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

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dc.contributorSistema FMUSP-HC: Faculdade de Medicina da Universidade de São Paulo (FMUSP) e Hospital das Clínicas da FMUSP
dc.contributor.authorGRECCO, Simone S.
dc.contributor.authorCOSTA-SILVA, Thais A.
dc.contributor.authorJERZ, Gerold
dc.contributor.authorSOUSA, Fernanda S. de
dc.contributor.authorLONDERO, Vinicius S.
dc.contributor.authorGALUPPO, Mariana K.
dc.contributor.authorLIMA, Marta L.
dc.contributor.authorNEVES, Bruno J.
dc.contributor.authorANDRADE, Carolina H.
dc.contributor.authorTEMPONE, Andre G.
dc.contributor.authorLAGO, Joao Henrique G.
dc.date.accessioned2018-03-06T15:35:11Z
dc.date.available2018-03-06T15:35:11Z
dc.date.issued2017
dc.description.abstractChagas 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.
dc.description.indexMEDLINE
dc.description.sponsorshipSao Paulo State Research Foundation [FAPESP 2015/11936-2, 2015/50075-2, 2013/50228-8]
dc.description.sponsorshipCAPES
dc.description.sponsorshipCNPq
dc.identifier.citationCHEMICO-BIOLOGICAL INTERACTIONS, v.277, p.55-61, 2017
dc.identifier.doi10.1016/j.cbi.2017.08.017
dc.identifier.eissn1872-7786
dc.identifier.issn0009-2797
dc.identifier.urihttps://observatorio.fm.usp.br/handle/OPI/25870
dc.language.isoeng
dc.publisherELSEVIER IRELAND LTD
dc.relation.ispartofChemico-Biological Interactions
dc.rightsrestrictedAccess
dc.rights.holderCopyright ELSEVIER IRELAND LTD
dc.subjectNectandra leucantha
dc.subjectNeolignans
dc.subjectTrypanosoma cruzi
dc.subjectPlasma membrane permeability
dc.subjectMitochondrial dysfunctions
dc.subjectADMET
dc.subject.othertrypanosoma-cruzi
dc.subject.otherantimicrobial peptides
dc.subject.othersilico prediction
dc.subject.otherleishmania
dc.subject.otherdiscovery
dc.subject.otheranalogs
dc.subject.othervivo
dc.subject.wosBiochemistry & Molecular Biology
dc.subject.wosPharmacology & Pharmacy
dc.subject.wosToxicology
dc.titleNeolignans from leaves of Nectandra leucantha (Lauraceae) display in vitro antitrypanosomal activity via plasma membrane and mitochondrial damages
dc.typearticle
dc.type.categoryoriginal article
dc.type.versionpublishedVersion
dspace.entity.typePublication
hcfmusp.affiliation.countryAlemanha
hcfmusp.affiliation.countryisode
hcfmusp.author.externalGRECCO, Simone S.:Fed Univ ABC, Ctr Nat Sci & Humanities, BR-09210180 Santo Andre, SP, Brazil; Tech Univ Carolo Wilhelmina Braunschweig, Inst Food Chem, D-38106 Braunschweig, Germany; Anhanguera Univ Sao Paulo, Biotechnol & Innovat Hlth Program, BR-05145200 Sao Paulo, Brazil
hcfmusp.author.externalCOSTA-SILVA, Thais A.:Fed Univ ABC, Ctr Nat Sci & Humanities, BR-09210180 Santo Andre, SP, Brazil
hcfmusp.author.externalJERZ, Gerold:Tech Univ Carolo Wilhelmina Braunschweig, Inst Food Chem, D-38106 Braunschweig, Germany
hcfmusp.author.externalSOUSA, Fernanda S. de:Univ Fed Sao Paulo, Inst Environm Chem & Pharmaceut Sci, BR-09972270 Diadema, SP, Brazil
hcfmusp.author.externalLONDERO, Vinicius S.:Univ Fed Sao Paulo, Inst Environm Chem & Pharmaceut Sci, BR-09972270 Diadema, SP, Brazil
hcfmusp.author.externalGALUPPO, Mariana K.:Adolfo Lutz Inst, Ctr Parasitol & Mycol, BR-01246902 Sao Paulo, Brazil
hcfmusp.author.externalNEVES, Bruno J.:Univ Fed Goias, Fac Pharm, Lab Mol Modeling & Drug Design, LabMol, BR-74605170 Goiania, Go, Brazil; Unievangel Univ Ctr, Postgrad Program Soc Technol & Environm, BR-75083515 Anapolis, Go, Brazil
hcfmusp.author.externalANDRADE, Carolina H.:Univ Fed Goias, Fac Pharm, Lab Mol Modeling & Drug Design, LabMol, BR-74605170 Goiania, Go, Brazil
hcfmusp.author.externalTEMPONE, Andre G.:Adolfo Lutz Inst, Ctr Parasitol & Mycol, BR-01246902 Sao Paulo, Brazil
hcfmusp.author.externalLAGO, Joao Henrique G.:Fed Univ ABC, Ctr Nat Sci & Humanities, BR-09210180 Santo Andre, SP, Brazil
hcfmusp.citation.scopus22
hcfmusp.contributor.author-fmusphcMARTA LOPES LIMA
hcfmusp.description.beginpage55
hcfmusp.description.endpage61
hcfmusp.description.volume277
hcfmusp.origemWOS
hcfmusp.origem.pubmed28864277
hcfmusp.origem.scopus2-s2.0-85028705229
hcfmusp.origem.wosWOS:000416216100006
hcfmusp.publisher.cityCLARE
hcfmusp.publisher.countryIRELAND
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