Rev. bras. farmacogn. vol.26 número6

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w ww . e l s e v i e r . c o m / l o c a t e / b j p

Review

Folk

medicine,

phytochemistry

and

pharmacological

application

of

Piper

marginatum

Jennifer

Brú,

Juan

David

Guzman

∗

DepartamentodeQuímicayBiología,DivisióndeCienciasBásicas,UniversidaddelNorte,Barranquilla,Colombia

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Articlehistory:

Received16February2016 Accepted31March2016

Keywords: Pipermarginatum Piperaceae Folkmedicine Phytochemistry Pharmacology Biologicalapplications

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PipermarginatumJacq.,Piperaceae,isawidelydistributedNeotropicalspeciesabundantintheCaribbean, exhibitingacharacteristicwingedpetioleandaheart-shapedleaf,itstwovegetativelandmarksforrapid identification.Thespecieshasbeenemployedbytraditionalindigenousculturesforitsreputedmedicinal properties.TheplantismostfrequentlyemployedbylocalhealersinCentralAmerica,theAntillesand SouthAmerica,foralleviatinggastrointestinalailments,administeredasadecoctionorinfusionforits tonic,diureticandcarminativeeffects.Thesebeneficialpropertiesmaybeattributedtothepresenceof variousphytochemicalswithinP.marginatum,withmostofthestudiesfocusingontheessentialoilof theplant.Monoterpenoids,sesquiterpenoidsandphenylpropanoidsofavariedchemicalstructurehave beenidentifiedintheessentialoil,whilephenylalkanoids,aristolactams,amidesandflavonoidshavebeen purifiedbychromatographictechniquesfromtheextracts.Thebiologicalandpharmacological exami-nationofP.marginatumshowedthattheplantmaybeavaluablesourceofmosquitocidal,antifungal, antitumoralandhemostaticagents.Futurebioguidedresearchmayyieldbiologicallyrelevantmolecules usefulinmedicineoragriculture.

Introduction

The species Piper marginatum Jacq., Piperaceae, was first describedin1781byDutchbotanistNikolausJosephvonJacquin. ThespecieshadbeencollectedduringexcursionstoCentraland SouthAmerica,andthemorphologicalcharacterswererecorded asheart-shaped,acuminated,multi-veinedandreticulatedleaves, withamarginal,groovedandwingedpetiole,andsolitary flow-ers(Jacquin,1786).TheSwissbotanistAnneCasimirPyramede Candollewasthefirsttoobservesmallmorphologicaldifferences betweendifferent collections of P.marginatum,and recognized threesubspecies:P.marginatumJacq,P.marginatumvar.anisatum

(Kunth)C.DC.andP.marginatumvar.catalpifolium(Kunth)C.DC. (Candolle,1902).Inthecomprehensivework“ThePiperaceaeof NorthernSouthAmerica”,WilliamTreleaseandTrumanG.Yuncker, differentiatedthesubspeciesbasedonthepuberulent(var. anisa-tum)orpillose(var.catalpifolium)natureofthenervesontheupper surfaceoftheleaves(TreleaseandYuncker,1950).Howeverthe difficultytocharacterize specimensatthesubgenuslevel given itsextensivehomoplasy(the developmentofsimilarcharacters byparallelor convergentevolution) wasrecognizedbyRicardo

∗ Correspondingauthor.

E-mail:jguzmand@uninorte.edu.co(J.D.Guzman).

Callejas(Callejas,1986),andthusthemodernclassifications con-siderthesubspeciesassynonymsofP.marginatumJacq.(Andrade etal.,2008).Inthiswork,thesensulatoofP.marginatumwas con-sidered, followingthe criteriaof theMissouriBotanical Garden (Tropicos.org,2015),whichcollatesunderP.marginatumseveral speciesandsubspecies,includingPipersan-joseanumC.DC.,Piper patulumBertol.,PiperuncatumTrel.,PiperquiriguanumTrel.,among others.

ThephylogeneticanalysisofthegenusPiperusingthesequence alignmentoftheinternaltranscribedspacer(ITS)ofthe18S-26S nuclearribosomalDNAandthechloroplastintronregionpsbJ-petA, indicatedthatthespeciesP.marginatumiscloselyrelatedtoP. mul-tiplinerviumandP.schwakei,andtogetherthesethreespeciesbuild theP.marginatumcomplex(Jaramilloetal.,2008).Moreoverthe Pothomorphegroupspecies(whichincludesP.auritum,P. pelta-tumandP.umbellatum)showedtobephylogeneticallyrelatedto theP.marginatumcomplex.

ThespeciesP.marginatumhasbeenwidelyrecognizedforits medicinalpurposeswithinanumberofindigenouscultureslocated intheCaribbeanandAmazonregions,fromCentralAmericaand theAntillestoBrazil(deNú ˜nezandJohnson,1943;Braga,1960; D’Angeloetal.,1997;DiStasiandHiruma-Lima,2002).Inaddition thedriedleaveshavebeenusedasanaturalsweetener(Hussain et al., 1990; Surana et al., 2006). Its major secondary metabo-litesare terpenoidsand phenylalkanoids(Andradeetal.,2008).

http://dx.doi.org/10.1016/j.bjp.2016.03.014

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Inadditionanumberofbiologicalandpharmacologicalpublished data(Sequeda-Casta ˜nedaetal.,2015)seemstosupportitsusein traditionalmedicine.Thisreviewcoverstheethnomedicinal, phy-tochemicalandbiologicalliteraturepublishedonP.marginatum

withtheaimtoidentifytheresearchvoidsforfuture investiga-tionandcriticallyassessthepotentialapplicationofthespeciesin medicineandagriculture.

Folkmedicineandtraditionaluses

Theindigenous communitiesinCentralAmerica, theAntilles andSouthAmericarepeatedlyreportedtouseP.marginatumfor treatingavariedarrayofdiseasesandailments.Gastrointestinal problemsarethemostcommontherapeuticuseinthetraditional medicine,spanning differentlocationsand cultures (Fig.1,Box 1).The plant is recurrently employed either as a decoction or infusionforits tonic,diureticand carminative effects(Foungbe

etal.,1976;Johnson,1998;DiStasiandHiruma-Lima,2002;de

Albuquerque et al., 2007). It is also used to treat gallbladder, liver,stomach,spleen,urinaryandgastrointestinalailments(van denBerg,1982;Pereiraetal.,2011;YukesandBalick,2011),but alsodysentery(deNú ˜nezand Johnson,1943).In Central Amer-ica,thespeciesisknownas“Aniseto”and itis employedasan infusionfortreatingflatulencedisorders,inasimilarwaytostar anise.

PainreliefisthesecondmostfrequentuseofP.marginatumin thetraditionalmedicine(Fig.1,Box1).Theplantisusedtorelieve toothache,headachesandpaincausedbyitching,andasageneral analgesic(Hazlett,1986;GiraldoTafur,1996;DiStasiand Hiruma-Lima,2002;Pereiraetal.,2011).Theplantisemployedtopically asacataplasmtoalleviatethepainofthelimbsorabdomen,oras adecoctionorinfusionforteeth,headandstomachaches(García, 1974;GiraldoTafur,1996;YukesandBalick,2011).

ThespeciesP.marginatumisalsocommonlyusedasa hemo-static(Fig.1,Box1).Theplanthasbeenreportedtostopbleeding particularly in the case of ophidian accidents (de Nú ˜nez and Johnson,1943;Braga,1960;D’Angeloetal.,1997;Sánchezetal., 2011;Ortega-Galvan,2014).Reportsofthetopicalapplicationof theplanttoalleviateitchingandscratchingfrominsectbites includ-ingants(ElisabetskyandGely,1987)hasbeenrecurrentlyreported (Box1),anditremainstobedeterminedifthispropertyisduesolely totheanalgesiceffect.InadditionP.marginatumdisplays antimi-crobialpropertieswithrecordedapplicationsinBrazil(Corrêaand Pena,1984;D’Angeloetal.,1997),Colombia(DukeandVasquez, 1994),Cuba(Sánchezetal.,2011)andPuertoRico(deNú ˜nezand Johnson,1943).Thespeciesisalsoemployedtotreatfemale disor-ders,skinproblemsandinsectbites(vanAndeletal.,2008;Lans andGeorges,2011;Pereiraetal.,2011).InSuriname,Trinidadand PuertoRico,theplantiswidelyusedtotreatfemaledisorderssuch astocleanfemalesexualorgans,tohelpparturition,andtoreduce themenstruationflow,respectively(Morton,1977;vanAndeletal., 2008;LansandGeorges,2011).IntheFrenchGuiana,P.marginatum

isusedtotreatcutaneouseruptionsandskinrashes(Foungbeetal., 1976;Morton,1977;D’Angeloetal.,1997),andinBrazilitisused toalleviatehitchingcausedbyinsectbites(Pereiraetal.,2011).

Phytochemistry

The species P. marginatum shows a distinct phytochemistry withthepresenceofspecificsecondarymetabolites,notfoundin otherPiperspecies.Forinstance,P.marginatumistheonlyPiper

speciescontaininganethole,estragole, isoeugenolmethylether, thephenylalkanoids3-farnesyl-4-hydroxybenzoicand 3-farnesyl-4-methoxybenzoic acids and the glycosides marginatoside and vitexin(Parmaretal.,1997).NootherPiperspecieshaveshown thepresenceofthesechemotaxonomicmarkers.

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7

6

5

4

3

2

F

requency of repor

ted usage

1

0

Analgesic

Anti-inflammator y

Anti-microbialAnti-tumor al Febr

ifuge

Female disorders

Gastrointestinal prob lems

HemorrhoidsHemostaticInsect bites Malar

ia

Rheumatism_{Skin prob} lems

Snak e bites

Stim ulant

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Box1

TraditionalmedicineapplicationsofPipermarginatumbylocalcommunities.

Location Organoftheplant Medicinalproperties,or afflictionstreated

Modeofapplication References

Amazonregion Roots Carminative,diuretic,tonic, usefulagainsttoothacheand cobravenom

Baths DiStasiandHiruma-Lima(2002)

Roots Toalleviatepainanditchingof insectbites

Cataplasm

Fruitsandleaves Stimulant nd

Stem,leaves Againstitchingfromantbites Cataplasm ElisabetskyandGely(1987) nd Asantispasmodicandagainst

liverandgallbladderdiseases

Decoction vandenBerg(1982)

Brazil Leaves Rheumatism,bleedingskin wounds,toothacheandtumors

Decoction CorrêaandPena(1984),D’Angeloetal.(1997)

Leaves Toreduceswellings Rubbedwithfatas cataplasm,poultice

BranchandSilva(1983),DukeandVasquez(1994)

Roots Toalleviatehitchingcausedby insectbites,andalsoasateeth painreliever

Maceration Pereiraetal.(2011)

Leavesandfruits Asantispasmodic,totreat cough,andaffectionsofthe spleen,liverandintestinal problems

Usedtopically Pereiraetal.(2011)

Stem,leaves,roots Againsthighbloodpressure, asthma,erysipelas,problems withurinarysystemandasa diuretic

nd deAlbuquerqueetal.(2007)

nd Totreathemorrhoids Infusion RodriguesandAndrade(2014)

nd Hemostatic,snake-bite medicine

nd Braga(1960),D’Angeloetal.(1997)

Colombia Leaves,stem Forprotectingteethagainst cavities

Chewed DukeandVasquez(1994),García(1974)

Leaves Analgesic Infusionandcataplasm GiraldoTafur(1996) Roots Usedagainstmalariaandas

stimulant

Juice García(1974)

Entireplant Toreducefevers Decoction García(1974)

CostaRica Leaves Totreatheadaches Decoction Hazlett(1986)

Cuba nd Antiseptic,astringent,

antihemorrhagicand hemostatic

nd Sánchezetal.(2011)

DominicanRepublic Leaves Indigestionandflatulence disordersbutalsoagainst stomachpain

Infusion YukesandBalick(2011)

FrenchGuiana Leaves Usedincombinationwith Quassiaamaratotreatmalaria

Decoction Vigneronetal.(2005)

Leaves Totreatcutaneouseruptions andinsectbites

Decoction Foungbeetal.(1976)

Roots Diureticandsudorific Infusion Foungbeetal.(1976)

nd Usedtotreatskinrashes nd D’Angeloetal.(1997),Morton(1977)

Panama nd Carminative,diuretic,

emmenagogue,hemostatic

nd Johnson(1998)

nd Reducefeverandlung secretions

nd D’Angeloetal.(1997),Morton(1977)

PuertoRico Leaves Hemostatic Cataplasm deNú ˜nezandJohnson(1943)

Leaves Astreatmenttodysentery Infusion deNú ˜nezandJohnson(1943)

nd Reducesmenstruationflow nd Morton(1977)

Suriname Leaves Tocleansethevagina,cleanse theuterus,disguisebadsmell, enhancesexualpleasure amongstotherapplications

Steambath vanAndeletal.(2008)

TrinidadandTobago nd Tohelpparturition Infusionordecoctiondrank LansandGeorges(2011)

ndreferstonodata.

Accordingtotheessentialoil(EO)components,seven chemo-typeswererecognizedbyAndradeetal.intheircomprehensive studywith22samplesofP.marginatumcollectedthroughoutthe BrazilianAmazon(Andradeetal.,2008).Theexistenceofseven chemotypesmayinduce toconsiderthe assumptionof ancient characterofP.marginatum,allowingpotentialspeciationeventsto occurduringrecentevolution.Thishypothesismaybetestedinthe futurebymolecularphylogeneticanalysis.Thecompositionofthe EOoftheleaf,stemandinflorescencefromaP.marginatumspecies collectedinnearRecife,Brazil,showedthatthemajorcomponent

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anEOrichingermacreneD(36.6%)(Jaramillo-Coloradoetal.,2015). Thesestudiessuggestthattherearemorethansevenchemotypes ontheEOofP.marginatumsensulato.Theseresultspointoutto adramaticvariationinchemicalcompositionforasetofrelated marginatum-phenotypespeciesbutinadditionitisnecessaryto considerthevariabilityassociatedtochronobiologicalphenomena (monthly,weeklyanddailyvariation)ashypothesizedbyMoraes etal.(2014).

MostofthephytochemicalstudiesonP.marginatumhavebeen carriedoutontheEOof theplant.Twentyfive monoterpen(e)-oids(1–25,Box 3), andfifty sevensesquiterpen(e)-oids(26–82,

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The sole sesquiterpenoid which has been purified using chromatographic techniques is caryophyllene oxide (40) (de

Oliveira Chaves and de Oliveira Santos, 2002). Among the

thirty-nine phenylalkanoids (83–122, Box 2) reported for P.

marginatum, most of them were identified by CG-MS

anal-ysis of the EO of the plant, while some of them were isolatedtopuritybychromatographictechniques(apiol(87),(E )-asarone(89),croweacin(92), 2,6-dimethoxy-3,4-methylenedioxy-1-(2-propenyl)-benzene (95), 3-farnesyl-4-hydroxybenzoic acid

(99) and 3-farnesyl-4-methoxybenzoic acid (100), 2-hydroxy-3,4-methylenedioxypropiophenone (101), marginatine (106), 3,4-methylenedioxypropiophenone (108), 2-methoxy-4,5-methylenedioxypropiophenone (109), pipermargine (118) piperonal (119), 1-(1-(Z)-propenyl)-2,4,6-trimethoxybenzene (120), safrole (121), 2,4,5-trimethoxypropiophenone (122)) (de

Diaz and Gottlieb, 1979; Maxwell and Rampersad, 1988; de

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ThealkaloidsoramidessofaridentifiedfromP.marginatumare thearistolactamscepharanoneB(123)andpiperolactamA(124), (E,E)-N-isobutyl-2,4-octadienamide(125)andcinnamoyl pirroli-dide (126) (de Oliveira Santos and de Oliveira Chaves, 1999a; deOliveiraChavesetal.,2003;deOliveiraChaveset al.,2006). Two flavanones 5,4′_{-dihydroxy-7-methoxyflavanone} ₍₁₂₇₎ _and

5,7-dihydroxy-4′_{-methoxyflavanone}₍₁₂₈_),_and_two_flavonoid

gly-cosidesmarginatoside(129)andvitexin(130)havebeenisolated fromtheleavesofP.marginatum(Tillequinetal.,1978;Reigada etal.,2007).Thecatecholaminenoradrenaline(131)was identi-fiedbyhighperformanceliquidchromatography(D’Angeloetal., 1997),andthefattyacidstearicacid(132)hasbeenpurifiedfrom theleaves(deDiazandGottlieb,1979).

Biologicalandpharmacologicalapplications

Thesweeteningeffectoftheplantrecordedinthetraditional applicationwasattributedtothepresenceof(E)-anethole(83),a sweetphenylpropanoidandmajorcompound incertain chemo-types of the EO of P. marginatum but also present in fennel (Foeniculum vulgare), staranise (Illicium verum), cicely(Myrrhis odorata) and anise root (Osmorhiza longistylis) (Hussain et al., 1990).(E)-Anetholehasbeenreportedtoprovideprotectionagainst chemically-inducedapoptosisandgenotoxicity(Abraham,2001; Galickaetal.,2014),andtobenon-carcinogenicinmice(Miller etal.,1983)posingnorisktohumanhealth(Newberneetal.,1999).

Most studies evaluating the biological and pharmacological properties of P. marginatum have focused on the essential oil (Box3).TheleafEOdemonstratedgrowthinhibitionofEscherichia coli bacteria with a minimum inhibitory concentration (MIC) valuebetween700and900␮g/mlagainsttwopathogenicstrains STEC0157 and EPEC0312 respectively (Duarte et al., 2007). A muchlowerMICvalueof120␮g/mlwasfoundagainstthe phy-topathogenicbacteriumXanthomonasalbilineans (Sánchezetal., 2012).TheleafEOwasalsoscreenedforfungalinhibitionagainst bothAlternariasolaniiandFusariumoxysporum,displaying moder-ateactivityindiskdiffusionassays(dosSantosetal.,2011;Duarte

etal.,2013).HoweveranotherstudyreportedthattheEOfromP. marginatumwasinactiveagainstF.oxysporumwithanMICvalue higherthan500␮g/ml,whileitwasfoundtobeslightlymoreactive againstTrichophytonrubrumandTrichophytonmentagrophyteswith respectiveMICvalues of500and 250␮g/ml (Tangarife-Casta ˜no etal.,2014).MoreoverboththeEOandtheethanolicextractofP. marginatumwerereportedtobeinactiveagainstCandidaalbicans

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Box2

ReportedphytochemicalsidentifiedinPipermarginatum.

Class Compound Presentinorgan Reference

Monoterpeneand monoterpenoids

Allocymene(1) Leaf,stem Ramosetal.(1986)

Borneol(2) Leaf Andradeetal.(2008)

Camphene(3) Leaf Andradeetal.(2008)

Camphor(4) Leaf Andradeetal.(2008)

␦-3-Carene(5) Leaf,stem Andradeetal.(2008),Autranetal.(2009),Moraesetal. (2014),Ramosetal.(1986),Vogleretal.(2006) p-Cymene(6) Leaf,stem Andradeetal.(2008),Ramosetal.(1986),Vogleretal.

(2006)

8-p-Cymenol(7) Leaf,stem Vogleretal.(2006)

Isoborneol(8) Leaf Andradeetal.(2008)

Isopentylisovalerate(9) Leaf Autranetal.(2009),Moraesetal.(2014) Isosylvestrene(10) Leaf Andradeetal.(2008)

Limonene(11) Leaf,stem Andradeetal.(2008),Ramosetal.(1986),Vogleretal. (2006)

Linalool(12) Leaf,stem Andradeetal.(2008),Autranetal.(2009),Moraesetal. (2014),Ramosetal.(1986),Vogleretal.(2006)

p-Mentha-1-(7),8-diene(13) Leaf Andradeetal.(2008)

Myrcene(14) Leaf,stem Andradeetal.(2008),Ramosetal.(1986) (E)-␤-ocimene(15) Leaf,stem Andradeetal.(2008),Ramosetal.(1986)

(Z)-␤-ocimene(16) Leaf,stem Andradeetal.(2008),Autranetal.(2009),Moraesetal. (2014),Ramosetal.(1986)

␣-Phellandrene(17) Leaf,stem Andradeetal.(2008),Ramosetal.(1986) ␣-Pinene(18) Leaf,stem Andradeetal.(2008),Ramosetal.(1986)

␤-Pinene(19) Leaf,stem Andradeetal.(2008),Autranetal.(2009),Moraesetal. (2014),Ramosetal.(1986)

Sabinene(20) Leaf Andradeetal.(2008)

Sylvestrene(21) Leaf Autranetal.(2009),Moraesetal.(2014) ␣-Terpinene(22) Leaf,stem Andradeetal.(2008),Ramosetal.(1986) ␥-Terpinene(23) Leaf,stem Andradeetal.(2008),Ramosetal.(1986) ␣-Terpineol(24) Leaf Autranetal.(2009),Moraesetal.(2014) ␣-Terpinolene(25) Leaf,stem Andradeetal.(2008),Ramosetal.(1986)

Sesquiterpeneand sesquiterpenoids

␣-Acoradiene(26) Leaf,inflorescence Autranetal.(2009),Moraesetal.(2014) ␤-Acoradiene(27) Leaf Autranetal.(2009),Moraesetal.(2014) Alloaromadendrene(28) Leaf Andradeetal.(2008)

Alloaromadendreneepoxide(29) Leaf Andradeetal.(2008)

Aromadendrene(30) Leaf Andradeetal.(2008)

Bicycloelemene(31) Leaf Sánchezetal.(2011)

Bicyclogermacrene(32) Leaf Andradeetal.(2008),Autranetal.(2009),Moraesetal. (2014),Sánchezetal.(2011)

␤-Bourbonene(33) Leaf,stem Andradeetal.(2008),Ramosetal.(1986)

␣-Cadinene(34) Leaf Moraesetal.(2014)

␦-Cadinene(35) Leaf,stem Andradeetal.(2008),Ramosetal.(1986)

␥-Cadinene(36) Leaf,stem,

inflorescence

Autranetal.(2009),Moraesetal.(2014)

␣-Cadinol(37) Leaf Andradeetal.(2008)

␦-Cadinol(38) Stem Ramosetal.(1986)

␤-Caryophyllene(39) Leaf,stem, inflorescence

Andradeetal.(2008),Autranetal.(2009),Moraesetal. (2014),Ramosetal.(1986)

Caryophylleneoxide(40) Leaf,stem Andradeetal.(2008),Autranetal.(2009),deOliveira ChavesanddeOliveiraSantos(2002)

␣-Copaene(41) Leaf,stem,

inflorescence

Andradeetal.(2008),Ramosetal.(1986),Autranetal. (2009),Moraesetal.(2014),Sánchezetal.(2011)

␣-Cubebene(42) Leaf,stem,

inflorescence

Andradeetal.(2008),Autranetal.(2009)

␤-Cubebene(43) Leaf Andradeetal.(2008)

Cyclosativene(44) Leaf Andradeetal.(2008)

␤-Dihydroagarofuran(45) Leaf Andradeetal.(2008) ar-Dihydroturmerone(46) Stem Autranetal.(2009)

␤-Elemene(47) Leaf,stem,

inflorescence

Andradeetal.(2008),Autranetal.(2009),Moraesetal. (2014),Ramosetal.(1986),Sánchezetal.(2011) ␦-Elemene(48) Leaf,stem Autranetal.(2009),Moraesetal.(2014),Ramosetal.

(1986)

␥-Elemene(49) Leaf, Ramosetal.(1986)

Elemol(50) Leaf,stem Andradeetal.(2008),Autranetal.(2009),Moraesetal. (2014),Ramosetal.(1986),Sánchezetal.(2011) ␣-Eudesmol(51) Leaf Andradeetal.(2008),Sánchezetal.(2011)

␤-Eudesmol(52) Leaf,stem Bernaletal.(2011),Ramosetal.(1986),Andradeetal. (2008),Sánchezetal.(2011)

10-epi-␥-Eudesmol(53) Leaf Andradeetal.(2008)

␥-Eudesmol(54) Leaf Andradeetal.(2008)

GermacreneA(55) Leaf Andradeetal.(2008)

GermacreneD(56) Leaf,inflorescence Andradeetal.(2008),Autranetal.(2009) GermacreneD-4ol(57) Leaf Andradeetal.(2008)

Globulol(58) Leaf Andradeetal.(2008)

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Box2(Continued)

(E)-␤-guaiene(60) Leaf Autranetal.(2009),Moraesetal.(2014) (Z)-␤-guaiene(61) Leaf,inflorescence Autranetal.(2009),Moraesetal.(2014)

␤-Gurjunene(62) Leaf Andradeetal.(2008)

␥-Gurjunene(63) Inflorescence Autranetal.(2009)

␥-Himachalene(64) Leaf Autranetal.(2009),Moraesetal.(2014)

␣-Humulene(65) Leaf,stem,

inflorescence

Andradeetal.(2008),Autranetal.(2009),Moraesetal. (2014),Ramosetal.(1986)

HumuleneepoxideII(66) Leaf Andradeetal.(2008)

Isoledene(67) Leaf Autranetal.(2009),Moraesetal.(2014) (Z)-Isolongifolanone(68) Stem Autranetal.(2009)

Ledol(69) Leaf Autranetal.(2009),Moraesetal.(2014)

␣-Muurolene(70) Leaf Andradeetal.(2008)

␥-Muurolene(71) Leaf,stem Ramosetal.(1986)

epi-␣-Muurolol(72) Leaf Andradeetal.(2008)

(E)-Nerolidol(73) Leaf Andradeetal.(2008),Sánchezetal.(2011)

(Z)-Nerolidol(74) Stem Autranetal.(2009)

Patchoulol(75) Leaf,stem,

inflorescence

␣-Selinene(76) Leaf Andradeetal.(2008)

␤-Selinene(77) Leaf,stem Andradeetal.(2008),Autranetal.(2009)

7-epi-␣-Selinene(78) Leaf Andradeetal.(2008)

Selin-11-en-4␣-ol(79) Leaf Andradeetal.(2008)

Seychellene(80) Stem Autranetal.(2009)

Spathulenol(81) Leaf Andradeetal.(2008)

Valencene(82) Inflorescence Autranetal.(2009)

Phenylalkanoids (E)-anethole(83) Leaf,stem Andradeetal.(2008),Sánchezetal.(2011),Vogleretal. (2006)

(Z)-anethole(84) Leaf Andradeetal.(2008)

p-Anisaldehyde(85) Leaf,stem Vogleretal.(2006)

Anisylketone(86) Leaf,stem Vogleretal.(2006)

Apiol(87) Root Santosetal.(1998)

Asaricin(88) Leaf Andradeetal.(2008)

(E)-asarone(89) Leaf,stem,root, inflorescence

Andradeetal.(2008),Autranetal.(2009),Moraesetal. (2014),Sánchezetal.(2011),Sánchezetal.(2011),Santos etal.(1998)

(Z)-asarone(90) Leaf,stem,

inflorescence

Andradeetal.(2008),Autranetal.(2009),Moraesetal. (2014)

␥-Asarone(91) Leaf Andradeetal.(2008)

Croweacin(92) Root Andradeetal.(2008),deOliveiraSantosetal.(1997) Dillapiole(93) Leaf,stem Andradeetal.(2008),Ramosetal.(1986),Sánchezetal.

(2011)

3,4-Dimethoxycinnamicacid(94) Leaf Sánchezetal.(2011)

2,6-Dimethoxy-3,4-methylenedioxy-1-(2-propenyl)-benzene (95)

Root Santosetal.(1998)

Elemicin(96) Leaf,stem Autranetal.(2009),Moraesetal.(2014),Ramosetal. (1986),Sánchezetal.(2011)

Estragole(97) Leaf,stem Andradeetal.(2008),Ramosetal.(1986),Sánchezetal. (2011),Vogleretal.(2006)

Exalatacin(98) Leaf Andradeetal.(2008)

3-Farnesyl-4-hydroxybenzoicacid(99) Leaf,stem deOliveiraChavesanddeOliveiraSantos(2002),Maxwell andRampersad(1988)

3-Farnesyl-4-methoxybenzoicacid(100) Leaf,stem MaxwellandRampersad(1988)

2-Hydroxy-3,4-methylenedioxypropiophenone (101)

Leaf,stem Andradeetal.(2008),deDiazandGottlieb(1979),Ramos etal.(1986)

Isocroweacin(102) Leaf Sánchezetal.(2011)

Isolelemicin(103) Leaf,stem Andradeetal.(2008),Ramosetal.(1986) (E)-Isoosmorhizole(104) Leaf Andradeetal.(2008)

Isosafrole(105) Leaf Sánchezetal.(2011)

3,4-Methylenedioxy-1-(2E-octenyl)-benzene (marginatine,106)

1-(3,4-Methylenedioxyphenyl)-propan-1-ol (marginatumol,107)

Leaf Reigadaetal.(2007)

3,4-Methylenedioxypropiophenone(108) Leaf,stem Andradeetal.(2008),deDiazandGottlieb(1979),Ramos etal.(1986),Reigadaetal.(2007)

2-Methoxy-4,5-methylenedioxypropiophenone (109)

Root,leaf Andradeetal.(2008),deDiazandGottlieb(1979),Oliveira SantosandOliveiraChaves(2000),Reigadaetal.(2007)

Methyleugenol(110) Leaf,stem Andradeetal.(2008),Ramosetal.(1986),Sánchezetal. (2011)

Methyl3-farnesyl-4-hydroxybenzoate(111) Leaf,stem MaxwellandRampersad(1988) Methyl3-farnesyl-4-methoxybenzoate(112) Leaf,stem MaxwellandRampersad(1988) (E)-methylisoeugenol(113) Leaf,stem,

inflorescence

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Box2(Continued)

Myristicin(115) Leaf,stem Andradeetal.(2008),Ramosetal.(1986),Sánchezetal. (2011)

Norepinephrine(116) Leaf D’Angeloetal.(1997)

Nothosmyrnol(117) Leaf Sánchezetal.(2011)

1-(1E-propenyl)-2,4,6-trimethoxybenzene (pipermargine,118)

Piperonal(119) Leaf,stem deDiazandGottlieb(1979) 1-(1-(Z)-propenyl)-2,4,6-trimethoxybenzene

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Fruit deOliveiraChavesanddeOliveiraSantos(2002)

Safrole(121) Leaf,stem Andradeetal.(2008),deDiazandGottlieb(1979),Ramos etal.(1986),Sánchezetal.(2011)

2,4,5-Trimethoxypropiophenone(122) Root deOliveiraSantosanddeOliveiraChaves(1999b)

Alkaloidsandamides CepharanoneB(123) Wholeplant deOliveiraChavesetal.(2006) Cinnamoylpirrolidide(124) Stem deOliveiraChavesetal.(2003)

(E,E)-N-isobutyl-2,4-octadienamide(125) Root deOliveiraSantosanddeOliveiraChaves(1999a) PiperolactamA(126) Wholeplant deOliveiraChavesetal.(2006)

Flavonoids 5,4′_{-Dihydroxy-7-methoxyflavanone}₍₁₂₇₎ _Leaf _Reigada_et_al.₍₂₀₀₇₎

5,7-Dihydroxy-4′_{-methoxyflavanone}₍₁₂₈₎ _Leaf _Reigada_et_al.₍₂₀₀₇₎

Marginatoside(129) Leaf Tillequinetal.(1978)

Vitexin(130) Leaf Tillequinetal.(1978)

Others Noradrenaline(131) Leaf D’Angeloetal.(1997)

Stearicacid(132) Leaf,stem deDiazandGottlieb(1979)

fromstemandflowerbeingslightlymoreactivethantheEOfrom theleaf(Autranetal.,2009).AlowerLC50valueof8.3␮g/mlwas

reportedforaleafEOobtainedfromParaiba,Brazil(Costaetal., 2010)whereasaLC50valueof34␮g/mlwasfoundforaleafEO

fromaplantcollectedintheRondoniastateinBrazil(Santanaetal., 2015).MoreoverinthepresenceoftheEOat100␮g/ml,thegravid

A.aegyptifemalesreducedthenumberofeggslaidbyone-third comparedtothenegativecontrol(Autranetal.,2009).Theeffectof theP.marginatumEOonbrineshrimp(Artemiafranciscana) letha-lityandVerocellscytotoxicitywasfoundtobecomparableinthe concentration-responsewitha LC50 valueof22.4␮g/ml against

theA.franciscananaupliiafter24hofexposition(Olivero-Verbel etal.,2009),andanIC50valueof30.3␮g/mlagainsttheVerocells

(Tangarife-Casta ˜noetal.,2014).InadditiontheEOalso demon-stratedantiparasiticandinsecticidalproperties,with90%ofthe populationof Schistosomamansonibeinginhibitedwith5mgof theEO(Frischkornetal.,1978),and90%ofthepopulationofthe fireantSolenopsissaevissimabeinginhibitedwithaconcentration of427–480␮g/ml (Soutoetal.,2012).TheEOofP.marginatum

showedsignificant antioxidantactivity witha DPPH IC50 value

between1.2and1.5␮g/mlwhilethecontrolascorbicacidshoweda DPPHIC50valueof1.0␮g/ml(Jaramillo-Coloradoetal.,2015).

Fur-thermoretheEOdemonstratedrepellentactivityoftheredflour beetleTriboliumcastaneumfromaconcentrationof0.01␮l/ml,and alsoaconsiderableanti-alimentaryeffectagainstthecottonmoth

Spodopteralittoralis,beingnon-phytotoxicagainstLatuccasativa, and thussuggesting apotential applicationasan naturalagent tocontrolbeetlesand mothsin agriculturalsettings( Jaramillo-Coloradoetal.,2015).

Both leaf and root from P. marginatum collected in Yutaje, Venezuelawereextractedwithethanolandtheethanolicextracts weretestedforcytotoxicityagainstacollectionofcancercelllines (Villasmil et al., 2006).The leaf extract wasactive against the humancoloncarcinomalineHT-29witha GI50 of55␮g/mlbut

inactiveagainsttheothercancerlines,whereastherootextract wasfoundactiveagainstthehumanpancreaticcarcinomaPANC-1 (GI5065␮g/ml),andmoderatelyactiveagainstcolonHT-29(GI50

298␮g/ml)andlungA549(GI50240␮g/ml)carcinomacelllines

(Villasmiletal.,2006).Amurineinvivoexperimentwasperformed andtheleafextractshowedamarkedantitumoraleffectdecreasing byhalfthesizeofthetumorscomparedtothenegativecontrol.

Interestinglytherootextractwasinactivesuggestingthat poten-tialantitumoralcompoundsarepresentintheleafbutabsentin theroot,andthusthesecompoundscouldbeeasilydifferentiated byHPLCanalysisoftheextracts.Themethanolicextractobtained

from P. marginatum leaf collected in Pernambuco, Brazil, was

examinedforantifungalactivityagainstthephytopathogenicfungi

Colletotrichumscovillei,whichcausesanthracnoseonbellpeppers (Araújo et al.,2014).The methanolic extract displayed a dose-dependentinhibitionofmycelialgrowth,achieving50%inhibition withaconcentrationof750␮g/ml.Althoughthemethanolicextract was fractioned by column chromatography and a significantly active fractionwasseparated, theactiveantifungal compounds remainstobeidentified.Moreoverthehydroalcoholicextractwas screenedforactivityagainstLeishmaniainfantumamastigotesand showedanIC50valueof25␮g/ml,whilethepositivecontrol

pen-tamidineshowedanIC50valueof2.43␮g/ml(Iwanagaetal.,2014).

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Box3

BiologicalandpharmacologicalactivitiesofPipermarginatum.

Extractorcompound Biologicalactivity Assay Potency References

LeafEO Antibacterial Invitroagainsttwopathogenic strainsofEscherichiacoli

MIC(STEC0157)=700␮g/ml MIC(EPEC0312)=900␮g/ml

Duarteetal.(2007)

InvitroagainstXanthomonas albilineans

MIC=120␮g/ml Sánchezetal.(2012)

Antifungal InvitroagainstFusarium oxysporum

Inhibitiondiameter=22.5mm, Controldiameter=69.9mm

dosSantosetal.(2011)

InvitroagainstAlternaria solanii

Inhibition%=57with10␮lof EO

Duarteetal.(2013)

Larvicidal InvitroagainstAedes aegyptilarvae

LC50=8.3␮g/ml

Controltemefos LC50=0.3␮g/ml

Costaetal.(2010)

LC50=34␮g/ml

LC90=85␮g/ml

Santanaetal.(2015)

EO Antifungal InvitroagainstCandidaalbicans MIC>2.0mg/ml Duarteetal.(2005) Antifungalandcytotoxicity Invitroactivityagainst

Fusariumoxysporum, Trichophytonrubrumand Trichophytonmentagrophytes andcytotoxicityagainstVero cellline

F.oxysporumMIC>500␮g/ml T.rubrumMIC=500␮g/ml T.mentagrophytes MIC=250␮g/ml.

IC50=30.3␮g/mlagainstVero

cellline

Tangarife-Casta ˜noetal. (2014)

Antioxidant,repellent, anti-alimentaryandphytotoxic

InvitroDPPHantioxidant, Triboliumcastaneumrepellent, Spodopteralittoralis, antialimentary,andLatucca sativaandLoliumperenne phytotoxicityactivities

DPPHinhibitionwith IC50=1.2–1.5␮g/ml,whilethe

controlascorbicacidshowed IC50=1.0␮g/ml.

EOrepellentof>50%T. castaneumfrom0.01␮l/ml EOanti-alimentarytoS. littoraliswith64–80%effect with100␮g/cm2

EO(atunknownconcentration) inhibitedrootgrowthofL. perenneby54–62%,but increasedrootgrowthofL. sativaby119–170%

Jaramillo-Coloradoetal. (2015)

Brineshrimplethality InvitroagainstArtemia franciscanacysts

LC50=22.38␮g/ml(at24h)

LC50=12.64␮g/ml(at48h)

Olivero-Verbeletal.(2009)

Cercaricidal InvitroagainstSchistosoma mansoni

At10mg,96%ofcercariaedied At5mg,90%ofcercariaedied At1mg,24%ofcercariaedied

Frischkornetal.(1978)

Larvicidal InvitroagainstAedesaegypti larvae

LeafEOLC50=23.8␮g/ml

StemEOLC50=19.9␮g/ml

FlowerEOLC50=19.9␮g/ml

Autranetal.(2009)

Insecticidal Invitroagainsttheworkersof thefireantSolenopsis saevissima(Smith)

LC50=122–167␮g/ml

LC90=427–480␮g/ml

Soutoetal.(2012)

Oviposition InvitroongravidAedesaegypti femalesandcountingthe numberofeggslaid

%eggslaid(leaf)=33% %eggslaid(stem)=32% %eggslaid(flower)=35% At100␮g/mlwithrespectto thenegativecontrol

Autranetal.(2009)

Ethanolicextract Cytotoxicity Invitroagainstmurine melanomaB16/BL6,human coloncarcinomaHT-29,human lungcarcinomaA549,human cervicalcarcinomaHeLa,and humanpancreaticcarcinoma PANC-1

Leaf:

B16/BL6GI50>300␮g/ml

HT-29GI50=55␮g/ml

A549GI50>300␮g/ml

HeLaGI50>300␮g/ml

PANC-1GI50>300␮g/ml

Root:

B16/BL6GI50>300␮g/ml

HT-29GI50=298␮g/ml

A549GI50=240␮g/ml

HeLaGI50>300␮g/ml

PANC-1GI50=65␮g/ml

Villasmiletal.(2006)

Antitumoral Invivomurinetumorinduction assay

Theleafextract(andnotthe rootextract)ofP.marginatum showedantitumoralactivity

Villasmiletal.(2006)

Methanolicextract Antifungal InvitroagainstColletotrichum scovillei

Thepercentageofinhibitionof mycelialgrowth(PIC)was50% withaconcentrationof 750␮g/ml,andreached70%at 1.5mg/ml

Araújoetal.(2014)

Hydro-alcoholicextract Anti-leishmanial InvitroagainstLeishmania infantumamastigotes

IC50=25␮g/ml

Thepositivecontrol pentamidineshowed IC50=2.43␮g/ml

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Box3(Continued)

Extractorcompound Biologicalactivity Assay Potency References

Waterextract Toxicity InvivoonWistaradultratand albinomice

LD100=1g/kg(intraperitoneal)

LD>2g/kg(orally)

D’Angeloetal.(1997)

Bloodpressure Invivoonrat Dose-dependenthypertension wasobservedwithintravenous andoraladministrations

Vasdeferenscontractility Invivoonrat Dose-dependentcontractions withEC=38.02␮g/ml

Atriacontractility Invivoonguineapig Dose-dependentcontractions withdosesbetween2.5and 10␮g/ml

Perfusedmesentericbed pressure

Invivoonrat Dose-dependentincreaseof theperfusionpressureof mesentericarteriawith EC=159.6␮g

Analgesia Invivoonmice Areductionoftwist

movementswasobservedin treatedanimalswith0.5and 1.0mg/kgoraldoses

Anti-inflammatoryofpaw edema

Invivoonrat Dose-dependentreductionof swellingwith0.5and 1.0mg/kgoraldoses

Pleuralleukocytecount Invivoonrat Noeffectonexudatevolume andleukocytecountwith0.5 and1.0mg/kgoraldoses

Purifiedflavonoids Antifungal Invitroautobiographyagainst Cladosporuscladosporioidesand Cladosporussphaerospernum

Amountrequiredtoinhibit bothC.cladosporioidesandC. sphaerospernum:

(107)–10.0␮g (108)–5.0␮g (109)–5.0␮g (127)–1.0␮g (128)–1.0␮g

Reigadaetal.(2007)

countsinthepleurisyinducedbycarrageenin,suggestingthatthe anti-inflammatory effect is related to a vasoconstriction action of thewater extract of P.marginatum,and not a specific anti-inflammatoryaction(D’Angeloetal.,1997).

Among all the identified secondary metabolites present

in P. marginatum, only five have been tested for a

biological activity and these are three arylpropanoids 1-(3,4-methylenedioxyphenyl)-propan-1-ol (marginatumol, 107), 3,4-methylenedioxypropiophenone (108), 2-methoxy-4,5-methylenedioxypropiophenone (109), and the two flavanones 5,4′_{-dihydroxy-7-methoxyflavanone}₍₁₂₇₎_and_{5,7-dihydroxy-4}′

-methoxyflavanone(128).Abioautographicmethodwasemployed toevaluatetheirantifungal effect againstCladosporus

cladospo-rioides and Cladosporus sphaerospernum and the most active

compounds were the two flavanones (127) and (128), which inhibitedbothmicroorganismswithanamountaslittleas1␮g (Reigadaetal.,2007).Thetwo propiophenones(108)and(109) inhibitedthegrowthofthefungiwith5␮g,whereasthealcohol marginatumol,(107)required10␮gtoinhibitthefungi.

Conclusion

The species P. marginatum, widely used in the traditional medicine of the Caribbean region, primarily to treat gastroin-testinalproblemsbutalsoemployedasanalgesic,hemostaticand to cure insectbites, contains a variable mixture of terpenoids, phenylalkanoids, amides and flavonoids. Some of these com-pounds, includinganethole, estragole, isoeugenolmethyl ether, 3-farnesyl-4-hydroxybenzoic and 3-farnesyl-4-methoxybenzoic acids,marginatoside and vitexin,arenot presentin otherPiper

species,andarethuschemotaxonomicmarkersforP.marginatum. ThehighvariabilityofchemotypesobservedwithinP. margina-tumsensulatomayreflectuponspeciationevents,orotherfactors whichremainstobefullyinvestigated.Thedistinctivenessofthe

chemicalcompositiontranslateintoarangeofbiologicaland phar-macologicalapplications,whichaccordingtothereportedpotency, thelarvicidaleffectagainstA.aegypti,theantifungalactivityagainst phytopathogenicfungiandthehemostaticandantitumoral poten-tial,areworthhighlightingforfutureresearch.

Authors’contributions

JBandJDGsearchedtheliterature.JBcollecteddataintables. JDGorganizedtheinformation,preparedthefiguresandwrotethe paper.

Conflictsofinterest

Theauthorsdeclarenoconflictsofinterest.

Acknowledgments

The authors acknowledge financial support from the Uni-versidad delNorte (Agenda Interna2014-0014) for the project “Búsquedadenuevosagentesanti-tuberculosiseninflorescencias dePiperdelCaribeColombiano”.TheauthorsaregratefultoDr. MariaCristinaMartinez-Habibe(Uninorte)forusefuldiscussions.

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