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

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

Author Grecco, Simone S. Google Scholar
Costa-Silva, Thais A. Google Scholar
Jerz, Gerold Google Scholar
de Sousa, Fernanda S. Autor UNIFESP Google Scholar
Londero, Vinicius S. Autor UNIFESP Google Scholar
Galuppo, Mariana K. Google Scholar
Lima, Marta L. Google Scholar
Neves, Bruno J. Google Scholar
Andrade, Carolina H. Google Scholar
Tempone, Andre G. Google Scholar
Lago, Joao Henrique G. Google Scholar
Abstract 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]-4,5dimethoxybenzene (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.
Keywords Nectandra leucantha
Neolignans
Trypanosoma cruzi
Plasma membrane permeability
Mitochondrial dysfunctions
ADMET
xmlui.dri2xhtml.METS-1.0.item-coverage Clare
Language English
Sponsor Sao Paulo State Research Foundation
CAPES
CNPq
Grant number FAPESP: 2015/11936-2
FAPESP: 2015/50075-2
FAPESP: 2013/50228-8
Date 2017
Published in Chemico-Biological Interactions. Clare, v. 277, p. 55-61, 2017.
ISSN 0009-2797 (Sherpa/Romeo, impact factor)
Publisher Elsevier Ireland Ltd
Extent 55-61
Origin http://dx.doi.org/10.1016/j.cbi.2017.08.017
Access rights Closed access
Type Article
Web of Science ID WOS:000416216100006
URI https://repositorio.unifesp.br/handle/11600/58255

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