-hydroxy-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 (LD 50 810-2200 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.
(Copyright © 2017 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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