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

Show simple item record

dc.contributor Sistema FMUSP-HC: Faculdade de Medicina da Universidade de São Paulo (FMUSP) e Hospital das Clínicas da FMUSP
dc.contributor.author GRECCO, Simone S.
COSTA-SILVA, Thais A.
JERZ, Gerold
SOUSA, Fernanda S. de
LONDERO, Vinicius S.
GALUPPO, Mariana K.
LIMA, Marta L. FMUSP-HC
NEVES, Bruno J.
ANDRADE, Carolina H.
TEMPONE, Andre G.
LAGO, Joao Henrique G.
dc.date.issued 2017
dc.identifier.citation CHEMICO-BIOLOGICAL INTERACTIONS, v.277, p.55-61, 2017
dc.identifier.issn 0009-2797
dc.identifier.uri http://observatorio.fm.usp.br/handle/OPI/25870
dc.description.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.
dc.description.sponsorship · Sao Paulo State Research Foundation [FAPESP 2015/11936-2, 2015/50075-2, 2013/50228-8]
· CAPES
· CNPq
dc.language.iso eng
dc.publisher ELSEVIER IRELAND LTD
dc.relation.ispartof Chemico-Biological Interactions
dc.rights restrictedAccess
dc.subject Nectandra leucantha; Neolignans; Trypanosoma cruzi; Plasma membrane permeability; Mitochondrial dysfunctions; ADMET
dc.subject.other trypanosoma-cruzi; antimicrobial peptides; silico prediction; leishmania; discovery; analogs; vivo
dc.title Neolignans from leaves of Nectandra leucantha (Lauraceae) display in vitro antitrypanosomal activity via plasma membrane and mitochondrial damages
dc.type article
dc.rights.holder Copyright ELSEVIER IRELAND LTD
dc.identifier.doi 10.1016/j.cbi.2017.08.017
dc.identifier.pmid 28864277
dc.type.category original article
dc.type.version publishedVersion
hcfmusp.author LIMA, Marta L.:IMT:
hcfmusp.author.external · GRECCO, 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
· COSTA-SILVA, Thais A.:Fed Univ ABC, Ctr Nat Sci & Humanities, BR-09210180 Santo Andre, SP, Brazil
· JERZ, Gerold:Tech Univ Carolo Wilhelmina Braunschweig, Inst Food Chem, D-38106 Braunschweig, Germany
· SOUSA, Fernanda S. de:Univ Fed Sao Paulo, Inst Environm Chem & Pharmaceut Sci, BR-09972270 Diadema, SP, Brazil
· LONDERO, Vinicius S.:Univ Fed Sao Paulo, Inst Environm Chem & Pharmaceut Sci, BR-09972270 Diadema, SP, Brazil
· GALUPPO, Mariana K.:Adolfo Lutz Inst, Ctr Parasitol & Mycol, BR-01246902 Sao Paulo, Brazil
· NEVES, 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
· ANDRADE, Carolina H.:Univ Fed Goias, Fac Pharm, Lab Mol Modeling & Drug Design, LabMol, BR-74605170 Goiania, Go, Brazil
· TEMPONE, Andre G.:Adolfo Lutz Inst, Ctr Parasitol & Mycol, BR-01246902 Sao Paulo, Brazil
· LAGO, Joao Henrique G.:Fed Univ ABC, Ctr Nat Sci & Humanities, BR-09210180 Santo Andre, SP, Brazil
hcfmusp.origem.id 2-s2.0-85028705229
hcfmusp.origem.id WOS:000416216100006
hcfmusp.publisher.city CLARE
hcfmusp.publisher.country IRELAND
hcfmusp.relation.reference · Andrade CH, 2014, CURR DRUG METAB, V15, P514, DOI 10.2174/1389200215666140908102530
· Baell J, 2014, NATURE, V513, P481, DOI 10.1038/513481a
· Baell JB, 2010, J MED CHEM, V53, P2719, DOI 10.1021/jm901137j
· Braga R.C., 2015, ENCY DRUG METABOLISM, P1
· Braga RC, 2015, MOL INFORM, V34, P698, DOI 10.1002/minf.201500040
· Braga RC, 2014, CURR TOP MED CHEM, V14, P1399, DOI 10.2174/1568026614666140506124442
· Broccatelli F, 2011, J MED CHEM, V54, P1740, DOI 10.1021/jm101421d
· Cheng FX, 2012, J CHEM INF MODEL, V52, P3099, DOI 10.1021/ci300367a
· Cicora F, 2014, TRANSPL INFECT DIS, V16, P813, DOI 10.1111/tid.12265
· Costa EC, 2016, MOLECULES, V21, DOI 10.3390/molecules21060802
· da Costa-Silva TA, 2015, J NAT PROD, V78, P653, DOI 10.1021/np500809a
· Oliveira LGD, 2017, BASIC CLIN PHARMACOL, V120, P52, DOI 10.1111/bcpt.12639
· de Sousa FS, 2017, PHYTOCHEMISTRY, V140, P108, DOI 10.1016/j.phytochem.2017.04.024
· DIAS AD, 1988, PHYTOCHEMISTRY, V27, P3008
· Diaz A.M.P., 1980, PHYTOCHEMISTRY, V19, P681
· Drwal MN, 2014, NUCLEIC ACIDS RES, V42, pW53, DOI 10.1093/nar/gku401
· Ellis D, 2002, J ANTIMICROB CHEMOTH, V49, P7, DOI 10.1093/jac/49.suppl_1.7
· Esperandim VR, 2013, EXP PARASITOL, V133, P442, DOI 10.1016/j.exppara.2012.12.005
· Grecco SS, 2017, PHYTOMEDICINE, V24, P62, DOI 10.1016/j.phymed.2016.11.015
· Hansen K, 2009, J CHEM INF MODEL, V49, P2077, DOI 10.1021/ci900161g
· Irwin JJ, 2015, J MED CHEM, V58, P7076, DOI 10.1021/acs.jmedchem.5b01105
· Lagunin A, 2009, QSAR COMB SCI, V28, P806, DOI 10.1002/qsar.200860192
· Martins LF, 2016, J NAT PROD, V79, P2202, DOI 10.1021/acs.jnatprod.6b00256
· Martins S.C., 2016, MICROBES INFECT, pS1286
· MORGAN HL, 1965, J CHEM DOC, V5, P107, DOI 10.1021/c160017a018
· Neris PLN, 2013, EXP PARASITOL, V135, P307, DOI 10.1016/j.exppara.2013.07.007
· Pelizzaro-Rocha KJ, 2011, MICROBES INFECT, V13, P1018, DOI 10.1016/j.micinf.2011.05.011
· Perry SW, 2011, BIOTECHNIQUES, V50, P98, DOI 10.2144/000113610
· Pinto EG, 2013, EXP PARASITOL, V135, P655, DOI 10.1016/j.exppara.2013.09.016
· Riniker S, 2013, J CHEMINFORMATICS, V5, DOI 10.1186/1758-2946-5-26
· Rogers D, 2010, J CHEM INF MODEL, V50, P742, DOI 10.1021/ci100050t
· Luque-Ortega JR, 2010, METHODS MOL BIOL, V618, P393, DOI 10.1007/978-1-60761-594-1_25
· Sartorelli P, 2010, PLANTA MED, V76, P1454, DOI 10.1055/s-0029-1240952
· Saubern S, 2011, MOL INFORM, V30, P847, DOI 10.1002/minf.201100076
· SUAREZ M, 1983, PHYTOCHEMISTRY, V22, P609, DOI 10.1016/0031-9422(83)83066-0
· Tasdemir D, 2006, ANTIMICROB AGENTS CH, V50, P1352, DOI 10.1128/AAC.50.4.1352-1364.2006
· van de Waterbeemd H, 2003, NAT REV DRUG DISCOV, V2, P192, DOI 10.1038/nrd1032
· Vial HJ, 2003, MOL BIOCHEM PARASIT, V126, P143, DOI 10.1016/S0166-6851(02)00281-5
· Volpato H, 2015, PLOS ONE, V10, DOI 10.1371/journal.pone.0130652
dc.description.index MEDLINE
dc.identifier.eissn 1872-7786
hcfmusp.citation.scopus 7
hcfmusp.citation.wos 6
hcfmusp.affiliation.country Brasil
hcfmusp.affiliation.country Alemanha


Files in this item

This item appears in the following Collection(s)

Show simple item record

Search DSpace



Browse

My Account

Statistics