Rev. bras. farmacogn. vol.25 número5

w w w. s b f g n o s i a . o r g . b r / r e v i s t a

Review

Article

The

genus

Cordia

:

botanists,

ethno,

chemical

and

pharmacological

aspects

Edinardo

Fagner

Ferreira

Matias,

Erivania

Ferreira

Alves,

Maria

Karollyna

do

Nascimento

Silva,

Victoria

Regina

de

Alencar

Carvalho,

Henrique

Douglas

Melo

Coutinho

_,

_José

_Galberto

_Martins

_da

_Costa

FaculdadeLeãoSampaio,JuazeirodoNorte,CE,Brazil

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received7February2015

Accepted22May2015

Availableonline23July2015

Keywords:

Bioactivity

Cordia

Ethnopharmacology Phytochemical Flavonoids Terpenes

a

b

s

t

r

a

c

t

SpeciesofthegenusCordia,Boraginaceae,arewidelystudiedwithregardtothevariousethnobotanical andethnopharmacologicalaspects.Theyarefoundprincipallyintropicalandsubtropicalregionsofthe American,AsianandAfricancontinents,wheretheyoccurinvariouscountries.InthegenusCordia,there aremanyspeciescultivatedforornamentalplants,woodandmedicinalapplications,wheretheyare extensivelyutilizedbytraditionalcommunities.Inthelastdecades,scientificstudiesofCordiaspecies haveintensified,demonstratingthegreatinterestinphytochemical,biologicalandpharmacological stud-ies.Inthisreview,wedescribetheprincipalbotanicalaspects,ethnopharmacologicalinformationand evaluationofthebioactiveandpharmacologicalpropertiesofCordia,itsphytochemicalconstituentsand themostcommonclassesofsecondarymetabolitesidentified.Theinformationreportedinthiswork contributesscientificallytorecognizingtheimportanceofthegenusCordiaasatargetinthesearchfor newbiotechnologicalinvestments.

©2015SociedadeBrasileiradeFarmacognosia.PublishedbyElsevierEditoraLtda.Allrightsreserved.

Introduction

Althoughreportsofthefirstcivilizationspointedoutthe cura-tivepotentialoftheplants,onlyinthelastdecadeshastherebeen atrueandgrowinginterestinevaluatingand establishingtheir chemical and pharmacologicalproperties. A varietyof research groupsfromwidelyvaryingsectors, suchas industry,institutes andresearchinthechemistryandpharmacologyofplants,have beenworkingonamoreconcreteunderstandingofthetrue ther-apeuticpropertiesanddiscoveryofnewsubstancesthatcanbe utilizedasactiveprinciplesinthetreatmentofdiseases(Novais etal.,2003).

Thefirst reports of thegenus Cordia,Boraginaceae included botanical and reproductive characteristics. The plants were characterizedasbeingfertile,becausetheyareincapableof self-fertilization,whichisanimportantcriterionfortheidentification ofthespeciesbelongingtothegenus(Bawa,1974;Boshier,1995; Gibbs and Taroda, 1983; Machado and Loiola, 2000; Melo and Andrade,2007;Opleretal.,1975).

∗ _{Correspondingauthor.}

E-mail:[email protected](H.D.M.Coutinho).

ThegenusCordiaencompassesabout250species;the major-ityaretree-orshrub-sizedandnativetotheAmericas,andthey occurfromCentralAmericadowntothecentralregionofArgentina (BarrosoandOliveira,2009;Corrêa,1984).

In popular medicine, the species of the genus Cordia, are reportedasplantsutilizedforthetreatmentofvariousillnesses thataffectmanyhumansystems.Box2liststhevarious ethnophar-macological applications, which are notably for antimicrobial, antiinflammatory,anthelmintic, analgesicanddiureticpurposes andfortreatingdigestivesystem,respiratory,urogenital,cardiac, vascularandblooddisorders(Akisueetal.,1983;Arrebolaetal., 2004;BhattacharyaandSaha,2013;Biavattietal.,2007;Costaetal., 2008;Matiasetal.,2010b;Medeirosetal.,2007;Menezesetal., 2001;Oliveiraetal.,2012a;Paulinoetal.,2011a;Scheerenetal., 2002;Sertiéetal.,1990).

Due to thevarious ethnopharmacological reports attributed tospecies ofthegenusCordia, numerousresearchgroups have conducted studies toprove their pharmacological or biological propertiesthroughavarietyofmethodsandassaysinvitroand invivoofpre-clinicalnature,whicharedescribedinBox2.There arepublishedreportsdescribingthroughawidevarietyofmethods theirdiverseactivities:antimicrobial,antibiotic-modifying, antiin-flammatory,antinociceptive,antifertility,toxicity,anti-snakebite, hypolipidemic,immunomodulatory,insecticidalandantioxidant

http://dx.doi.org/10.1016/j.bjp.2015.05.012

(Al-Musayeibetal.,2011;Bayeuxetal.,2002;Bhattacharyaand Saha,2013;Caparroz-Assefetal.,2008;Cardozoetal.,2008;Costa etal., 2008; Matiaset al.,2010b, 2013a;Panghal etal., 2011b; Salazar-Arandaetal.,2011;Ticlietal.,2005).

Variousresearchgroupshavecarriedoutphytochemical stud-iesresultingintheidentificationofdifferentclassesofsecondary metabolites,aswelltheisolationofvariousconstituentsof differ-entparts(root,stem,leaves,flowersandfruits)ofvariousspecies ofthegenusCordia,asdescribedinBox1.

Box1:ListofidentifiedsubstancesofCordia_{reportedintheliteratureinchronologicalorder.}

Species(partused) Substance Reference

C.verbenacea(leaves) CordialinA(1) Veldeetal.(1982)

C.myxa(leaves) ␣-Linolenicacid(2) Linoleicacid(3) Oleicacid(4)

Wasseletal.(1987) Mirallesetal.(1989)

C.macleodii(leaves andflowers)

p-Hydroxyphenylaceticacid(5) Quercetin(6)

El-Sayedetal.(1998)

C.trichotoma(stem) Trichotomol(7) CordiachromeC(8)

␣-Cadinol(9) Oleanolicacid(10) OncocalyxoneA(11)

␤-Sitosterol

␤-Sitosterol-␤-D-glucoside Allontoin(12)

Saccharose

Menezesetal.(2001) Dinietal.(2001)

Box1(Continued)

Species(partused) Substance Reference

C.dichotoma(leaves) Arabinoglucan(14)

␥-Linolenicacid(15)

Guil-Guerreroetal. (2003)

C.verbenacea(leaves) ␣-Humulene(16) Allo-aromadendrene(17) Trans-caryophyllene(18)

Douglasetal.(2004) Ticlietal.(2005)

C.trichotoma(stem) ␣-Cadinol(19)

␣-Muurolol(20) epi-␣-Muurolol(21)

Sylvestreetal.(2006) Lagoetal.(2006)

C.verbenacea(leaves) Rosmarinicacid(22)

␣-Pinene(23)

Fernandesetal.(2007) Sartorellietal.(2007)

C.verbenacea(leaves) 1,8-Cineole(24)

␦-Elemene(25)

␤-Elemene(26)

Medeirosetal.(2007)

C.globosa(leaves) 5-Hydroxy-4′ ,7-dimethoxyflavanone(27) Eriodictiol(28)

Box1(Continued)

Species(partused) Substance Reference

C.sinensis(leaves) Protocatechuicacid(29) Trans-caffeicacid(30) Methylrosmarinate(31) Rosmarinicacid(32) Kaempferide-3-O-␤-D -glucopyranoside(33) Kaempferol-3-O-␤-D -glucopyranoside(34) Quercetin-3-O-␤-D -glucopyranoside(35) Kaempferide-3-O-␣-L -rhamnopyranosyl (1→6)-␤-D-glucopyranoside (36)

Kaempferol-3-O-␣-L -rhamno-pyranosyl

(1→6)-␤-D-glucopyranoside (37)

Al-Musayeibetal. (2011)

deSouzaetal.(2011) Quetal.(2011) Xiaoetal.(2011)

C.verbenacea(leaves) ␦-Cadinene(38)

␤-Bisabolene(39)

deSouzaetal.(2011) Pinholetal.(2012)

C.leucocephala(roots) (11S,13S,16R)-CordiaquinoneJ (40)

6-[10-(12,12-Dimethyl-13␣ - hydroxy-16-methenyl- cyclohexyl)ethyl]-1,4-naphthalenedione(41) 5-Methyl-6-[10-(12.12-dimethyl-13␤

-hydroxy-16- ciclohexil)methyl-1,4-naphthalenedione (42)

Oliveiraetal.(2012b) Rodriguesetal.(2012)

C.verbenacea(leaves) Caffeicacid(43) Gallicacid(44) Chlorogenicacid(45)

Box1(Continued)

Species(partused) Substance Reference

C.dichotoma(leaves) Luteolina(46) Apigenin(47) Hentricontanol(48) Hesperidine(49) Octasanole(50) Lupeol(51)

␣-Amyrin(52) Robonine(53) Rutin Betulin(54) Dihydrorobenetin(55)

BhattacharyaandSaha (2013)

HussainandKakoti (2013)

Theobjectiveofthisreviewwastodiscusstheprincipal chem-ical,biologicalandpharmacologicalaspectsofthespeciesofthe genusCordia,featuringthecompoundsidentifiedandtheir biolog-icalorpharmacologicalproperties.Weemphasizethatthisreview isanupdatereportonthegenusCordiaandwillserveasthe founda-tionfornewinvestigationsaimedatobtainingmoredetailsabout theplantsofthisimportantbotanicalgenus.

Materialandmethods

Thestudywascarriedoutinthefollowingdatabases:Pubmed, Scielo, Webof Science,Scirus, Bireme and ScienceDirect, with updatinguntilMarch2014,usingassearchtermsthekeywords andcombinations:Cordia,naturalproduct,chemicalcomposition, ethnopharmacologicalactivity,pharmacologicalactivity,biological activity.

Occurrenceanddistribution

ThegenusCordiashowsanoccurrenceanddistributioninareas withtropicalandsubtropicalclimateinCentralandSouthAmerica, India,AsiaandAfrica.ThespeciesofthegenusCordiaareespecially includedinstudiesofnaturalproductsofplantoriginduetotheir diversityof chemical,biological andpharmacologicalproperties (Matiasetal.,2010a,b).

Theprincipalspeciesreportedindatabanksonthegenus Cor-diaare:C.abyssinicaR.Br.,C.africanaLam.,C.alliodora(Ruiz& Pav.)Oken,C.corymbosaWilld.ex.Roem.&Schult.,C.curassavica (Jacq.)Roem.&Schult.,C.cylindrostachyaRoem.&Schult.,C.dentata Poir.,C.dichotomaG.Forst.,C.ecalyculataVell.,C.flavescensAubl., C.fragrantissimaKurz.,C.francisciTen.,C.globosa (Jacq.)Kunth., C.goeldianaGürke.,C.latifoliaRoxb.,C.leucocephalaMoric.,C. lin-naeiStearn.,C.macleodiiHook.F.&Thomson,C.martinicensis(Jacq.) Roem.&Schult.,C.monosperma(Jacq.)Roem.&Schult.,C. multispi-cataCham.,C.myxaL.,C.nodosaLam.,C.obliqueWilld.,C.oncocalyx Fr.All.,C.piauhiensesFresen.,C.tothiiL.,C.rufescensA.DC.,C. salici-foliaCham.,C.sellowianaCham.,C.sinensisLam.,C.superbaCham., C.thaisianaG.Agostini,C.trichotoma(Vell.)Arráb.exSteud.eC.

verbenaceaDC.

C.trichotoma,popularlyknownas“louro-pardo,”isdistributed inBrazilfromCearátoRioGrandedoSulstates,butcanalsobe foundinArgentina,ParaguayandsouthernBolivia.Itisextensively utilized asan ornamentalplantand is indicated principallyfor reforestationandrecoveryofdegradedareas(Freitasetal.,2006, 2008;Mendonc¸aetal.,2001;Souza,2008).C.curassavicaoccursin BrazilfromtheAmazonregiontothestateofRioGrandedoSul, normally500–1000mfromtheshoreline(Bayeuxetal.,2002).C. dichotoma,knownpopularlyasIndiancherryisasmallshrubwith globousfruits,yellowishbrown,blackorrose.ItisfoundinIndia andotherregionswithwarmerclimate(Scheerenetal.,2002).C. piauhiensisandC.tothiiareendemictoBrazilanddistributedinthe South,Southwest,SoutheastandNortheastregions(Santiagoetal., 2005).C.verbenacea,knownpopularlyaservabaleeiraisfoundin Brazilalongitscostalregion(Medeirosetal.,2007;Pimenteletal., 2012),butisalsofoundinCentralAmericaandincentralregion ofArgentina,sinceitisanativeplantoftheAmericas(Rosaetal., 2008).C.obliquaisafruittreefoundinvariouscountriesonthe Indiancontinent,whereitsfruitsaregreatlyappreciatedbythe localpopulation(Mukherjeeetal.,2008).C.rufescensisashrub foundinNortheastBrazil(Costaetal.,2008).C.salicifoliaandC. ecalyculatacanbefoundinBrazil,mostoftenfromthestateof MinasGeneraltoRioGrandedoSul,whereitisfoundeveninAcre andBrasilia(Alvesetal.,2004)butitcanalsooccurintropical for-estareasofArgentinaandParaguay(Cardozoetal.,2008;Siqueira etal.,2006).C.dentataeislocalizedinthetropicalforestsofthe

ColombianCaribbeanregionandisutilizedasafoodsourceinthe dryperiod(Garciaetal.,2009).C.sellowianaandC.myxaarespecies foundinthetemperateregionsofthewholeworldandinthe trop-ics(Barrosoetal.,2009).C.flavescens,C.globosaandC.goeldianaare widelydistributeinvariousregionsincluding:Florida,Caribbean, CentralAmericaandnortheasternSouthAmerica,itislimitedto theCaatinga(Machadoetal.,2010).C.laureceaandC.leucocephala arespeciesendemictoNortheastBrazilandarewidelycultivated forornamentalpurposes(Machadoetal.,2010;Milet-Pinheiroand Schlindwein,2010).C.macleodiiandC.nodosahaveawide distribu-tionintropicalAmerica(IzzoandPetInI-BenellI,2011).C.sinensis, C.superbaandC.thaisianaarefoundinthedrierareasofIndia,Africa andSaudiArabia(Al-Musayeibetal.,2011;Araqueetal.,2009).C. abyssinica,C.africana,C.alliodoraarespeciesthathavewood uti-lizedinproductionofhigh-qualityfurnitureandotherobjectsand domesticutensils.ItishighlyvaluedcommerciallyinEthiopia,and itisalsoanativespeciesofSaudiArabiaandtropicalAfrica(Derero etal.,2011).

Chemicalcomponents

Studiesaimedatidentifyingnewphytotherapeuticcompounds inspeciesofthegenusCordiahaveledtothequalificationofvarious classesofsecondarymetabolitesandtotheisolationofanumber ofcompoundsbelongingtovariousclasses(Box1).

Traditionalapplicationandbiological/pharmacological activitiesattributedtogenusCordia

Box2:ListofthegenusCordia_{appliedandevaluatedin} traditional,chronologicallyrelatedbiologicalactivities medicine. Species Ethnopharmacological applicationsand biologicaland/or pharmacological activity Reference

C.myxa Analgesic Anti-inflammatory Antimicrobial

TiwariandSrivastava (1967)

Rimandoetal.(1987)

C.goetzei Antifungal Marstonetal.(1988)

C.verbenacea Antimicrobial Sertiéetal.(1990) Sertieetal.(1991)

C.dichotoma Nutritional Duhanetal.(1992)

C.corymbosa Antimicrobial SilvaFilhoetal.(1993)

C.latifólia Anti-ulcer Anti-histamine

AkhtarandAhmad (1995)

C.myxa Analgesic Ficarraetal.(1995)

C.verbenacea Analgesic Anti-inflammatory

Lameiraetal.(1997)

C.myxa Antimicrobial CarvalhoandMarchini (1999)

C.alliodora Antifungal Larvicidal

Iosetetal.(2000)

C.trichotoma Antimicrobial Anthelmintic Anti-inflammatory Antimalarial Healing Diuretic Respiratorysystem disorder Urogenitalsystem disorder

Menezesetal.(2001)

C.multipicata Antiandrogen Kuroyanagietal.(2001)

C.curassavica Antinociceptive Anti-inflammatory

Bayeuxetal.(2002)

C.curassavica Anti-inflammatory Bayeuxetal.(2002)

C.dichotoma Anti-inflammatory Anti-helminth Diuretic Digestivesystem disorder Respiratorysystem disorder

Scheerenetal.(2002)

C.myxa Digestivesystem disorder

Arrebolaetal.(2004)

C.ecalyculata Respiratorysystem disorder

Alvesetal.(2004)

C.verbenacea Fetaltoxicity Carvalho-Júnioretal. (2004) C.salicifolia C.verbenacea Toxicological Antiophidic Analgesic

Caparroz-Assefetal. (2008)

Ticlietal.(2005)

C.salicifolia Diuretic

Cardiovascularsystem disorder

Digestivesystem disorder

Caparroz-Assefetal. (2008)

C.salicifolia Hypolipidemic Siqueiraetal.(2006)

C.verbenacea Anti-inflammatory Medeirosetal.(2007)

C.salicifolia Diuretic

Cardiovascularsystem disorder

Digestivesystem disorderhypolipidemic

Cardozoetal.(2008)

C.superba C.rufescens

Abortive Anti-inflammatory Immunomodulatory

Costaetal.(2008)

C.verbenacea Bone/musclesystem disorder

Matiasetal.(2010b)

C.verbenacea Antibacterial Matiasetal.(2010c) Matiasetal.(2010d)

C.dichotoma Anti-inflammatory SharmaandAsati (2010)

Box2(Continued)

Species Ethnopharmacological applicationsand biologicaland/or pharmacological activity Reference

C.globosa Analgesic Antibacterial Antihemorrhagic Digestivesystem disorder Bone/musclesystem disorder

Paulinoetal.(2011b)

C.boissieri Antibacterial Antifungal Antioxidant

Salazar-Arandaetal. (2011)

C.dichotoma Antibacterial Antifungal

Panghaletal.(2011a) Nariyaetal.(2011)

C.sinensis Anti-inflammatory Antioxidant

Al-Musayeibetal. (2011)

C.sinensis Digestivesystem disorder Respiratorysystem disorder

Al-Musayeibetal. (2011)

C.leucocephala Analgesic Digestivesystem disorder

Bone/musclesystem disorder

Oliveiraetal.(2012a)

C.verbenacea Antibacterial Pinholetal.(2012)

C.verbenacea Insecticide Knaaketal.(2012)

C.verbenacea Bacterialresistance modulatorto antibiotics

Matiasetal.(2013c) Matiasetal.(2013b)

C.curassavica Analgesic BhattacharyaandSaha (2013)

C.flavescens Urogenitalsystem disorder

BhattacharyaandSaha (2013)

C.dichotoma Analgesic Antifertility Antiglycemic Anti-helminth Antimicrobial Antiulcerogenic

BhattacharyaandSaha (2013)

Jamkhandeetal.(2013)

C.rothii Immunomodulatory Firdousetal.(2014)

areusedasananalgesicforpostpartumpain(Bhattacharya and Saha,2013).

Ethnopharmacologicalstudiesareimportantforinitiating phar-macological testsaimed atproving thepossible applicationsof naturalproductsfromplants(Matiasetal.,2013b).Box2liststhe biologicalactivitiesofessentialoils,extractsandfractionsofCordia speciesandpharmacologicalstudiesofisolatedsubstances evalu-atedbyexperimentalmethodsofthisgenus.

Antinociceptiveactivity

Antibacterialactivity

StudieshaveevaluatedmanyspeciesofthegenusCordiain rela-tiontotheirantibacterialpotential.Salazar-Arandaetal.(2011)

carried out studies to determine the antibacterial activity of theextractofC.boissierie;theyobservedactivityagainst Gram-negativebacteria(Pseudomonasaeruginosa,Klebsiellapneumonia andAcinetobacterbaumanii),buttheextractobtainedfromits flow-ersshowedsignificantresultswhentestedagainststandardand resistantstrainsofStaphylococcusaureusanalyzedthe antibacte-rialactivityofthehexaneandmethanolicextractsofleavesofC. verbenaceaDCagainststrainsofEscherichiacoliandS.aureusby determiningtheminimalinhibitoryconcentration(MIC).Thetwo extractsshowedconsiderableantibacterialactivity,wherethebest resultswereobtainedwiththehexaneextract:MICof128␮g/ml for E.coli and 256␮g/ml for S. aureus.In thestudy of Panghal etal.(2011a) andPinholetal.(2012),theacetoneextractofC. dichotoma also showed significantantibacterial activity against S. aureus. Anotherstudy utilizing the extract of the bark of C. dichotomarevealedthatE.coliandP.aeruginosaweremost sen-sitiveinrelationtoS.aureusandS.pyogeneswhenevaluatingthe antibacterialactivityofthisspecies(Nariyaetal.,2011).Evaluated theantibacterialactivityofdifferentconcentrationsofthestandard hydroalcoholicextract,obtainedfromtheleavesofC.verbenacea againstS.aureusandE.coli.Intheagardiffusiontest,theextract inaconcentration≥400mg/ml)inhibitedthegrowthofS.aureus butnotE.coli,whichcanberelatedtothelowersusceptibilityof Gram-negativebacteriatoplantextracts(Pinholetal.,2012).

Antifungalactivity

Evaluatedtheantifungal activityoftheextractof C.boissieri againstaclinicalisolateoftheyeastCandidaglabrata,utilizingthe microdilutionassaytodetermineMICvalues(Salazar-Arandaetal., 2011).AMICof125␮g/mlwasobtained,revealingthatthisspecies ofCordiawasactiveagainstthisfungus.InthestudyofNariyaetal. (2011),theextractofthebarkofC.dichotomawasevaluatedagainst threecommonpathogenicfungi(Aspergillusniger,Aspergillus clava-tus,andCandidaalbicans)andtheinhibitionzonewiththeextract wascomparedwiththatfortheconventionalantifungalsnystatin andgriseofulvin.Theresultsshoweda notableinhibitionofthe growthzoneofthefungi,withbetterresultsforC.albicansthanA. nigerorA.clavatus.

Toxicity

Conductedastudywiththeobjectiveofobtainingsafetydata inrelationtotoxicityoftheextractofC.salicifolia,consideringthe extensiveuseofthisspeciesinBrazilianpopularmedicine.Instudy utilizedmaleadultrats(200–250g)andmalemice(25–30g).The extractwasadministeredorallyorintraperitoneally.Therewereno deathsorothersignsandsymptomsoftoxicityuptothehighest dosetested (2000mg/kg body weight) in mice when adminis-teredorally,andnecropsyafter7daysoforaltreatmentwiththe extractalsodidnotrevealanypathologicalchange.Letalitywas observedonlyafterintraperitoneal administrationof920mg/kg bodyweight.Intherats,repeatedoraladministration(chronic tox-icity)ofdifferentdosesofextract(20,100,200mg/kg)for90days didnotproducesignscharacteristicoftoxicity,andalso,therewere notdeathsoftheanimals(Caparroz-Assefetal.,2008).Theresults showedloworaltoxicityoftheextractofC.salicifoliaandno evi-dencethatitposesriskafterprolongeduse.Phototoxicityofthe methanolicextractof C.verbenaceawasevaluatedinaninvitro studydonebyMatiasetal.(2010c),utilizingthebacteriaE.coli

andS.aureus.Thisspeciesshowedsignificantphototoxicactivity againstS.aureus,butnotE.coli.

Antiinflammatoryactivity

The antiinflammatoryactivity ofthe extract of C.dichotoma seedswasevaluatedinastudycarriedoutbySharmaandAsati (2010),whereWistarratsweighing160–180gofbothsexeswere exposed to aninflammatory process (footpad edema)with the administrationofcarrageenan.Onehouraftertheinjectionofthis substance,theethanolicandaqueousextractswereadministered atdifferentconcentrationsforeachtestgroup.Theresultsrevealed antiinflammatoryactivityoftheextractsforalldosestested. At adoseof500mg/kg,theaqueousandethanolicextractsshowed maximal inhibition of edema (69.52% and 58.09%, respectively) in relation to the control group, demonstrating theefficacy of theextractofC.dichotomaasanantiinflammatoryagent,which explainsthewideuseofthisplantasanantiedemaagentinpopular medicine.Isolatednine compoundsfromtheethylacetate frac-tionofthemethanolicextractof C.sinensisand evaluatedtheir antiinflammatory activity also using rats with induced inflam-mation (footpad edema) by the administration of carrageenan. The non-steriodal antiinflammatorydiclofenac was usedas the reference compound. Two compounds isolated from C. sinen-sisshowedapotentialandsignificantantiinflammatoryactivity: kaempferide-3-O-␤-D-glucopyranoside(62.4%)and kaempferol-3-O-␤-D-glucopyranoside(59.6%);theywereasactiveasdiclofenac (57.6%).Bayeuxetal.(2002)demonstratedantiedematogenic activ-ityforsubstancesisolatedfromC.curassavicausingthismethod. Theyutilizedsomeextractsobtainedfromleavesand stemand theflavonoidartemitinisolatedfromtheacetoneextractofthis species.Thedichloromethaneextract(1000mg/kg)reducededema by59%after4handby68%after5h,whiletheethanolicextract atthissameconcentrationreducededemaby44%,after4h.The petroleum etherextract didnot showsignificant results. Study suggestthatartemitinisthecompoundresponsibleforthe anti-inflammatoryactivityofthisspecies(Bayeuxetal.,2002),butin thisstudynoantiedematogenicactivitywasfoundforthis com-poundatdosesupto300mg/kg.Twoactivecompoundsobtained fromtheessentialoilofC.verbenaceawereanalyzedwithregard totheirantiinflammatoryactivity,utilizing alsothe experimen-tal footpad edema model in ratsin a studyby Medeiroset al. (2007).TheseauthorsutilizedmaleWistarrats(140–180g)treated orallywiththesesquiterpenesofC.verbenacea:␣-humuleneand

trans-caryophyllene.Thetwocompoundsshowedactivity,

inhibi-tingvariouscompoundsresponsiblefortheinflammatoryprocess, butonly␣-humulenewasabletopreventtheproductionof pro-inflammatorycytokines.

Anti-snakebiteactivity

Activityhypolipidemica

Examinedthe efficacyof the extract ofC. salicifolia in male mice(Musmusculus)subjectedtoahyperlipidemicdiet.The ani-malsweredividedintofourgroups:waterandnormaldiet,water and hyperlipidemic diet, normal diet and C. salicifolia extract (100mg/kg/day),andhyperlipidemicdietandC.salicifoliaextract (100mg/kg/day).Theextractwasadministeredbygavagefor15 days.Theresultsshowedthattherewasareductioninserumtotal cholesterollevelsinthetwogroupsgivenadietwiththeextract andalsoasignificantreduction intriglyceridelevelsin the ani-malsgivena hyperlipidemicdietwiththeextractin relationto thosethatreceivedahyperlipidemicdietwithwater(Cardozoetal., 2008).It wastherefore suggestedthatthediminution observed couldhaveoccurredduetothepresenceofcomponentsofC. sali-cifoliathatexertaninhibitory actiononsalivaryandpancreatic lipase,hinderingtheabsorptionofthetriglyceridesorthat acti-vatelipoproteinlipase,theenzymeresponsibleforthedegradation ofchylomicronsandVLDL.Analyzedtheantihyperlipemiceffect ofpulverizeddryleavesofC.salicifoliautilizingmaleWistarrats weighingabout200g.Thisproduct wasdissolvedin water and thesolutionobtainedwasadministered(20mg/kg/day)bygavage for13days.Onthelastday,theratsweresacrificedby decapita-tionandbloodwasobtainedforcholesterolandtriglycerideassays. Althoughtherewasnoeffectoncholesterolemia,ahypolipidemic effectwasobservedforthis speciesofCordiawheretriglyceride levelswerereduced(Siqueiraetal.,2006).

Immunomoduladoryactivity

Determinedtheimmunomodulatoryactivityofsixextractsof C.superbaandC.rufescensbyinvitroassaysusingmurineactivated macrophagesandlymphocytes.Theextractswereobtainedfrom driedstemsandleavesofC.superba andstalksandleavesofC. rufescens.MacrophageswerestimulatedbyIFN-␥andLPSinthe presence/absenceofthesamples,andtheproductionofnitricoxide wasmeasuredindirectlybytheGriessmethod.Thesamplestested didnotshowahighinhibitoryeffectonnitricoxideproduction, whereonlythreeoftheminhibitedthisproductionbyabout50%: theextractofC.superbaandtwoofC.rufescens,however,showeda stronginhibitionoflymphocyteproliferationandIL-2production (Costaetal.,2008).Thus,theseresultsjustifythetraditionaluseof

someCordiaspeciesinthetreatmentofimmunesystem-mediated

pathologies.Theimmunomodulatoryactivityoftheconstituents isolatedfromthefractionsobtainedfromthemethanolicextract ofleavesofC.rothiiwasevaluatedinaninvitrostudycarriedout byFirdousetal.(2014).Theresultsofthisstudysuggestedthatthe compoundsisolatedcouldbepotentialinhibitorsofmediatorsin innateandadaptiveimmuneresponses.

Antioxidantactivity

AStudiedtheantioxidantactivityoftheextractofC.boissieri usingthe DPPH free radical assay.Moderate antioxidant activ-itywasobservedonachromatographicplate,wherethisspecies showedsmallspotsorpointswithlowintensity(Salazar-Aranda etal.,2011).Ninecompoundsfromtheethylacetatefractionofthe methanolicextractofC.sinensiswereisolatedandevaluatedfor antioxidantactivityinastudybyAl-Musayeibetal.(2011)using thesamemethod.Sevencompoundsshowedsignificantfree rad-icalquenchingactivityinthisassay,andfouroftheseshoweda highantioxidantactionincomparisonwiththecontrolsubstance utilized.

Insecticidalactivity

InevaluatedtheeffectoftheaqueousextractofC.verbenaceaon thedevelopmentofSpodopterafrugiperda,examiningthevariables durationandmortalityforthelarvalandpupalperiods,size,weight andpresenceofmorphologicalalterationsofthepupaeandfertility oftheadults.Asaresult,thelarvalstateand pupalperiodofS.

frugiperdawereprolonged,andmorphologicalalterationsinthe

pupaewerealsoobserved(Knaaketal.,2012).

Antibiotic-modifyingactivity

Evaluated the antibiotic-modifying effect of thehexane and methanolicextractsoftheleavesofC.verbenaceaonnorfloxacin againstS.aureus.Theextractsata sub-inhibitoryconcentration of32␮g/mlimprovedtheinhibitionzoneby50%whencombined withtheantibioticcomparedtotheantibioticalone.Thatis,the antibioticactivityofnorfloxacinwasenhancedinthepresenceof theextractsofC.verbenacea,showingsignificantsynergism(Matias etal.,2013b).Anotherstudyutilizingthemethanolicextractand themethanolicfractionofthemethanolicextractofC.verbenacea leaveswasconducted toevaluatethedrug-modulatoryactivity of this species. Thebacteria utilized were E.coli, S.aureus and

P.aeruginosaandtheantibioticsweregentamicin,amikacinand

neomycin.Theextractaswellasthefractionpotentiatedtheeffect oftheantibioticsagainstallbacteriatestedwithexceptionofonly themethanolicextractcombinedwithgentamicinagainstE.coli (Matiasetal.,2013c).

Antifertilityactivity

A investigation about effect of the extract obtained from leavesofC.dichotomaonreproductionutilizingadultfemalerats (140–220g).Apotentialantiimplantationactivitywasobserved, depending on the dose of extract administered. At a dose of 1000mg/kg,noimplantationsiteswereobserved,buttherewere somebehavioralchangessuchasgeneralweakness,asnotedby slow and uncoordinated movements. At 800mg/kg, pregnancy was blocked 100% and there were no alterations in behavior (BhattacharyaandSaha,2013).

Conclusion

ThisreviewgatheredinformationonthegenusCordia,featuring botanical,ethnopharmacological,phytochemical,pharmacological andtoxicologicalaspects.StudiesonthegenusCordiadescribethat thespecies are distributed indiverse regionsof theworld and areutilized bytraditionalpopulations forthetreatmentof var-iousmaladies suchasinfections,inflammations and pain.With respecttopharmacologicalpotential,speciesofthegenusCordia havebeensubjectedtoantimicrobial,antinociceptive, toxicologi-cal,antiinflammatoryandantiparasitictests,amongothers.Various substanceshavebeenidentifiedandisolatesfromspeciesofthe genusCordia,particularlysecondarymetabolitesoftheclassof ter-penoids,flavonoidsandtannins,aswellastheirrespectivechemical structures.

Authorscontributions

Conflictsofinterest

Theauthorsdeclarenoconflictsofinterest.

Acknowledgments

Theauthorsacknowledgethesupportandcooperationreceived fromRENORBIO/UECE,UniversidadeRegionaldoCariri, CE, Lab-oratório de Pesquisa em Produtos Naturais e Laboratorio de MicrobiologiaeBiologiaMolecular.Theworkwasdevelopedwith financialandtechnicalsupportoftheFALSandFUNCAP.

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