In another step it has been elicited the cell suspension culture with jasmonic acid and only erysodine increased its production (San Miguel-Chávez, et al., 2007).

## **10. Compounds of non alkaloid composition**

Besides of the presence of alkaloids in the *Erythrina* plants, has been detected the presence of diverse metabolites, for example glucoproteins or lectins with the characteristic to agglutinate cells (Ortega, et al. 1990). Stojanovic & coworkers , characterized a lectin isolated from *E. velutina* which is a good agglutinant agent of erytrocites A, B and O in human beings (Stojanovic, et al., 1994).

The saponins sigmoidin C and D were isolated from the steam bark of *E. sigmoidea* Hua and have been used in Cameroon as antimicrobial agents (Mbafor, et al., 1997). Also from this species have been recently isolated a new antibacterial triterpenoid saponin called Sigmoiside E (Kouam, et al., 2007). In *E. crista-galli* were isolated 3 new pterocapans: cristacarpin, erystagallin and phaseollidin with phytoalexin properties and possessing antimicrobial activity against Gram- positive bacteria (Tanaka, et al., 1997). The erystagallin-A also isolated from the stem bark of *E. variegata* L. showed significant anti-cancer activity against breast cancer T47D cell-lines *in vitro* using the Sulforhodamine B(SRB) assay and anti-malarial activity against *Plasmodium falciparum in vitro* using the lactate dehydrogenase (LDH) assay (Tati, et al., 2011). It is interesting to note that the pterocarpene, erycristagallin isolated from root bark of *E. mildbraedii* (Njamen, et al., 2003) showed anti-inflammatory properties through its capacity to inhibit the arachidonic acid metabolism via the 5 lipooxygenase pathway.

Fomum and coworkers (1986) found in the bark of *E.sigmoidea* three new phenyl flavanones: sigmoidine A, B and C with a notorious activity against, Gram- positive bacteria (Fomum, et al., 1986).

In the seeds of *Erythrina* also have been detected protease inhibitors, for instance Joubet & coworkers found this kind of compounds against tripsine, which acts as activator of the plasminogen tissue (Joubet, et al. 1987). In this way, continue an intense research with diverse species of *Erythrina* with the aim to characterize other compounds with notorious antibiotic activity and anticancer for example Cui & coworkers described four new chalcones 1 to 4 called abyssinones A-D isolated from *E. abyssinica*. They showed a moderate cytotoxic against Caco2 cell line of human colorectal cancer with IC50 13.3, 15.1 and 11.1 µM respectively( Cui, et al. 2008).

Previously in this species Yenesew & coworkers (2004) found in the ethyl acetate extract of the bark, anti plasmodial activity against the chloroquine sensible (D6) and chloroquineresistant (W-2) strains in *Plasmodium falciparum* with values of IC30 of 7.9 ± 1.1 and 5.3 I 0.7 mg ml respectively (Yenesew, et al. 2003, 2004).

Also several flavonoids (Chacha, et al. 2005; Chukwujekwu, et al., 2011; Doughari, 2011), isoflavonoids (Sato, et al., 2006; Kamdem Waffo, et al., 2006; Redko, et al., 2007) and pterocarpanes (Rukachaisirikul, et al., 2007a; 2007b) have been mentioned as antimicotic and antibacterial agents. For instance, an arylbenzofuran, erypoegin F and four isoflavonoids, erypoegins G-J were isolated from the roots of *E. poeppigiana* and their structure were elucidated by spectroscopic evidence (Tanaka, et al., 2003).

Also is important to mention the study done by Tanaka & coworkers (Tanaka, et al. 2010) in which they isolated two new compounds from the roots of *E. herbaceae*, erybacin A and erybacin B, as a 1-hydroxy-1,3-diphenylpropan-2-one derivatives. These compounds were evaluated for their antibacterial activities against 13 strains of methicillin resistant *Staphylococcus aureus* (MRSA), the erybacy B showed a potent bactericidal activity against MRSA.

The stem bark of *E. senegalensis* studied by its hepatoprotective properties have been recently studied by the presence of prenyl isoflavonoids as novel HIV-1 protease inhibitors (Lee, et al., 2009). These authors found that the prenyl isoflavonoids had a dose-dependant inhibitory activities on HIV-1 PR with IC50 values from 0.5 to 30 μM and mention that the isoflavonoid with prenyl groups at 6 and 8 positions of the ring A and one hydroxyl group in the 4´ position of B ring was the most potent HIV-1 PR inhibitor.

## **11. Conclusions**

178 Bioactive Compounds in Phytomedicine

In another step it has been elicited the cell suspension culture with jasmonic acid and only

Besides of the presence of alkaloids in the *Erythrina* plants, has been detected the presence of diverse metabolites, for example glucoproteins or lectins with the characteristic to agglutinate cells (Ortega, et al. 1990). Stojanovic & coworkers , characterized a lectin isolated from *E. velutina* which is a good agglutinant agent of erytrocites A, B and O in

The saponins sigmoidin C and D were isolated from the steam bark of *E. sigmoidea* Hua and have been used in Cameroon as antimicrobial agents (Mbafor, et al., 1997). Also from this species have been recently isolated a new antibacterial triterpenoid saponin called Sigmoiside E (Kouam, et al., 2007). In *E. crista-galli* were isolated 3 new pterocapans: cristacarpin, erystagallin and phaseollidin with phytoalexin properties and possessing antimicrobial activity against Gram- positive bacteria (Tanaka, et al., 1997). The erystagallin-A also isolated from the stem bark of *E. variegata* L. showed significant anti-cancer activity against breast cancer T47D cell-lines *in vitro* using the Sulforhodamine B(SRB) assay and anti-malarial activity against *Plasmodium falciparum in vitro* using the lactate dehydrogenase (LDH) assay (Tati, et al., 2011). It is interesting to note that the pterocarpene, erycristagallin isolated from root bark of *E. mildbraedii* (Njamen, et al., 2003) showed anti-inflammatory properties through its capacity to inhibit the arachidonic acid metabolism via the 5-

Fomum and coworkers (1986) found in the bark of *E.sigmoidea* three new phenyl flavanones: sigmoidine A, B and C with a notorious activity against, Gram- positive bacteria (Fomum, et

In the seeds of *Erythrina* also have been detected protease inhibitors, for instance Joubet & coworkers found this kind of compounds against tripsine, which acts as activator of the plasminogen tissue (Joubet, et al. 1987). In this way, continue an intense research with diverse species of *Erythrina* with the aim to characterize other compounds with notorious antibiotic activity and anticancer for example Cui & coworkers described four new chalcones 1 to 4 called abyssinones A-D isolated from *E. abyssinica*. They showed a moderate cytotoxic against Caco2 cell line of human colorectal cancer with IC50 13.3, 15.1 and 11.1 µM

Previously in this species Yenesew & coworkers (2004) found in the ethyl acetate extract of the bark, anti plasmodial activity against the chloroquine sensible (D6) and chloroquineresistant (W-2) strains in *Plasmodium falciparum* with values of IC30 of 7.9 ± 1.1 and 5.3 I 0.7

Also several flavonoids (Chacha, et al. 2005; Chukwujekwu, et al., 2011; Doughari, 2011), isoflavonoids (Sato, et al., 2006; Kamdem Waffo, et al., 2006; Redko, et al., 2007) and pterocarpanes (Rukachaisirikul, et al., 2007a; 2007b) have been mentioned as antimicotic and antibacterial agents. For instance, an arylbenzofuran, erypoegin F and four isoflavonoids, erypoegins G-J were isolated from the roots of *E. poeppigiana* and their structure were

erysodine increased its production (San Miguel-Chávez, et al., 2007).

**10. Compounds of non alkaloid composition**

human beings (Stojanovic, et al., 1994).

lipooxygenase pathway.

respectively( Cui, et al. 2008).

mg ml respectively (Yenesew, et al. 2003, 2004).

elucidated by spectroscopic evidence (Tanaka, et al., 2003).

al., 1986).

This review represents the work done in the last seventy five years in the knowledge of the *Erythrina* genus, a group of 120 species of the Leguminosae, with seventy of them in the Neotropics, 50 species are in Mexico, Central America and Caribbean where is used as ornamental (coral or lucky bean tree) , shade tree, timber (construction, implements), living fences and enclosures, green manure, livestock, fodder, medicine and seeds are used for necklaces.

These features have contributed to a deep research of their chemical constituents as alkaloids, flavonoids, isoflavonoids, saponins and lectins. The review remarked the potential which each type of compounds have now days.

Alkaloids for instance with their unique structure have attracted attention for their synthesis and structural elucidation or their pharmacological potential given by the relaxant properties.

The flavonoids and isoflavonoids represent other of the potentials of the genus because in recent years the literature has described not only novel structures but also notorious biological activity mainly related with antimicrobial agents.

Their impact is large in developing countries due to a relative unvailability of medicines and the emergence of widespread drug resistance. Therefore researchers are increasingly diverting their attention to folk medicine, looking for new leads to develop better drugs against microbial infections

It is hoped that this review can stimulate the development of new strategies in the manage of these kind of compounds and possibly to find new active agents from this beautiful genus of plants.

## **12. References**

Aguilar, M.I.; Giral, F. & Espejo, O. (1981) Alkaloids from the flowers of *Erythrina americana. Phytochem* 20: 2061-2062.

Altamirano, F. (1888) Nuevos Apuntes para el estudio del Colorin, *Erythrina coralloides*. *Gaceta Médica de Mexico* 23: 369

Erythrina, a Potential Source of Chemicals from the Neotropics 181

Faria, T.D.J. , Cafèu, M.C.; Akiyoshi, G.; Ferreira, D.T.; Galao, O.F., Andrei, C.C.; Pinge Filho,

Flausino, O. Jr.; de Avila Santos, L.; Verli, H.; Pereira, AM., da Silva Bolzani, V. & Nunez-de-

Flaustino, O.P. Jr.; Pereira, A.M., da Silva Bolzani, V & Nunez-de-Souza R.L. (2007b) Effects

Folkers, K. & Koniuszy, F. (1939) *Erythrina* alkaloids, III. Isolation and Characterization of a

Folkers, K. & Koniuszy, F. (1940a) *Erythrina* Alkaloids. VII. Isolation and Characterization of the New Alkaloids, *Erythraline* and *Erythratine, J. Am Chem Soc* 62:436 Folkers, K. & Unna K. (1938) Erythrina alkaloids, II. A review, and New Data on the Alkaloids of Species of the Genus *Erythrina. J. Am Pharm Assoc* 27:693 Folkers, K. & Unna, K. (1939) *Erythrina* alkaloids V. Comparative Curare-like Potencies of

Folkers, K.& Koniuszy, F. (1940b) *Erythrina* alkaloids VIII. Studies on the Constitution of

Folkers, K.& Koniuszy, F. (1940c) *Erythrina* Alkaloids. IX. Isolation and Characterization of *Erysodine*, *Erysopine*, *Erysocine* and *Erysovine, J Am Chem Soc* 62: 1677 Fomum, Z.T.; Ayafor, J.F.; Mbafor, J.T. & Mbi, Ch.M. (1986) Erythrina studies. Part 2.

García-Mateos, R.; Garín-Aguilar, M.E.; Soto-Hernández, M &. Martínez-Vazquez, M. (2000)

García-Mateos, R.; Soto-Hernández, M.; Martínez-Vázquez, M. & Villegas- Monter A. (1999)

Garín-Aguilar, M.E.; Ramírez- Luna, J.E.; Soto-Hernández, M.; Valencia del Toro, G. &

Garín-Aguilar, M.E.; Valencia del Toro, G., Soto-Hernández, M. & Kite, G. (2005) High-

extracted from seeds of *Erythrina herbacea*, *Phytochemical Analysis* 16: 302-306 Ghosal, S.; Dutta, S. & Bhattacharya, S.K. (1972) *Erythrina* – Chemical and Pharmacological

Greshoff, M (1890) Mitteilungen aus dem chemisch-pharmakologisehen Laboratorium de

Evaluation II: Alkaloids of *Erythrina variegata 1, J. Pharm Sci* 61:1274

Botanischen Gartens zu Buitenzorg (Java), *ChemBer* 23: 3537.

Structures of three novel prenylated antibacterial flavanones, sigmoidins A-C, from

Effect of β-Erythroidine and β-Dihydroerythroidine from *Erythrina americana* on

Isolation of alkaloids of *Erythrina* from tissue culture, *Phytochemical analysis*. 10: 12-16.

Martínez- Vazquez, M. (2000) Effect of crude Extracts of *Erythrina americana* Mill. on

performance liquid chromatography-mass spectrometric analysis of alkaloids

Submitted to Animal Model of Anxiety, *Biol. Pharm. Bull*. 30(2): 375-378. Folkers, K. & Major, R.T. (1937) Isolation of Erythroidine, an Alkaloid of Curare Action from

and leaves of *Erythrina speciosa* Andrews, *Quimica Nova* 30 (3): 525-527. Fischer, L.G..O.; Leitao, R.; Etcheverry, S.R.; De Campos-Buzzi, F.; Vazquez, A.A.; Heinzen,

*crista-galli* (Fabaceae) leaves, *Nat. Prod. Res*. 21(8): 759-766.

*Erythrina americana* Mill. *J. Am Chem Soc* 59:1580

new alkaloid, *Erythramine, J. Am Chem Soc* 31:1232

Species of the Genus *Erythrina*. *J. Pharm Assoc* 28:1019.

*Erythrina sigmoidea* Hua, *J Chem Soc Perkin* Trans I: 33-37.

rats Aggressive Behavior, *Pharm Pharmacol Lett* 10:34

aggressive behaviour in Rats, *J. Ethnopharmacol* 69:189

*Erythramine* and *Erythraline*, *J Am Chem Soc* 62:1673

*mulungu*, *J. Nat. Prod*. 70: 48-53.

P.; Paiva, M.R.C.; Barbosa, A.D.M. & Braz-Filho, R. (2007) Alkaloids from flowers

H.A. & Filho, C.(2007) Analgesic properties of extracts and fractions from *Erythrina*

Souza R.L. (2007a) Anxiolytic Effects of Erythrinan Alkaloids from *Erythrina*

of Erythrinan Alkaloids isolated from *Erythrina mulungu* (Papilionaceae) in Mice

Amer, M.E.; Shamma, M. & Freyer, A.J. (1991) The Tetracyclic *Erythrina* Alkaloids, *J Nat Prod*

Atsarno, AD.; Nguelefack, T.B.; Datte, J.Y. & Kamanyi, A. (2011) Acute and subchronic oral

Barton, D.H.R. & Cohen, T. (1957) Some Biogenetic Aspects of Phenol Oxidation. In

Barton, D.H.R.; Boar, R.B. & Widdowson, D.A. (1970) Phenol Oxidation and Biosynthesis Part XXI. The Biosynthesis of the *Erythrina* Alkaloids*, J Chem Soc C* 1213. Barton, D.H.R.; Potter, C.J. & Widdowson, D.A. (1974) Phenol Oxidation and Biosynthesis

Barton, D.H.R.; James, R.; Kirby, G.W.; Turner, D.W. & Widdowson, D.A. (1968) Phenol

Boekelheide, V. ;Weinstock, J.; Grundon, M.F.; Sauvage, G.L. & Agnello, E.J. (1953) The structure of β-Erythoidine and its derivatives*. J. Amer. Chem. Soc*. 75:2550 Bourgard, F.; Gravot, A.; Milesi, S. & Gontier, E. (2001) Production of plant secondary

Carvalho, A.C.C.S.; Almeida, D.S.; Melo, M.G.D.; Cavalcanti, S.C.H. & Marçal, R.M. (2009)

Carmack, M., MacKusick, B.C. & Prelog, V. (1951) *Erythrina*-Alkaloide,2. Mitt Über das Apo-

Chacha, M.; Bojase-Moleta, G. & Majinda, R.R.T. (2005) Antimicrobial and radical scavenging flavonoids from the stem wood of *Erythrina latissima, Phytochemistry*. 66 (1): 99-104. Cheeta, S.; Tucci, S. & File, S.E. (2001) Antagonism of the Anxiolytic Effect of Nicotine in the

Chukwujekwu, J.C.; Van Heerden, F.R. & Van Staden, J. (2011) Antibacterial Activity of Flavonoids from the Stem Bark of *Erythrina caffra* Thumb., *Phytother. Res*. 25: 46-48. Craig, L.E. (1955) Curare-like Effects In: The alkaloids, Chemistry and Physiology Vol.5- Pharmacology. Manske, R.H.F. (Ed.) p. 265-290, Academic Press, New York. Cui, L. ; Thuong,P.T.; Lee, H.S; Njamen, D.; Mbafor, J.T.; Fomum, Z T , Lee, J.; Kim Y.H. & Oh,

Decker, M.W.; Anderson, D.J.; Brioni, J.D.; Donelly-Roberts, D.L.; Kang, C.H.; O´Neill, A.B.:

Doughari, J.H. (2010) Evaluation of antimicrobial potential of stem bark extracts of *Erythrina*

Dyke, S.F. & Quessy S.N. (1981). *Erythrina* and related alkaloids, In: The Alkaloids. Vol. 18.

Fabre, N.; Claparols, C.; Richelme, S.; Angelin, M.L.; Fourasté, I. & Moulis, C. (2000) Direct

Dominguez, M. & Altamirano, F. (1877) Del Colorín, *Gaceta Médica de México* 12:77.

*senegalensis* DC , *Afr. J. Microbiol. Res*. 4(7): 1836-1841.

Manske R F H (ed.),1-98 Academic Press. New York.

*Eschscholziacalifornica, J. Chromatogr. A*. 904, 35-46

metabolites: a historical perspective, *Plant Science* 161, 839-851.

erysodin und das Apo-erythralin. *Helv Chim Acta* 34:1601

aqueous extract, *J.Ethnopharmacol*. 122: 374-378.

DC(Fabaceae) in rodents, *J. Ethnopharmacol*. 134 (3): 697-702.

Festschrift Professor Dr. Artur Stoll. Basel: Birkhäuser

assessment of the aqueous extract from the stem bark of *Erythrina senegalensis*

Part XXIII. On the benzyltetrahydroisoquinoline Origins of the *Erytrina* Alkaloids*. J*

Oxidation and Biosynthesis. Part XVIII.The Structure and Biosynthesis of *Erythrina*

Evidence of the mechanism of action of *Erythrina velutina* Wild (Fabaceae) leaves

dorsal raphé nucleus by dihydro-β-erythroidine, *Pharmacol. Biochem Behavior* 70:491-496

W.K. (2008) Four new chalcones from *Erythrina abyssinica, Planta Medica*, 74 (4): 422-426.

Piattoni-Kaplan, M.; Swanson, S. & Sullivan, J.P. (1995) Erysodine, a competitive antagonist at neuronal nicotinic acetylcholine receptors, *Eur J. Pharmacol* 280: 79.

characterization of isoquinoline alkaloids in a crude plant extract by ion-pair liquid chromatography-electrospray ionization tandem mass spectrometry: example of

54:329-363

*Chem Soc Perkin Trans* 1 346

Alkaloids*. J Chem Soc C* 1529

Erythrina, a Potential Source of Chemicals from the Neotropics 183

Mondon, A.; Hansen, K.F.; Boehme, K.; Faro, H.P.; Nestler, H.J.; Vilhuber, H.G. & Böttcher,

Murphy, A.C. (2011) Metabolic engineering is key to sustainable chemical industry, *Nat Prod*

Nagaraja, T.S., Mahmood, R.; Krishna, V. & Maruthi,E.T. (2011) Evaluation of antimicrobial activity of *Erythrina mysorensis* Gamb. *Int J. Drug Devel. & Res*., 3 (2):198-202. Njamen,D.; Talla, E.; Mbafor, J.T.; Fomum, Z.T.; Kamanyi, A.; Mbanya, J.C.; Cerda-Nicolas, M.;

Ortega, M.; Sánchez, C.; Chacón, E.; Rendón, L.J.; Estrada, R.; Masso, F. Montaño, F.L. &

Ozawa, M.; Kawamata, S.; Etoh, T.; Hayashi, M.; Komiyama, K.; Kishida, A.; Kuroda, Ch. &

Pick, E.P. & Unna, K. (1945) The effect of Curare and Curare –like substances on the Central

Ramírez, E. & Rivero, M.D. (1935) Pharmacodynamic Action of *Erythrina americana* Mill

Redko, F. ; Clavin, M.L.; Weber, D.; Ranea, F.; Anke, T. & Martino, V. (2007) Antimicrobial

Reiman, E. & Ettmayr, C. (2004) An Improved Stereocontrolled Route to *cis*-Erythrinanes by

Rey, P. (1883) Note sur les proprietés thérapeutiques de l´*Erythrina corallodendron Le Journal*

Rukachaisirikul,T.; Innok, P.; Aroonrerk, N.; Boonamnuaylap, W.; Limrangsun, S.; Boonyon,

Rukachaisirikul, T.; Saekee, A.; Tharibun, Ch.; Watkoulham, S. & Suksamrarn, A.(2007b)

Rukachaisirikul, T.; Innok, P. & Suksamrarn, A. (2008) *Erythrina* Alkaloids and a Pterocarpan from the Bark of *Erythrina subumbrans, J. Nat Prod*. 71: 156-158. San Miguel-Chávez, R.; Soto-Hernández, M.; Ramos-Valdivia A.C. & Kite, G. (2007)

San Miguel-Chávez, R.; Soto-Hernández, M.; Ramos-Valdivia, A.C.; Kite, G.; Martínez-

*vitro* culture of *Erythrina americana* Miller, *Biotechnol Lett. 25(13):* 1055-1059*.*  San Miguel-Chávez, R.; Soto-Hernández, M.; Terrazas, T. & Kite,.G. (2006) Morphology and

isoflavonoids from *Erythrina crista galli* infected with *Phomopsis* sp., Z.

Combined Intramolecular Strecker and Bruylants Reaction. *Monatsh Chem* 135:1143

Ch.; Woonjina, U.;Suksamrarn, A. (2007) Antibacterial pterocarpans from *Erythrina*

Biological Activities of the Chemical Constituents of *Erythrina stricta* and *Erythrina*

Alkaloid production in elicited cell suspension cultures of *Erythrina americana*

Vázquez, M.; García-Mateos, R.& Terrazas, T. (2003) Production of alkaloids by *in*

alkaloidal profile of the seedlings of *Erythrina americana* Mill, and *E. coralloides* A.D,

XI; Anwendungen der Glyoxylester-Synthese, *Chem Ber* 103:615

*americana* by affinity chromatography, *Plant Science* 72: 133-140.

*velutina, Chem Pharm. Bull*. 59(5):564-567.

Naturforschung. C, 62 (3-4):164-168.

*de Terapeutique* 10: 843.

Nervous System, *J*. *Pharmacol. Exp Therap* 83:59

*subumbrans*, *J Ethnopharmacol*. 110 (1): 171-175.

*subumbrans, Arch.Pharm Res* 30(11): 1398-1403

Miller*, Phytochem Rev*. 6: 167-173.

*Feddes Repertorium*. 117 (3-4): 232-239.

[family leguminosae]. *Anales Inst. Biol.* (Mex) 6:301 .

*Rep* 28, 1406-1425.

K. (1970) SynthetischeArbeiten in der Reidhe der aromatischen *Erythrina*-Alkaloide,

Giner, R.M.; Recio, M.C. & Ríos, J.L.(2003) Anti-inflammatory activity of erycristagallin, a pterocarpene from *Erythrina mildbraedii*, *Eur. J. Pharmacol*. 468:67-74.

Zenteno,E. (1990) Purification and characterization of a lectin from *Erythrina*

Ohsaki, A. (2010) Structures of new Erythrinan alkaloids and Nitric Oxide Production Inhibitors from *Erythrina crista-galli*, *Chem Pharm. Bull*. 58(8): 1119-1122 Ozawa, M.; Kishida, A. & Ohsaki, A. (2011) Erythrinan Alkaloids from Seeds of *Erythrina*

Hargreaves, R.T., Johnson, R.D.; Millington, D.S.; Mondal, M.H.; Beavers, W.; Becker, L.;

Iturriaga-Vasquez, P.; Carbone, A.L.; García-Beltrán, O.; Livingstone, P.D; Biggin, P.C.;

Jackson, A.H.; Ludgate, P.; Mavraganis, V. & Redha, F.M. (1982). Studies of *Erythrina* alkaloids,

*rubinervia, E. acanthocarpa, E. variegate* and *E. melanacantha, Allertonia* 3: 47-51 Joubet, J.J.; Merrifiel, E.H. & Dowdle, E.B.D. (1987). The reactives sites of proteinase inhibitors from *Erythrina* seeds, *International Journal of Biochemistry* 19: 601-606. Juma, B. & Majinda, R.R.T. (2004) Erythrinaline alkaloids from the flowers and pods of *Erythrina lysistemon* and their DPPH radical scanvenging properties, *Phytochem*. 65: 1397-1404. Kamdem Waffo, A.F.; Coombes, P.H.; Mulholland, D.A.; Nkengfack, A.E. & Fomum Z.T. (

Kawasaki, T.; Onoda, N.; Watanabe, H. & Kitara, T. (2001) Total Synthesis of (±)

Kenner, G.W., Khorana, H.G. & Prelog, V. (1951) *Erythrina*-Alkaloide, 3. Mitt. Über den

Kouam, J. ; Noundou, X.Siewe Noundou, X.; Kouitcheu Mebeku, L.B.; Meli Lannang, A.;

Lee, J.S.; Oh, W.K.; Ahn, J.S.; Kim, Y.H.;Mbafor, J.T.; Wandji, J. & Fomum, Z.T. (2009)

Lozoya, X. & Lozoya, M. (1982) Flora Medicinal de México. In*: Plantas Indígenas del Seguro*

Maier, U.H. & Zenk, M.H. (1997), (S)-Norrreticuline is the precursor for the biosynthesis of

Maier, U.H*.*; Rödl, W.; Deus-Neumann B. & Zenk, M.H. (1999) Biosynthesis of *Erythrina*

Mantle, P.G. (1995). Direct analysis of aromatic diene *Erythrina* alkaloids by capillary GC-MS

Mbafor, T. J.; Ndom, J.C. & Fomum, T.Z..( 1997). Triterpenoids saponins from *E. sigmoidea*,

Lehman, A.J. (1936) Curare-Actions of *Erythrina americana*, *Proc Soc Exp Biol Med* 33: 501 Lehman, A.J. (1937) Action of *Erythrina americana*, a possible Curare Substitute, *J Pharmacol*

Saponin from *Erythrina sigmoidea* HUA, *Bull. Chem. Soc Ethiop* 21(3): 373-378. Kumar, A; Lingadurai, S.; Shirivastava, T.P.; Bhattacharya, S. & Haddar, P.K. (2011)

Hegnauer, R. (1963). Chemotaxonomy, past and present*. Lloydia* 28: 267-278.

*Lloydia* 37:569-580

*Molec Pharmacol*. 78(3): 366-375.

*Phytochem* 67: 459-463

*Helv Chim Acta* 34:1969

*Planta Med.* 75:268-270.

*Social*, México, D.F. p 174

*Phytochemistry* 38: 135-1316

*Phytochemistry* 44 (6): 1151-1155.

*Erythrina* alkaloids, Chem Commun.2313-2314.

Alkaloids in *Erythrina crista-galli* . *Phytochemistry* 52: 373

*Exp Ther* 60: 69

rats, *Pharm. Biol*. 49(6): 577-582.

Cocculolidine. *Tetrahedron Lett* 42: 8003

Young, C., & Rinehart, K.L. Jr (1974) Alkaloids of American Species of *Erythrina*,

Cassels, B.K.; Wonnacott, S.; Zapata-Torres, G. & Bemudez, I. (2010) Molecular Determinants for Competitive Inhibition of α4β2 Nicotinic Acetylcholine Receptors,

part V.GC/MS investigation of alkaloids in the seeds of *E. subumbrans, E. lanata, E.*

2006) Flavones and isoflavones from the west African Fabaceae *Erythrina vogelii*,

*Hoffman*´schenAbbau des Tetrahydro-erysotrins und des Tetrahydro-erythralins.

Choudhary, M.I. & Fomum, Z.T.(2007) Sigmoiside E: A New Antibacterial Triterpenoid

Hypoglycemic activity of *Erythrina variegata* leaf in streptozotocin-induced diabetic

Prenylisoflavonoids from *Erythrina senegalensis* as Novel HIV-1 Protease Inhibitors,

**10**

*Colombia*

*Zanthoxylum* **Genus as Potential Source**

L. Oscar Javier Patiño, R. Juliet Angélica Prieto and S. Luis Enrique Cuca *Laboratorio de Productos Naturales Vegetales, Universidad Nacional de Colombia,*

Natural products have been used for thousands of years for the benefit of mankind, as important sources of food, clothing, cosmetics, building materials, tools, medicines and crop protection agents. They have made enormous contributions to human health through compounds such as quinine, morphine, aspirin (a natural product analog), digitoxin and many others. Researches in this field are becoming more numerous, to the point of getting about half of pharmaceuticals and pesticides from natural sources (Newman & Cragg, 2007). The main reasons because natural products are so important to undertake research are that they can be a source of new compounds because they produce many bioactive secondary metabolites that are used as a chemical defense against predators. Also, in the past, they have provided many new drugs, some of which can't be obtained by other sources and because they can provide the necessary templates to design new products in the future

Dissatisfied therapeutic needs in the treatment of bacterial, parasitic, viral and fungal infections, cancer, Alzheimer's and AIDS, among other diseases, have led to the search of new substances with therapeutic applications. Although for most diseases there is a treatment, many of them have begun to be ineffective due to the development of resistance to medicaments that were initially effective and to the low security that they exhibit for patients. Consequently, the development of effective and safe therapeutic alternatives is essential to ensure the availability of new products that reduce mortality and morbidity due to diseases (Pan et al., 2010; Nwaka & Hudson, 2006; Segal & Elad, 2006; Waldvogel, 2004). The search for new phytosanitary agents to control plant pests and diseases that affect many plant sources of food and/or industrial use is also of great interest, because the indiscriminate and permanent use of agrochemicals has led to the emergence of resitant pests and phytopathogenic microorganisms, that can cause partial or complete loss of crops (Agrios,

Research in plants represents an invaluable source discovering new substances, considering that each of these can contain hundreds or even thousands of secondary metabolites. From the 250,000 to 300,000 plant species reported, only a small part has been the subject of

(Colegate and Molyneux, 2008; Kaufman et al., 2006; Cragg et al., 2005).

phytochemical and biological activity studies (Tringali, 2001).

**1. Introduction**

2005; Strand, 2000).

**of Bioactive Compounds**

## *Zanthoxylum* **Genus as Potential Source of Bioactive Compounds**

L. Oscar Javier Patiño, R. Juliet Angélica Prieto and S. Luis Enrique Cuca *Laboratorio de Productos Naturales Vegetales, Universidad Nacional de Colombia, Colombia*

## **1. Introduction**

184 Bioactive Compounds in Phytomedicine

Sato, M.; Tanaka, H.; Tani, N.; Nagayama, M. & Yamaguchi, R.( 2006). Different antibacterial

resistant *Staphylococcus aureus*, *Letters Applied Microbiology.* 43 (3): 243-248. Schoffelmer, A.N.M.; De Vries, T.J.; Wardeh, G.; van de Ven, H.W.M. & Venderschuren I.

Silva, D.S.B.S.; Garcia, A.CF.S.; Mata, S.S.; de Oliveira, B.; Estevam, Ch.S.; Scher, R. &

Soto-Hernández, M. & Jackson, A.H. (1994) *Erythrina* alkaloids: isolation and characterization of alkaloids from seven *Erythrina* species*, Planta Med* 60: 175-177 Stojanovic, D.; Fernández, M.; Casale, I.; Trujillo, D. & Castes, M.. (1994). Characterization and mitogenicity of a lectin from *Erythrina velutina* seeds, *Phytochem* 37: 1069-1074. Tanaka, H.; Tanaka, T. & Etoh, H.( 1997). Three pterocarpans from *E. crista-galli*, *Phytochem*

Tanaka, H.; Etoh, H.; Shimizu, H.; Oh-Uchi, T.; Terada, Y. & Tateishi, Y.( 2001) Erythrinan alkaloids and isoflavonoids from *Erythrina poeppigiana, Planta Med* 67:871-873. Tanaka, H.; Oh-Uchi, T.; Etoh, H.; Sako, M.; Sato, M.; Fukai, T. & Tateishi, Y. (2003) An

Tanaka, H.; Hattori, H.; Tanaka, T.; Sakai, E.; Tanaka, N.; Kulkarni, a. & Etoh H.(2008) A new *Erythrina* alkaloid from *Erythrina herbacea, J Nat Med* 62:228-231. Tanaka, H.; Sudo, M.; Kawamura, T.; Sato, M.; Yamaguchi, R.; Fukai, T.; Sakai, E. & Tanaka

Tati, H.; Nurlelasari ; Dikdik, K.; Unang, S. and Zalinar, U. (2011) In vitro anticancer and antimalarial Erystagallin-A from *Erythrina variegata* (L) stem bark, *Med Plant* 3(1) Tsuda, Y. & Sano, T. (1996) *Erythrina* and Related Alkaloids. In: The Alkaloids, vol. 48, G.A

Verpoorte, R. & Niesse, W.M.A. (1994). Liquid chromatography coupled with mass spectrometry in the analysis of alkaloids*. Phytochem. Anal*. 5. 217-232 Wanjala, C.C.W. & Majinda, R.T. (2000) Two Novel Glucodienoid Alkaloids from *Erythrina*

Wanjala, C. C.W.; Juma, B.F.; Bojase, G.; Gashe, B.A. & Majinda, R.R.T. (2002) Erythrinaline alkaloids and Antimicrobial Flavonoids from *Erythrina latissima, Planta Med* 68:640-642 Wanjala, C.W., Akeng´a, T.; Obiero, G.O. & Lutta, K.P. (2009) Antifeedant Activities of the

Yenesew, A.; Derese, S.; Irungu, B.; Midiwo, J.O.; Waters, N.C., Liyala, P.; Akala, H.;Heydenreich,

Yenesew, A.; Induli, M.; Derese, S.; Midiwo, J. O.; Heydenreich, M.; Peter, M.G.; Akala, H.;

Erythrinaline Alkaloids from *Erythrina latissima* against *Spodoptera littoralis*

M. & Peter, M.G. (2003) Flavonoids and Isoflavonoids with Antiplasmodial Activities

Wangui, J.; Liyala, P.& Waters, N.C. (2004) Anti-plasmodial flavonoids from the

Methicillin-resistant *Staphylococcus aureus, Planta Med* 76: 916-919.

Cordell (Ed.), 249-338 Academic Press, Inc., New York.

(Lepidoptera noctuidae), *Rec. Nat. Prod*. 3(2):96-103

from the Root Bark of *Erythrina abyssinica, Planta Med* 69:658-661

stem bark of *Erythrina abyssinica*, *Phytochem* 65 (22): 3029-3032

*latissima* Seeds, *J Nat Prod* 63: 871-873.

arylbenzofuran and four isoflavonoids from the roots of *Erythrina poeppigiana,*

N. ( 2010) Antibacterial Constituents from the Roots of *Erythrina herbacea* against

Nicotinic Receptor Activation, *J. Neurosci* 22:3269

45 (4): 835-838.

*Phytochem* 63: 597-602.

actions of isoflavones isolated from *Erythrina poeppigiana* against methicillin-

J.M.J. (2002) Psychostimulant-Induced Behavioral Sensitization Depends on

Pantaleao, S.M. (2011) Genotoxicity and citotoxicity of *Erythrina velutina* Willd., Fabaceae, on the root meristem cells of *Allium cepa, Braz. J. Pharmacog*. 21(1):92-97. Sonia, J.; Latha, P.G; Gowsalya, P.; Anuja, G.I.; Suja, S.R.; Shine, V.J.; Shymal, S.; Shikha, P.;

Krishnakumar, N.M.; Sreejith, G.; Sini, S.& Sekharan, S. (2011) Antidiarrhoeal effects of ethanolic leaf extract of *Erythrina indica* L. in experimental animals, *Med. Plants* 3(1)

> Natural products have been used for thousands of years for the benefit of mankind, as important sources of food, clothing, cosmetics, building materials, tools, medicines and crop protection agents. They have made enormous contributions to human health through compounds such as quinine, morphine, aspirin (a natural product analog), digitoxin and many others. Researches in this field are becoming more numerous, to the point of getting about half of pharmaceuticals and pesticides from natural sources (Newman & Cragg, 2007). The main reasons because natural products are so important to undertake research are that they can be a source of new compounds because they produce many bioactive secondary metabolites that are used as a chemical defense against predators. Also, in the past, they have provided many new drugs, some of which can't be obtained by other sources and because they can provide the necessary templates to design new products in the future (Colegate and Molyneux, 2008; Kaufman et al., 2006; Cragg et al., 2005).

> Dissatisfied therapeutic needs in the treatment of bacterial, parasitic, viral and fungal infections, cancer, Alzheimer's and AIDS, among other diseases, have led to the search of new substances with therapeutic applications. Although for most diseases there is a treatment, many of them have begun to be ineffective due to the development of resistance to medicaments that were initially effective and to the low security that they exhibit for patients. Consequently, the development of effective and safe therapeutic alternatives is essential to ensure the availability of new products that reduce mortality and morbidity due to diseases (Pan et al., 2010; Nwaka & Hudson, 2006; Segal & Elad, 2006; Waldvogel, 2004).

> The search for new phytosanitary agents to control plant pests and diseases that affect many plant sources of food and/or industrial use is also of great interest, because the indiscriminate and permanent use of agrochemicals has led to the emergence of resitant pests and phytopathogenic microorganisms, that can cause partial or complete loss of crops (Agrios, 2005; Strand, 2000).

> Research in plants represents an invaluable source discovering new substances, considering that each of these can contain hundreds or even thousands of secondary metabolites. From the 250,000 to 300,000 plant species reported, only a small part has been the subject of phytochemical and biological activity studies (Tringali, 2001).

*Zanthoxylum* Genus as Potential Source of Bioactive Compounds 187

from *Z. xanthoxyloides* (Ngassoum et al., 2003), *Z. gillettii* (Jirovetz et al., 1999) and *Z.*

A common feature of almost all species of the genus *Zanthoxylum* is the ability to produce tires, which could be used in the pharmaceutical industry as encapsulants, emulsifying agents or diluents. Some investigations have been conducted on the rubber collected on the

Many species of the *Zanthoxylum* genus have been used in different parts of the world especially in Asia, Africa and America to treat a number of diseases in humans and animals (McGaw et al., 2008; Rochfort et al., 2008; Adesina, 2005; Chaaib, 2004; Diéguez et al., 2004; Patiño, 2004). For example, the bark of *Z. integrifolioum* is used in traditional medicine by Ya-Mei and Lanyu indigenous tribes in Taiwan, as a remedy for snakebite, dyspepsia and as an aromatic tonic for fever. The bark of *Z. liebmannianum*, is used in Mexico for the treatment of stomach pains, amebiasis, intestinal parasites and as a local anesthetic agent (Ross et al., 2004). Some species are used for the treatment of malaria, such is the case of *Z. rhoifolium* (Jullian et al., 2006; Bertani et al., 2005), *Z. acutifolium* (Arruda et al., 1992), *Z. chalybeum* (Jullian et al., 2006) and *Z. usambarense* (Kirira et al., 2006). Venezuelan traditional medicine is known to use *Z. monophyllum* in the treatment of runny nose or nasal mucosal inflammation, jaundice, ophthalmia and as an anesthetic (Gomez et al., 2007; Diaz & Ortega,

According to reports of ethnobotanical properties of the *Zanthoxylum* genus, in general it is emphasized that the most commonly used extraction methods are infusion and decoction, using mainly water as solvent. In Table 1 are summarized the main ethnobotanical uses of 45 species of the genus *Zanthoxylum*, as well as the plant part used and method of preparation. The major ethnobotanical properties attributed to these plant species are: relief of dental problems, treatment of malaria, gastrointestinal disorders, gonorrhea and lung diseases, antidiarrheal use in animals and humans, emmenagogue action, effective for rheumatism, anthelmintic use in animals and humans, aphrodisiac, analgesic, action against various skin diseases, febrifuge, antihemorrhagic, effective for genitourinary diseases, anticancer, diuretic, stomachic, anti-convulsive, tonic and stimulant. In addition to the medicinal properties, some

Some plants have been used as components of natural medicines, because of the important ethnomedical properties of *Zanthoxylum* genus species. *Z. tingoassuiba* has been marketed since 1923 by Flora Medicinal J. Monteiro da Silva Laboratory, as part of herbal medicinal product called Uva do Mato®, which is prescribed for muscle cramps and spasms (Da Silva et al., 2008). *Z. rhoifolium* also has been commercialized in Brazil as a component of herbal tea mixtures sold in drugstores, supermarkets and popular markets (Pereira et al., 2010; Da

Phytochemical studies carried out on species of the genus *Zanthoxylum*, alkaloids of various types, lignans, coumarins amides are commonly secondary metabolites reported and have chemotaxonomic importance to the genre. Also, other metabolites have been isolated such as flavonoids, sterols and terpenes, among others (Adesina, 2005; Patiño, 2004, Waterman &

2006). Another use has been given as a textile dye (De Garcia et al., 1989).

species are also used as pesticides, building materials and textile dyes.

*simulans* (Chyau et al., 1996).

Silva et al., 2007a).

Grundon, 1983).

**4. Phytochemistry**

bark of *Z. tessmannii* (Adesina, 2005).

This chapter shows information about the importance of ethnobotany, phytochemistry and biological activities of species of the genus *Zanthoxylum*, information that can be the base for undertaking future research.

## **2. Overview of** *Zanthoxylum* **genus**

*Zanthoxylum* genus belongs to the Rutaceae family. It is economically important because of their alimentary, industrial and medicinal applications (Seidemann, 2005; Chase et al., 1999). *Zanthoxylum* comes from the word *Xanthoxylum* wich derives from Greek: "xanthon xylon" that means "yellow wood", hence the use of the terms *Xanthoxylum* or *Zanthoxylum* by some authors. The genus *Zanthoxylum* was created by Linné in 1757 and since its inception has been confused with the genus *Fagara*. In 1896, Engler made the distinction between the two genera by the following characteristics: species of the genus *Zanthoxylum* have a simple perianth, while in species of the genus *Fagara* is twofold. Brizicky in 1962, discovered some species with intermediate perianth, which showed that simple perianth of *Zanthoxylum* drift from the *Fagara* due to failure of some sepals, and concluded that *Fagara* and *Zanthoxylum* genus are the same. Finally, in 1966, Hartley grouped *Zanthoxylum* and *Fagara* under the name of *Zanthoxylum*. However, some authors still use the term *Fagara* (Chaaib, 2004).

*Zanthoxylum* comprises about 549 species distributed worldwide mainly in tropical and temperate regions (Global Biodiversity Information Facility, 2010). This genus includes trees and shrubs, usually dioecious. The trees have leafy crown, with few branches and reach up to 20 meters. The species of this genus are characterized by the presence of recurved spines on its trunk and branches. The leaves are varied, may be alternate or opposite, simple or composed, imparipanadas or parimpanadas with up to 15 pairs of leaflets. The inflorescences are usually in form of panicles or umbels compound, axillary or terminal of small flowers. The flowers are actinomorphic, hermaphrodite and unisexual, rarely bisexual, usually white or green. The fruits are follicles or esquizocarp, contains from one to five carpels usually aromatic, and the are ordinarily bivalve with a single red or black, shiny seeds (Melo & Zickel, 2004; Silva & Paoli, 2004).

The genus *Zanthoxylum* has great importance due to its ethnobotanics, phytochemistry and biological activity, and it is a promising source of various secondary metabolites including benzophenanthridine alkaloids.

## **3. Ethnobotanical uses**

Species of this genus are of economic importance as sources of edible fruits, oils, wood, raw materials for industries, medicinal plants, ornamentals, culinary applications, and are characterized by a satin wood commonly used in woodworking (Yang, 2008; Da Silva *et al.*, 2006; Adesina, 2005; Seidemann, 2005). For example in Africa is used the wood of *Z. gillettii*, *Z. tessmannii*, *Z. lemairei* and *Z. leprieurii* for houses, buildings, drums and ships construction, and for decorative woodwork, carpentry, and paper industry. In some countries of this continent, root bark and stem of many species of *Zanthoxylum* for used as a vermifuge, febrifuge and piscicides (Adesina, 2005).

*Zanthoxylum* species are also used in the field of perfumery and food industry because of its essential oils from leaves, fruits and inflorescences. The most used essential oils are obtained

This chapter shows information about the importance of ethnobotany, phytochemistry and biological activities of species of the genus *Zanthoxylum*, information that can be the base for

*Zanthoxylum* genus belongs to the Rutaceae family. It is economically important because of their alimentary, industrial and medicinal applications (Seidemann, 2005; Chase et al., 1999). *Zanthoxylum* comes from the word *Xanthoxylum* wich derives from Greek: "xanthon xylon" that means "yellow wood", hence the use of the terms *Xanthoxylum* or *Zanthoxylum* by some authors. The genus *Zanthoxylum* was created by Linné in 1757 and since its inception has been confused with the genus *Fagara*. In 1896, Engler made the distinction between the two genera by the following characteristics: species of the genus *Zanthoxylum* have a simple perianth, while in species of the genus *Fagara* is twofold. Brizicky in 1962, discovered some species with intermediate perianth, which showed that simple perianth of *Zanthoxylum* drift from the *Fagara* due to failure of some sepals, and concluded that *Fagara* and *Zanthoxylum* genus are the same. Finally, in 1966, Hartley grouped *Zanthoxylum* and *Fagara* under the name of *Zanthoxylum*. However, some authors still use the term *Fagara* (Chaaib, 2004).

*Zanthoxylum* comprises about 549 species distributed worldwide mainly in tropical and temperate regions (Global Biodiversity Information Facility, 2010). This genus includes trees and shrubs, usually dioecious. The trees have leafy crown, with few branches and reach up to 20 meters. The species of this genus are characterized by the presence of recurved spines on its trunk and branches. The leaves are varied, may be alternate or opposite, simple or composed, imparipanadas or parimpanadas with up to 15 pairs of leaflets. The inflorescences are usually in form of panicles or umbels compound, axillary or terminal of small flowers. The flowers are actinomorphic, hermaphrodite and unisexual, rarely bisexual, usually white or green. The fruits are follicles or esquizocarp, contains from one to five carpels usually aromatic, and the are ordinarily bivalve with a single red or black, shiny

The genus *Zanthoxylum* has great importance due to its ethnobotanics, phytochemistry and biological activity, and it is a promising source of various secondary metabolites including

Species of this genus are of economic importance as sources of edible fruits, oils, wood, raw materials for industries, medicinal plants, ornamentals, culinary applications, and are characterized by a satin wood commonly used in woodworking (Yang, 2008; Da Silva *et al.*, 2006; Adesina, 2005; Seidemann, 2005). For example in Africa is used the wood of *Z. gillettii*, *Z. tessmannii*, *Z. lemairei* and *Z. leprieurii* for houses, buildings, drums and ships construction, and for decorative woodwork, carpentry, and paper industry. In some countries of this continent, root bark and stem of many species of *Zanthoxylum* for used as a

*Zanthoxylum* species are also used in the field of perfumery and food industry because of its essential oils from leaves, fruits and inflorescences. The most used essential oils are obtained

undertaking future research.

**2. Overview of** *Zanthoxylum* **genus**

seeds (Melo & Zickel, 2004; Silva & Paoli, 2004).

vermifuge, febrifuge and piscicides (Adesina, 2005).

benzophenanthridine alkaloids.

**3. Ethnobotanical uses**

from *Z. xanthoxyloides* (Ngassoum et al., 2003), *Z. gillettii* (Jirovetz et al., 1999) and *Z. simulans* (Chyau et al., 1996).

A common feature of almost all species of the genus *Zanthoxylum* is the ability to produce tires, which could be used in the pharmaceutical industry as encapsulants, emulsifying agents or diluents. Some investigations have been conducted on the rubber collected on the bark of *Z. tessmannii* (Adesina, 2005).

Many species of the *Zanthoxylum* genus have been used in different parts of the world especially in Asia, Africa and America to treat a number of diseases in humans and animals (McGaw et al., 2008; Rochfort et al., 2008; Adesina, 2005; Chaaib, 2004; Diéguez et al., 2004; Patiño, 2004). For example, the bark of *Z. integrifolioum* is used in traditional medicine by Ya-Mei and Lanyu indigenous tribes in Taiwan, as a remedy for snakebite, dyspepsia and as an aromatic tonic for fever. The bark of *Z. liebmannianum*, is used in Mexico for the treatment of stomach pains, amebiasis, intestinal parasites and as a local anesthetic agent (Ross et al., 2004). Some species are used for the treatment of malaria, such is the case of *Z. rhoifolium* (Jullian et al., 2006; Bertani et al., 2005), *Z. acutifolium* (Arruda et al., 1992), *Z. chalybeum* (Jullian et al., 2006) and *Z. usambarense* (Kirira et al., 2006). Venezuelan traditional medicine is known to use *Z. monophyllum* in the treatment of runny nose or nasal mucosal inflammation, jaundice, ophthalmia and as an anesthetic (Gomez et al., 2007; Diaz & Ortega, 2006). Another use has been given as a textile dye (De Garcia et al., 1989).

According to reports of ethnobotanical properties of the *Zanthoxylum* genus, in general it is emphasized that the most commonly used extraction methods are infusion and decoction, using mainly water as solvent. In Table 1 are summarized the main ethnobotanical uses of 45 species of the genus *Zanthoxylum*, as well as the plant part used and method of preparation. The major ethnobotanical properties attributed to these plant species are: relief of dental problems, treatment of malaria, gastrointestinal disorders, gonorrhea and lung diseases, antidiarrheal use in animals and humans, emmenagogue action, effective for rheumatism, anthelmintic use in animals and humans, aphrodisiac, analgesic, action against various skin diseases, febrifuge, antihemorrhagic, effective for genitourinary diseases, anticancer, diuretic, stomachic, anti-convulsive, tonic and stimulant. In addition to the medicinal properties, some species are also used as pesticides, building materials and textile dyes.

Some plants have been used as components of natural medicines, because of the important ethnomedical properties of *Zanthoxylum* genus species. *Z. tingoassuiba* has been marketed since 1923 by Flora Medicinal J. Monteiro da Silva Laboratory, as part of herbal medicinal product called Uva do Mato®, which is prescribed for muscle cramps and spasms (Da Silva et al., 2008). *Z. rhoifolium* also has been commercialized in Brazil as a component of herbal tea mixtures sold in drugstores, supermarkets and popular markets (Pereira et al., 2010; Da Silva et al., 2007a).

## **4. Phytochemistry**

Phytochemical studies carried out on species of the genus *Zanthoxylum*, alkaloids of various types, lignans, coumarins amides are commonly secondary metabolites reported and have chemotaxonomic importance to the genre. Also, other metabolites have been isolated such as flavonoids, sterols and terpenes, among others (Adesina, 2005; Patiño, 2004, Waterman & Grundon, 1983).

*Zanthoxylum* Genus as Potential Source of Bioactive Compounds 189

ADMINISTRATION REFERENCES

Suryanto et al., 2004

Sheen et al., 1994

Xiong & Shi, 1991

Chou et al., 2011

Batool et al., 2010

Bafi-Yeboa et al., 2005

Ranawat et al., 2010

Ramanujam & Ratha, 2008

Oral route (dried fruits, decoction powder).

Local and oral routes (decoction or ointment).

Oral route (chopped

Oral route (macerated or decoction powder).

Local and oral routes (macerated or decoction).

Oral route (powdered seeds, macerated powder).

Oral route (macerated or decoction powder).

Oral route (dry fruit).

Local and oral routes (macerated or decoction powder, paste, sticks).

Oral route (Powder and decoction).

Oral route (Infusion).

leaves)

USED POPULAR USES FORM OF

As spice. Also has been used to heal stomach ache and toothache.

Epigastric pain, vomiting, diarrhea, abdominal pain, colds, snake bites.

Substitute for the green onion in Chinese dishes.

Myocardium disorder attenuation, cold resistance and bone-injury alleviation.

Used as carminative, stomachic and as a remedy for toothache.

Spice, aromatic tonic, stomachic and for fever, dyspepsia,

Skin diseases, abdominal pain, anorexia, worm infestation.

Mixed with salt for dyspepsia and headache.

To treat rheumatic conditions, toothaches, sore throats and burns, and as a tonic for various ailments.

Piscicide, aromatic tonic in fever, dyspepsia, and for

expelling roundworms.

Carminative, stomachic and

cholera.

PLANT SPECIES

*Z. acanthopodium*

*Z. ailanthoides*  Siebold.&Zucc.

*Z. alatum* Roxb.

*Z. americanum*  Mill.

*Z. armatum* DC.

DC. Fruits

PART

Bark and fruits

Tender leaves

Steam

Fruits, branches and thorns

Seeds

Bark

Fruits

All parts of the plant

Fruits and seeds

Bark, branches

## **4.1 Alkaloids**

The alkaloids are most important compounds for the genus *Zanthoxylum*, because they are present in most species and have been found in all plant organs, being abundant in the trunk and root bark (Dieguez et al., 2004). The main isolated alkaloids from the genus are of two types: isoquinolines (benzophenanthridine, benzylisoquinoline, aporphine, protoberberine and berberine) and quinolines (Krane et al. 1984; Waterman & Grundon, 1983; Cordell, 1981). Other types of alkaloids have also been found in some species of the genus.

## **4.1.1 Isoquinoline alkaloids**

The **benzophenanthridines** are the most frequently reported type of alkaloid in the genus *Zanthoxylum* and have great interest due to important and varied biological activity that they present, among which highlights the antitumor activity (Maiti & Kumar, 2009; Tillequin, 2007; Maiti & Kumar, 2007; Dvorak et al., 2006; Nyangulu et al., 2005; Eun & Koh, 2004; Tang et al. 2003; Slaninová et al., 2001; Simeon et al., 1989).  Their distribution is very limited in plants, and only they have been isolated from some genera belonging to the families Papaveraceae, Rutaceae and Fumiraceae mainly, where they are considered chemotaxonomic markers. In Rutaceae family they are present in species of the genera *Phellodendron*, *Fagaropsis*, *Tetradium*, *Toddalia* and *Zanthoxylum* (including *Fagara*), the latter with a majority presence of these alkaloids from the others (Krane et al., 1984; Cordell, 1981). The main representatives of this type of alkaloids are fagaronine **1**, nitidine **2**, chelerythrine **3** and sanguinarine **4**. Compounds with similar chemical structure to iwamide **5** and integriamide **6**, isolated from various species of the genus *Zanthoxylum*, have been classified by different authors within benzophenanthridine alkaloids (Krane et al., 1984).

The alkaloids are most important compounds for the genus *Zanthoxylum*, because they are present in most species and have been found in all plant organs, being abundant in the trunk and root bark (Dieguez et al., 2004). The main isolated alkaloids from the genus are of two types: isoquinolines (benzophenanthridine, benzylisoquinoline, aporphine, protoberberine and berberine) and quinolines (Krane et al. 1984; Waterman & Grundon, 1983; Cordell, 1981). Other types of alkaloids have also been found in some species of the

The **benzophenanthridines** are the most frequently reported type of alkaloid in the genus *Zanthoxylum* and have great interest due to important and varied biological activity that they present, among which highlights the antitumor activity (Maiti & Kumar, 2009; Tillequin, 2007; Maiti & Kumar, 2007; Dvorak et al., 2006; Nyangulu et al., 2005; Eun & Koh, 2004; Tang et al. 2003; Slaninová et al., 2001; Simeon et al., 1989).  Their distribution is very limited in plants, and only they have been isolated from some genera belonging to the families Papaveraceae, Rutaceae and Fumiraceae mainly, where they are considered chemotaxonomic markers. In Rutaceae family they are present in species of the genera *Phellodendron*, *Fagaropsis*, *Tetradium*, *Toddalia* and *Zanthoxylum* (including *Fagara*), the latter with a majority presence of these alkaloids from the others (Krane et al., 1984; Cordell, 1981). The main representatives of this type of alkaloids are fagaronine **1**, nitidine **2**, chelerythrine **3** and sanguinarine **4**. Compounds with similar chemical structure to iwamide **5** and integriamide **6**, isolated from various species of the genus *Zanthoxylum*, have been classified by different authors within benzophenanthridine alkaloids (Krane et

**4.1 Alkaloids**

genus.

al., 1984).

R5

R4

HO

R3

OMe

N+

N

H

O

R1

R2

O

OH <sup>N</sup>

**5 6**

O

O

O

**1:** R1 = OH; R2 = OMe; R3 = H; R4 = R5 = OMe **2:** R1 + R2 = OCH2O; R3 = H; R4 = R5 = OMe **3:** R1 + R2 = OCH2O; R3 = R4 = OMe; R5 = H **4:** R1 + R2 = R3 + R4 = OCH2O; R5 = H

H

OH

O

O

O

**4.1.1 Isoquinoline alkaloids**

*Zanthoxylum* Genus as Potential Source of Bioactive Compounds 191

decoction powder, paste, sticks, juice).

Local and oral routes (macerated or decoction).

Local routes (infusion or decoction material,

Local and oral routes (macerated or decoction).

Local route (Rootbark decoctions)

Local route (decoction).

Oral route

(decoction).

Oral route (decoction).

Wood

Local route (decoction).

Oral route (tea of

leaves). Guy et al., 2001

Local and oral routes

Oral route (infusion).

(decoction). Schnee, 1984

Ferreira et al., 2007

Tarus et al., 2006

Marr & Tang, 1992

Facundo et al., 2005

Amaro et al., 1988

Addae et al., 1989

Jirovetz et al., 1999

Adesina, 2005

Marr & Tang, 1992

Oral route (decoction).

paste).

Used in treatment of

As antimalaric, emmenagogue and antirheumatic properties.

To treat snakebite, severe coughs and colds and chest

Used for infected wounds.

Treat boils, pleurisy and toothache.

Used for mouth ulcers, sore throats and as aphrodisiac.

Tonic both for man and animals and to treat toothache.

Insecticide – ovicidal.

sudorific.

sudorific.

For malaria, in vaginal washes and to relieve toothache.

Used as sedative and

Antihypertensive, analgesic and to treat gonorrhea.

Used in house and boat-building, decorative paneling, joinery, construction of talking drums and in the paper and pulp industry.

Insecticide – ovicidal.

sudorific, emetic and

coughs.

pains.

Fruits

Root bark

Leaves

Spines

Stem bark

Root

Root bark

Leaves and pericap

Standl. Bark Diuretic and

Leaves and roots

Leaves, fruits and seeds

Leaves

Wood

Leaves and pericap

Hil. Leaves As painkiller,

*Z. chiloperone*  var. *angustifolium* Engl.

*Z. davyi* (I.Verd.) Waterm.

*Z. dipetalum* H. Mann var. *tomentosum*

*Z. dugandii*

*Z. ekmanii*  (URB.) ALAIN.

*Z. fagara* (L.) Sarg.

*Z. gillettii (*Wild) Waterm*.*

*Z. hawaiiense* Hbd.

*Z. hyemale* A. St.

treat snake bites. Oral route (Infusion). Thuy et al., 1999

Local and oral routes (macerated or decoction).

Oral route (aqueous extract of the leaves)

Oral route (bark

Oral route (dried pericarps, macerated or decoction powder).

Oral route (macerated

Local and oral routes (decoction powder, paste, sticks, juice).

Local and oral routes (macerated or decoction powder, paste, sticks, juice).

Local and oral routes (macerated or

Oral route ( infusion) Amabeoku &

or decoction powder). Schnee, 1984

juice).

Cheng et al., 2004

Islam et al., 2001

Gong et al., 2009

Kinyua, 2010

Kamikawa et al., 1996

Matu & Staden, 2003

> Nguta et al., 2010

and seeds anthelmintic.

Stomach tonic, to

and skin diseases.

Used for treating dyspepsia and some forms of diarrhea.

Dysentery, coughs and headache.

Food condiment and seasoning in China. Treatment of vomiting, toothache, stomach ache and abdominal pain owing to roundworm.

Treat fever, stomachache, flatulent colic, toothache and epilepsy.

For asthma, spasm, fever, herpes and skin ulcers.

Treating severe colds and pneumonia.

Malaria, colds, coughs, and dizziness. Chewed to alleviate toothaches. The Masai and Sonjo use this for small children by adding its juice to milk to give a better appetite. The decoction is given to sick goats, especially those suffering from

diarrhea.

Malaria, colds, coughs, toothache, sores, wounds and headache.

Branches and stems

Leaves

Stem bark

stem bark

Leaves

Bark

Roots

K. Koch Leaves For treat bellyache

*Z. avicennae* (Lam.) DC.

*Z. beecheyanum*

*Z. budrunga*  Wall.

*Z. bungeanum*

*Z. capense*

*Z. chalybeum*  Engl.

*Z. chalybeum*  Engl

Maxim. Pericarps

(Thunb.) Harv. Leaves

*Z. caribeum* Lam. Leaves and

*Zanthoxylum* Genus as Potential Source of Bioactive Compounds 193

Local and oral routes (macerated or decoction powder, paste, sticks).

Oral route (tea of

Oral route (dried fruits, infusion or decoction material).

Local and oral routes (infusion or decoction material, paste).

Oral route (infusion or decoction material).

Oral route (ground

Oral route (macerated or decoction powder).

Local route (paste prepared by rubbing the hard spines on a rock along with water).

Local and oral routes (seeds oil, infusion or decoction material,

Oral route (decoction)

Wood Moccelini et al.,

paste).

pericarp)

leaves).

Patiño & Cuca, 2011

Bastos et al., 2001

Guy et al., 2001

Chen et al., 2011

Bhattacharya et al., 2009

Lee & Lim, 2008

Yamazaki et al., 2007

Lalitharani et al., 2010

Reddy & Jose, 2011

Fernandes et al., 2009

2009

as well as to prepare poisonous arrows.

Used as a colorant and to treat of runny nose, jaundice, ophthalmia and as an anesthetic.

Preparations have been used to treat illness associated with inflammatory

Spice and in to treat stomachache, vomiting, diarrhea, cough, colic, and paresis and as an aromatic, stimulant and piscicide.

Used in toothache, stomachache, fever, rheumatism, paresis, boils and as an insecticide and piscicide. Used in fever, diarrhea and

Commonly used as a spice in Japan.

process.

cholera.

Used to heal vomiting, diarrhea, and abdominal pain.

Applied on the breast to give relief from pain and increase lactation in nursing mothers.

Used as antiseptic, disinfectant, and for treat asthma, toothache and rheumatism.

 Used in different types of inflammations, rheumatism and skin stains.

Wood Used in building houses.

*Z. monophyllum*

*Z. naranjillo*  Griseb.

*Z. nitidum* (Roxb.) DC

*Z. nitidum* (Roxb.) DC

*Z. piperitum* DC.

*Z. rhetsa* Roxb.

*Z. riedelianum* Engl.

*Z. rigidum*  Humb. & Bonpl.

(Lam.) P. Wilson Bark

Leaves

Fruits

Root

Branches, seeds and stem bark

Pericarp

All parts of the plant

Spines

Seeds

Oral route (macerated or decoction powder).

Oral route (macerated or decoction powder).

Local and oral routes (macerated or decoction powder, paste, sticks).

paste).

sticks).

fruits).

Wood.

sticks)

Wood. Adesina, 2005

Cheng et al., 2007

Ngane et al., 2000

Ngoumfo et al., 2010

Adesina, 2005

Navarrete, 1996 Arrieta et al., 2001

Somanabandhu et al., 1992

Kuete et al., 2011

Tringali et al., 2001

to favor the salivation

aborigines.

industry.

bilharzia.

Used as antimicrobial, digestive aid, antidiarrheic, anticancerous, antiodontologic and parasticide.

Used as spices.

Used to treat amebiasis, intestinal parasites, and as a local anesthetic.

Used as febrifugal, sudorific and diuretic.

Used for toothache, colds, fever, malaria, stomachache, rheumatism and urogenital affections,

Used in house and boat-building, decorative paneling, joinery, construction of talking drums and in the paper and pulp industry.

Used for traditional treatment of stomatitis, gingivitis,

As antiulcerative, antiseptic, urinary antiseptic, antisickler, antibacterial.

Folk remedy for snake-bite by Ya-Mei

House and boatbuilding, decorative paneling, joinery, construction of talking drums and in the paper and pulp

*Z. integrifoliolum*

*Z. lemairie (*De

*Z. leprieurii*  Guill. et Perr.

*Z. liebmanianum*  (Engler.) P. Wilson

*Z. limonella*

*Z. macrophylla*  Engl.

Alston. Bark

Merr. Bark

Wild) Waterm*.* Wood

Leaves

Roots

Stem barks

Fruits

Wood

Bark

Bark and seeds

*Zanthoxylum* Genus as Potential Source of Bioactive Compounds 195

the teeth with twigs).

Nanyingi et al., 2008

Kassim et al., 2009

Ngassoum et al., 2003

> Ngane et al., 2000

Oral route (Grinding, hot decoction)

Oral route (crushed

Local and oral routes (infusion material,

Local and oral routes (macerated or decoction).

Local and oral routes; rectal and vaginal injections (macerated or decoction powder, paste, sticks).

Local and oral routes (macerated or decoction powder, paste, sticks).

seeds)

paste).

toothbrushes.

Condiment in Cameroon.

bite.

For respiratory tract infections, malaria and catarrhal fevers.

Used against cough, fever, colds, toothache and snake

As scaring and as antiseptic, astringent and laxative.

Used as antiseptic, anti-sickler, digestive aid and parasticide. Also are generally used as chewing sticks for teeth cleaning. Antirheumatic, antiodontalgic, diurectic, urinary antiseptic, digestive aid and parasticide.

Table 1. Main ethnobotanical uses of some species of the *Zanthoxylum* genus.

**Benzylisoquinoline alkaloids** have a restricted distribution in plants similar to that of benzophenanthridines. In the Rutaceae family they are present in a group of five genera named proto-Rutaceae (*Phellodendron*, *Fagaropsis*, *Tetradium*, *Toddalia* and *Zanthoxylum*) (Ling et al., 2009; Waterman, 2007)*.* In the genus *Zanthoxylum* they are not the most common but have been found in some species, such as quaternary alkaloids (*R*)-(*+*)- isotembetarine **7** and (*S*)-(*-*) xylopinidine **8** that have been isolated from the bark of *Z. quinduense* (Patiño & Cuca, 2010).

**Berberine** and **protoberberine alkaloids** have been reported in several species of the genus *Zanthoxylum*, for example tetrahydroberberines such as *N*-methyltetrahydrocolumbamine **9**  and *N*-methyltetrahydropalmatine **10**, have been isolated from the bark of *Z. quinduense* (Patiño & Cuca, 2010). Berberine **11** is characterized by its significant leishmanicidal and antimicrobial activities and is usually the responsible for the yellowing observed in wood and bark of some species of this genus, as in the case of *Z. monophyllum* that is used as a dye

In the genus *Zanthoxylum*, **aporphine alkaloids** there are not the most representative, but they have been isolated from various species and are of great importance because several have antitumoral activity (Adesina, 2005). For example, N,N-dimethyllindicarpine **12**,

obtained from the root bark of *Z. zanthoxyloides* (Queiroz et al., 2006).

twigs

Seeds

Seeds

Leaves and bark

Leaves

Roots

Stem bark

*Z. xanthoxyloides*  Waterm

*Z. xanthoxyloides*  Waterm

(Patiño & Cuca, 2011).

Local route

bark).

bark)

Oral route (infusion or decoction of roots

Oral route (decoction

Oral route (macerated or decoction powder, crushed material).

Oral route (macerated

Oral route (macerated or decoction powder).

Cleaning the teeth.

powder).

Wood

Oral route (decoction).

Oral route (teas or

Oral route (infusion or decoction powder).

Local route (cleaning

infusions).

Used to treat toothache and earache, also is used as an anti-venom serum, anti-tumor and in the treatment of hemorrhoids.

Used as culinary applications and drugs for epigastric

Used for snake bites and gastrointestinal

Used as a toothbrush

House and boatbuilding, joinery, decorative paneling and in the paper and pulp industry.

Used for the treatment of dyspepsia, rheumatism and some forms of diarrhea.

Antispasmodic, muscle relaxant, analgesic, sudorific, antifungal, diuretic, antiplatelet, antiparasitic and antihypertensive.

Used to treat rheumatism.

Used as

pain.

disorders

Used for treat tumors, swellings, inflammation and gonorrhea.

Used as a tonic, a febrifuge, against inflammatory and microbial processes, and in the treatment

Root bark

Bark

Leaves and ripe pericarp

Stem bark

Root bark

Wood

Bark

Young

ex Willd*.*

*Z. rhoifolium*  Lam.

*Z. schinifolium*  Sieb. & Zucc.

*Z. simulans*

*Z. tessmannii*  Engl.

*Z. tetraspermum*

*Z. tingoassuiba*

*Z. usambarense*  (Engl.) Kokwaro

Wight and Arn. Stem bark

A. St. Hil. Stem bark

Hance. Roots

Table 1. Main ethnobotanical uses of some species of the *Zanthoxylum* genus.

**Benzylisoquinoline alkaloids** have a restricted distribution in plants similar to that of benzophenanthridines. In the Rutaceae family they are present in a group of five genera named proto-Rutaceae (*Phellodendron*, *Fagaropsis*, *Tetradium*, *Toddalia* and *Zanthoxylum*) (Ling et al., 2009; Waterman, 2007)*.* In the genus *Zanthoxylum* they are not the most common but have been found in some species, such as quaternary alkaloids (*R*)-(*+*)- isotembetarine **7** and (*S*)-(*-*) xylopinidine **8** that have been isolated from the bark of *Z. quinduense* (Patiño & Cuca, 2010).

**Berberine** and **protoberberine alkaloids** have been reported in several species of the genus *Zanthoxylum*, for example tetrahydroberberines such as *N*-methyltetrahydrocolumbamine **9**  and *N*-methyltetrahydropalmatine **10**, have been isolated from the bark of *Z. quinduense* (Patiño & Cuca, 2010). Berberine **11** is characterized by its significant leishmanicidal and antimicrobial activities and is usually the responsible for the yellowing observed in wood and bark of some species of this genus, as in the case of *Z. monophyllum* that is used as a dye (Patiño & Cuca, 2011).

In the genus *Zanthoxylum*, **aporphine alkaloids** there are not the most representative, but they have been isolated from various species and are of great importance because several have antitumoral activity (Adesina, 2005). For example, N,N-dimethyllindicarpine **12**, obtained from the root bark of *Z. zanthoxyloides* (Queiroz et al., 2006).

 Canthin-6-one alkaloids of importance for its leishmanicidal activity are rare in the family Rutaceae, are found in a few genders including *Zanthoxylum*. For example from *Z. rugosum* (Diehl et al., 2000), *Z. chiloperone* (Ferreira et al., 2002) and *Z. budrunga* (Rahman et al., 2005), have been isolated canthin-6-one **23** and 5-methoxycanthin-6-one **24**. Quinazoline alkaloids have been isolated from *Z. budrunga*, as is the case lunacridina **25** (Ahmad et al., 2003). Carbazole alkaloids such as 3-methoxy-9-methyl-9H-carbazol-2-ol **26** were obtained from the wood of *Z. rhoifolium* (Taborda & Cuca, 2007). Recently, from the bark of *Z. monophyllum* was isolated an alkaloid derived from proline, called monophyllidin

N

Lignans are also widely distributed in higher plants and have numerous biological activities among which include the antimicrobial, antioxidant, antitumor, antiviral, antihepatotoxic, antituberculous, insecticides and inhibit specifically certain enzymes. At the ecological level, there is the evidence that lignans play a role in plant-fungus, plant-plant and plant-insect interactions. Some lignans are toxic to fungi and insects. They are biogenetically derived by the oxidative dimerization of two C6-C3 units, that is, two characteristic phenylpropanoid units. The degree of oxidation and types of substituents determine the emerging lignan structure. There are also naturally occurring dimers that exhibit peculiar-type linkages. Different types of lignans has been described in a large number of plants from the Rutaceae family, but in the genus *Zanthoxylum* the lignans most reported have been of two types, diarylbutirolactones and 2,6-diaryl-3,7-dioxabicyclo[3.3.0]octanes. Neolignans also have been reported in some

Furofuranic lignans as syringaresinol **28** were obtained from *Z. quinduense* and *Z. monophyllum* (Patiño and Cuca, 2010; 2011). From *Z integrifoliolum* (Chen et al., 1999), *Z. culantrillo* (Cuca et al., 1998) and *Z. naranjillo* (Bastos et al., 1999) ha been isolated (+)-sesamin **29**. Diarylbutirolactonic lignans such as (-)-cubebin **30** with trypanocidal activity has been isolated from *Z. monophyllum* (Cuca et al., 1998) and *Z. naranjillo* (Bastos et al., 1999). A nor-neolignan, ailanthoidol **31**, was isolated from the wood of *Z. ailanthoides*, as tree used in folk medicine in

**27** with antibacterial activity against *Enterococcus faecalis* (Patiño & Cuca, 2011).

**<sup>25</sup> <sup>26</sup>**

O

**19**

OH

N

N H

O

N

species of *Zanthoxylum* (Adesina, 2005; Waterman & Grundon, 1983).

Taiwan for the treatment of snake bite and the common cold (Sheen et al., 1994).

**4.2 Lignans**

#### **4.1.2 Quinoline alkaloids**

Quinoline alkaloids are very common in the genus *Zanthoxylum*, usually have been found two types: furoquinolines and pyranoquinolines. Many of them are characterized by contain a carbonyl group in position 2 of the simple quinolinic nucleus and are called 2-quinolones (Waterman & Grundon, 1983). Alkaloids of this type have been isolated from the bark of *Z. budrunga* founding two pyranoquinoline: N-methylflindersine **13** and zanthobungeanine **14**, together with two furoquinolines dictamine **15** and skimmianine **16** (Rahman et al., 2005). From *Z. simulans* also have been isolated pyranoquinoline alkaloids as zhantosimulin **17** and huajiaosimulim **18**, with cytotoxic activity (Chen et al., 1997).

#### **4.1.3 Other alkaloids**

Bishoderninyl terpene, indolopyridoquinazoline, canthin-6-one, quinazoline and carbazole alkaloids, among others, are not very common in the genus *Zanthoxylum*, they have been found in some particular species. Bishoderninyl terpene alkaloids such as **19** have been isolated from the leaves of *Z. integrifoliolum* (Liu et al., 2000). Indolopyridoquinazoline alkaloids with significant antiplatelet activity as 1-hydroxyrutaecarpine **20**, rutaecarpine **21**, and 1-methoxyrutaecarpine **22** have been obtained from the fruits of *Z. integrifoliolum* (Sheen

et al., 1996). Canthin-6-one alkaloids of importance for its leishmanicidal activity are rare in the family Rutaceae, are found in a few genders including *Zanthoxylum*. For example from *Z. rugosum* (Diehl et al., 2000), *Z. chiloperone* (Ferreira et al., 2002) and *Z. budrunga* (Rahman et al., 2005), have been isolated canthin-6-one **23** and 5-methoxycanthin-6-one **24**. Quinazoline alkaloids have been isolated from *Z. budrunga*, as is the case lunacridina **25** (Ahmad et al., 2003). Carbazole alkaloids such as 3-methoxy-9-methyl-9H-carbazol-2-ol **26** were obtained from the wood of *Z. rhoifolium* (Taborda & Cuca, 2007). Recently, from the bark of *Z. monophyllum* was isolated an alkaloid derived from proline, called monophyllidin **27** with antibacterial activity against *Enterococcus faecalis* (Patiño & Cuca, 2011).

#### **4.2 Lignans**

196 Bioactive Compounds in Phytomedicine

MeO HO

HO

MeO

OMe

OMe

N+

MeO

RO

MeO HO

HO

MeO

N O

O

O

R1

O

OMe

**9**: R=H

**10**: R = Me

N+

**15:** R1 = R2 = H **16:** R1 = R2 = OMe

**12**

N+

OMe

OMe

Quinoline alkaloids are very common in the genus *Zanthoxylum*, usually have been found two types: furoquinolines and pyranoquinolines. Many of them are characterized by contain a carbonyl group in position 2 of the simple quinolinic nucleus and are called 2-quinolones (Waterman & Grundon, 1983). Alkaloids of this type have been isolated from the bark of *Z. budrunga* founding two pyranoquinoline: N-methylflindersine **13** and zanthobungeanine **14**, together with two furoquinolines dictamine **15** and skimmianine **16** (Rahman et al., 2005). From *Z. simulans* also have been isolated pyranoquinoline alkaloids as zhantosimulin **17** and

Bishoderninyl terpene, indolopyridoquinazoline, canthin-6-one, quinazoline and carbazole alkaloids, among others, are not very common in the genus *Zanthoxylum*, they have been found in some particular species. Bishoderninyl terpene alkaloids such as **19** have been isolated from the leaves of *Z. integrifoliolum* (Liu et al., 2000). Indolopyridoquinazoline alkaloids with significant antiplatelet activity as 1-hydroxyrutaecarpine **20**, rutaecarpine **21**, and 1-methoxyrutaecarpine **22** have been obtained from the fruits of *Z. integrifoliolum* (Sheen

**17 18**

O N

huajiaosimulim **18**, with cytotoxic activity (Chen et al., 1997).

**13:** R=H

**14:** R = OMe R2

N

R

O

N

O

O

**4.1.2 Quinoline alkaloids**

MeO

N+

OH OH

O O OMe

**11**

**7 8**

N+

**4.1.3 Other alkaloids**

Lignans are also widely distributed in higher plants and have numerous biological activities among which include the antimicrobial, antioxidant, antitumor, antiviral, antihepatotoxic, antituberculous, insecticides and inhibit specifically certain enzymes. At the ecological level, there is the evidence that lignans play a role in plant-fungus, plant-plant and plant-insect interactions. Some lignans are toxic to fungi and insects. They are biogenetically derived by the oxidative dimerization of two C6-C3 units, that is, two characteristic phenylpropanoid units. The degree of oxidation and types of substituents determine the emerging lignan structure. There are also naturally occurring dimers that exhibit peculiar-type linkages. Different types of lignans has been described in a large number of plants from the Rutaceae family, but in the genus *Zanthoxylum* the lignans most reported have been of two types, diarylbutirolactones and 2,6-diaryl-3,7-dioxabicyclo[3.3.0]octanes. Neolignans also have been reported in some species of *Zanthoxylum* (Adesina, 2005; Waterman & Grundon, 1983).

Furofuranic lignans as syringaresinol **28** were obtained from *Z. quinduense* and *Z. monophyllum* (Patiño and Cuca, 2010; 2011). From *Z integrifoliolum* (Chen et al., 1999), *Z. culantrillo* (Cuca et al., 1998) and *Z. naranjillo* (Bastos et al., 1999) ha been isolated (+)-sesamin **29**. Diarylbutirolactonic lignans such as (-)-cubebin **30** with trypanocidal activity has been isolated from *Z. monophyllum* (Cuca et al., 1998) and *Z. naranjillo* (Bastos et al., 1999). A nor-neolignan, ailanthoidol **31**, was isolated from the wood of *Z. ailanthoides*, as tree used in folk medicine in Taiwan for the treatment of snake bite and the common cold (Sheen et al., 1994).

*Zanthoxylum* Genus as Potential Source of Bioactive Compounds 199

Amides are compounds that have chemotaxonomic importance for the genus *Zanthoxylum* and have been found mainly in the pericarp of the fruit, stems and roots of these species. The genus *Zanthoxylum* is characterized chemically by the frequent accumulation of olefinic alkamides (unsaturated aliphatic acid amides) and biogenetic capacity derived from the condensation of fatty acids such as linolenic and linoleic acids with isobutyl amines. Biologically, the isobutyl amides have been shown to have strong insecticidal properties. Alkamides have been used medicinally since ancient times as sialogogues, antitussive and analgesic and their presence in the *Zanthoxylum* genus may be of immense benefit to medicine (Adesina, 2005; Chaaib, 2004). An example of such amides is provided by the αsanshool **36**, isolated from *Z. liebmannianum* and is known for its anthelmintic properties

Other types of amides encountered in the *Zanthoxylum* genus are the aromatic amides described occasionally also as alkaloids or trans-cinnamoylamides. A typical example is the

Flavonoids are phenolic compounds widely available in this genus. They are present in almost all plant organs and play an important role in the antioxidant defense system. These secondary metabolites are known for their diverse biological properties, such as antioxidants, antiinflammatory, antithrombotic, antibacterial, antihepatotoxic, antitumor, antihypertensive, antiviral, antiallergic and estrogenic (Andersson et al. 1996; Harborne &

In *Zanthoxylum* genus, flavonoids are mainly represented by glycosides of flavones, flavonols and flavanones. Flavonoids found in the genus *Zanthoxylum*, like those isolated in other genera of the Rutaceae family are characterized to be polymethoxylated (Waterman & Grundon, 1983). Research carried out on fruits of *Z. integrifoliolum* lead to the isolation of

3,5-diacetyltambuline **38**, with significant antiplatelet activity (Chen et al., 1999).

active antiplasmodial syncarpamide **37**, isolated from *Z. syncarpum* (Ross et al., 2004).

**4.4 Amides**

(Navarrete & Hong, 1996).

**4.5 Flavonoids**

Williams, 2000).

#### **4.3 Coumarins**

Biologically, coumarins are very useful and many of them have exhibited antibacterial, antitumour, vasodilatory (in coronary vessels) and anticoagulant activities. It was long noted that most coumarins are free from toxic side effects and may be given for years without side effects; overdose, however, causes haemorrhages (Murray et al., 1989). Coumarins are widespread in the Angiosperms but they are rather rare in Gymnosperms and lower plants. They are occur in great structural variety especially in the Apiaceae and Rutaceae and are additionally found in many other plants families like the Asteraceae, Poaceae and Rubiaceae (Ribeiro & Kaplan, 2002). The family Rutaceae belongs to the order Rutales characterized by the occurrence of coumarins in all families that comprise it. Coumarins, although are very frequent in the family as a whole, are confined to four sub-families (Aurantioideae, Flindersioideae, Toddalioideae and Rutoideae). In the subfamily Rutoideae is present the genus *Zanthoxylum*, which is characterized by the presence of different types of coumarins (simple, linear, dihydrofurocoumarins, furocoumarins and pyranocoumarins). The linear and angular dihydrofurocoumarins and precursors have been identified in several species of the genus, but angular dihydrofurocoumarins are not common in other species of the family Rutaceae, so it can be chemotaxonomic value for the genus *Zanthoxylum*. The fact that prenyl substitution at C-8 is much less frequent than that at C-6 could explain why angular furanocoumarins are rather rare in the Rutaceae (Murray et al., 1989; Waterman & Grundon, 1983).

From stem of *Z. shinifolium* was isolated larcinatin **32**, a terpenylcoumarin with significant inhibitory activity against the enzyme monoamine oxidase (MAO), which is one of the two isozymes, MAO-B is associated with Parkinson's disease (Jo et al., 2002). In studies done on this species, from the bark of *Z. schinifolium* were isolated auraptene **33** and collinine **34**, terpenylcoumarins with antiplatelet activity and inhibitory activity of DNA replication in hepatitis B virus (Tsai et al., 2000). Furanocoumarins with cytotoxic activity against human tumor cells have been found in berries of *Z. americanum*, for example psoralen **35** (Saquib et al., 1990).

#### **4.4 Amides**

198 Bioactive Compounds in Phytomedicine

Biologically, coumarins are very useful and many of them have exhibited antibacterial, antitumour, vasodilatory (in coronary vessels) and anticoagulant activities. It was long noted that most coumarins are free from toxic side effects and may be given for years without side effects; overdose, however, causes haemorrhages (Murray et al., 1989). Coumarins are widespread in the Angiosperms but they are rather rare in Gymnosperms and lower plants. They are occur in great structural variety especially in the Apiaceae and Rutaceae and are additionally found in many other plants families like the Asteraceae, Poaceae and Rubiaceae (Ribeiro & Kaplan, 2002). The family Rutaceae belongs to the order Rutales characterized by the occurrence of coumarins in all families that comprise it. Coumarins, although are very frequent in the family as a whole, are confined to four sub-families (Aurantioideae, Flindersioideae, Toddalioideae and Rutoideae). In the subfamily Rutoideae is present the genus *Zanthoxylum*, which is characterized by the presence of different types of coumarins (simple, linear, dihydrofurocoumarins, furocoumarins and pyranocoumarins). The linear and angular dihydrofurocoumarins and precursors have been identified in several species of the genus, but angular dihydrofurocoumarins are not common in other species of the family Rutaceae, so it can be chemotaxonomic value for the genus *Zanthoxylum*. The fact that prenyl substitution at C-8 is much less frequent than that at C-6 could explain why angular furanocoumarins are rather rare in the Rutaceae (Murray et al., 1989; Waterman & Grundon,

From stem of *Z. shinifolium* was isolated larcinatin **32**, a terpenylcoumarin with significant inhibitory activity against the enzyme monoamine oxidase (MAO), which is one of the two isozymes, MAO-B is associated with Parkinson's disease (Jo et al., 2002). In studies done on this species, from the bark of *Z. schinifolium* were isolated auraptene **33** and collinine **34**, terpenylcoumarins with antiplatelet activity and inhibitory activity of DNA replication in hepatitis B virus (Tsai et al., 2000). Furanocoumarins with cytotoxic activity against human tumor cells have been found in berries of *Z. americanum*, for example psoralen **35** (Saquib et

**4.3 Coumarins**

1983).

al., 1990).

Amides are compounds that have chemotaxonomic importance for the genus *Zanthoxylum* and have been found mainly in the pericarp of the fruit, stems and roots of these species. The genus *Zanthoxylum* is characterized chemically by the frequent accumulation of olefinic alkamides (unsaturated aliphatic acid amides) and biogenetic capacity derived from the condensation of fatty acids such as linolenic and linoleic acids with isobutyl amines. Biologically, the isobutyl amides have been shown to have strong insecticidal properties. Alkamides have been used medicinally since ancient times as sialogogues, antitussive and analgesic and their presence in the *Zanthoxylum* genus may be of immense benefit to medicine (Adesina, 2005; Chaaib, 2004). An example of such amides is provided by the αsanshool **36**, isolated from *Z. liebmannianum* and is known for its anthelmintic properties (Navarrete & Hong, 1996).

Other types of amides encountered in the *Zanthoxylum* genus are the aromatic amides described occasionally also as alkaloids or trans-cinnamoylamides. A typical example is the active antiplasmodial syncarpamide **37**, isolated from *Z. syncarpum* (Ross et al., 2004).

#### **4.5 Flavonoids**

Flavonoids are phenolic compounds widely available in this genus. They are present in almost all plant organs and play an important role in the antioxidant defense system. These secondary metabolites are known for their diverse biological properties, such as antioxidants, antiinflammatory, antithrombotic, antibacterial, antihepatotoxic, antitumor, antihypertensive, antiviral, antiallergic and estrogenic (Andersson et al. 1996; Harborne & Williams, 2000).

In *Zanthoxylum* genus, flavonoids are mainly represented by glycosides of flavones, flavonols and flavanones. Flavonoids found in the genus *Zanthoxylum*, like those isolated in other genera of the Rutaceae family are characterized to be polymethoxylated (Waterman & Grundon, 1983). Research carried out on fruits of *Z. integrifoliolum* lead to the isolation of 3,5-diacetyltambuline **38**, with significant antiplatelet activity (Chen et al., 1999).

*Zanthoxylum* Genus as Potential Source of Bioactive Compounds 201

As noted in previous sections, *Zanthoxylum* genus is well known for their chemical diversity and ethnobotanical properties, characteristics that have been the basis for developing various biological activity studies, which have helped to find new bioactive extracts and compounds, some of which have good potential for the development of new drugs and

The biological activities for certain species of the genus *Zanthoxylum* are mainly associated with the evaluation of antimicrobial, insecticidal, anti-inflammatory, antioxidant, antiparasitic, antitumor, antihelmitic, antinociceptive and antiviral activities, as well as studies of enzyme inhibition and effects on the central nervous system and cellular components of blood. The information in this section is organized by type biological

There are few reports on allelopathic activity of *Zanthoxylum* species. One report shows a bioguided fractionation of the ethyl acetate extract of the *Z. limonella* fruits led to the isolation of xanthoxyline, a substance with allelopathic effects of on Chinese amaranth (*Amaranthus tricolor* L.) and Barnyardgrass (*Echinochloa crus-galli* (L.) Beauv.). At a concentration of 2500 µM, xanthoxyline completely inhibited seed germination and growth of Chinese amaranth, and showed a significantly inhibitory effect on seed germination of

Studies of analgesic activity in the genus *Zanthoxylum* have been focused mainly to validate its traditional uses. An example is the study of analgesic activity made with the aqueous extract of root bark of *Z. xanthozyloides*. This study showed that the extract induced analgesia, probably, by inhibiting prostaglandin production, because some isolated and

activity, including the most representative results found for the genus *Zanthoxylum*.

**5. Biological activity of** *Zanthoxylum* **genus**

Barnyardgrass by 43.59% (Charoenying et al., 2010).

different industrial products.

**5.1 Allelopathic activity**

**5.2 Analgesic activity**

#### **4.6 Terpenes and sterols**

Most species belonging to the family Rutaceae contain glands that secrete volatile substances in different organs of plants such as fruits, leaves, bark, wood, roots, rhizomes and seeds. The essential oils obtained are often complex mixtures of monoterpenes and sesquiterpenes. *Zanthoxylum* genus accumulates volatile oils in leaves, flowers and fruits. Recently was determined the chemical composition of essential oils isolated from fruits of *Z. monophyllum*, *Z. rhoifolium* and *Z. fagara* by steam distillation, as well as were testing their antifungal and insecticidal activities. Gas chromatography-mass spectrometry (GC/MS) analysis allows identified 57 compounds. The main constituents in *Z. rhoifolium* oil were βmyrcene **39** (59.03%), β-phellandrene **40** (21.47%), and germacrene D **41** (9.28%), the major constituents of *Z. monophyllum* oil were sabinene **42** (25.71%), 1,8-cineole **43** (9.19%), and cis-4-thujanol **44** (9.19%), whereas fruit oil of *Z. fagara* mainly contained germacrene D-4-ol **459** (21.1%), elemol **46** (8.35%), and α-cadinol **47** (8.22%). *Z. fagara* showed the highest activity on *Colletotrichum acutatum* (EC50 153.9 μL L-1 air), and *Z. monophyllum* was the most active against *Fusarium oxysporum* f. sp. *lycopersici* (EC50 140.1 μL L-1 air). *Z. monophyllum* essential oil showed significant fumigant activity against *Sitophilus oryzae* (Prieto et al., 2011).

Sterols are common components of many plants and have been isolated from virtually all plants. Whereas β-sitosterol **48** appears ubiquitous in nature, the triterpene lupeol **49** appears restricted to the *Zanthoxylum* genus. Lupeol, β-sitosterol, usually associated with stigmasterol **50**, campesterol **51** and β-amyrin **52** have been isolated from the various morphological parts of the main species of *Zanthoxylum* studied (Adesina, 2005).

Most species belonging to the family Rutaceae contain glands that secrete volatile substances in different organs of plants such as fruits, leaves, bark, wood, roots, rhizomes and seeds. The essential oils obtained are often complex mixtures of monoterpenes and sesquiterpenes. *Zanthoxylum* genus accumulates volatile oils in leaves, flowers and fruits. Recently was determined the chemical composition of essential oils isolated from fruits of *Z. monophyllum*, *Z. rhoifolium* and *Z. fagara* by steam distillation, as well as were testing their antifungal and insecticidal activities. Gas chromatography-mass spectrometry (GC/MS) analysis allows identified 57 compounds. The main constituents in *Z. rhoifolium* oil were βmyrcene **39** (59.03%), β-phellandrene **40** (21.47%), and germacrene D **41** (9.28%), the major constituents of *Z. monophyllum* oil were sabinene **42** (25.71%), 1,8-cineole **43** (9.19%), and cis-4-thujanol **44** (9.19%), whereas fruit oil of *Z. fagara* mainly contained germacrene D-4-ol **459** (21.1%), elemol **46** (8.35%), and α-cadinol **47** (8.22%). *Z. fagara* showed the highest activity on *Colletotrichum acutatum* (EC50 153.9 μL L-1 air), and *Z. monophyllum* was the most active against *Fusarium oxysporum* f. sp. *lycopersici* (EC50 140.1 μL L-1 air). *Z. monophyllum* essential

oil showed significant fumigant activity against *Sitophilus oryzae* (Prieto et al., 2011).

Sterols are common components of many plants and have been isolated from virtually all plants. Whereas β-sitosterol **48** appears ubiquitous in nature, the triterpene lupeol **49** appears restricted to the *Zanthoxylum* genus. Lupeol, β-sitosterol, usually associated with stigmasterol **50**, campesterol **51** and β-amyrin **52** have been isolated from the various

morphological parts of the main species of *Zanthoxylum* studied (Adesina, 2005).

**4.6 Terpenes and sterols**

## **5. Biological activity of** *Zanthoxylum* **genus**

As noted in previous sections, *Zanthoxylum* genus is well known for their chemical diversity and ethnobotanical properties, characteristics that have been the basis for developing various biological activity studies, which have helped to find new bioactive extracts and compounds, some of which have good potential for the development of new drugs and different industrial products.

The biological activities for certain species of the genus *Zanthoxylum* are mainly associated with the evaluation of antimicrobial, insecticidal, anti-inflammatory, antioxidant, antiparasitic, antitumor, antihelmitic, antinociceptive and antiviral activities, as well as studies of enzyme inhibition and effects on the central nervous system and cellular components of blood. The information in this section is organized by type biological activity, including the most representative results found for the genus *Zanthoxylum*.

## **5.1 Allelopathic activity**

There are few reports on allelopathic activity of *Zanthoxylum* species. One report shows a bioguided fractionation of the ethyl acetate extract of the *Z. limonella* fruits led to the isolation of xanthoxyline, a substance with allelopathic effects of on Chinese amaranth (*Amaranthus tricolor* L.) and Barnyardgrass (*Echinochloa crus-galli* (L.) Beauv.). At a concentration of 2500 µM, xanthoxyline completely inhibited seed germination and growth of Chinese amaranth, and showed a significantly inhibitory effect on seed germination of Barnyardgrass by 43.59% (Charoenying et al., 2010).

## **5.2 Analgesic activity**

Studies of analgesic activity in the genus *Zanthoxylum* have been focused mainly to validate its traditional uses. An example is the study of analgesic activity made with the aqueous extract of root bark of *Z. xanthozyloides*. This study showed that the extract induced analgesia, probably, by inhibiting prostaglandin production, because some isolated and

*Zanthoxylum* Genus as Potential Source of Bioactive Compounds 203

extensively studied for its inhibitory effects on inflammation under in vitro and in animal

Most reports of biological activity of the *Zanthoxylum* genus are related to the evaluation of antimicrobial activity. This activity has been evaluated mainly using human pathogenic strains, with few cases in which phytopathogenic strains are used. Most studies of antimicrobial activity have been made using disk diffusion method. Here are some examples of antimicrobial activity studies performed with species of the genus *Zanthoxylum*. The antifungal and antibacterial activities of some compounds isolated from *Z. tessmannii* were determined against *Bacillus subtilis, Escherichia coli, Staphylococcus aureus, Streptomyces viridochromogenes, Mucor miehei, Candida albicans, Chlorella vulgaris, Chlorella sorokiniana and Scenedesmus subspicatus*. 2,6-dimethoxy-1,4-benzoquinone showed activities against seven of the nine strains employed, while *3β*-acetoxy-*16β*-hydroxybetulinic acid showed weak activities against *Bacillus subtilis* and *Escherichia coli*, and *3β, 16β*-hydroxybetulinic acid showed weak activities against *Bacillus subtili*s and *Candida albicans* (Mbaze et al., 2007).

The fruits extract of *Z. armatum* has been tested for their antibacterial activity against *S. aureus*, *E. coli, Pseudomonas aeruginosa* and *Shigella boydii*. This ethanolic extract was inactive against *P*. *aeruginosa*, while showed positive activity on the other three strains. These results indicate that the ethanolic extract from fruits of *Z. armatum* may have broad spectrum antibacterial activity because it shows activity against *Gram*-positive and *Gram*-negative

The essential oils of *Z. xanthoxyloides* and *Z. leprieurii*, two Cameroonian plants used as spices in local food, showed antibacterial and antifungal activity against *E. coli*, *S. aureus*, *Klebsiella pneumoniae*, *Enterococcus faecalis*, *Corynebacterium glutamicum*, *B. cereus*, *B. subtilis*

Aqueous, hexane and methanol extracts of leaves, roots and stem bark obtained from *Z. chalybeum* and *Z. usambarense* were screened for in-vitro antibacterial activity using *Gram*positive bacteria (*B. subtilis*, *Micrococcus luteus* and *S. aureus*). The root and stem-bark extracts of the two *Zanthoxylum* species showed high antibacterial activity (Matu & Staden, 2003).

Aqueous, hexane and methanol extracts of leaves, roots and stem bark obtained from *Z. chalybeum* and *Z. usambarense* were screened for in vitro antibacterial activity using *Gram*positive bacteria (*B. subtilis*, *Micrococcus luteus* and *S. aureus*). The root and stem-bark extracts of the two *Zanthoxylum* species showed high antibacterial activity (Matu & Staden, 2003).

Ethanolic extracts of bark of *Z.fagara*, *Z. elephantiasis* and *Z.martinicense* were evaluated against *C. albicans*, *Saccharomyces cerevisiae*, *Aspergillus niger*, *A. flavus*, *Microsporum canis* and *Trichophyton mentagrophytes* to determined their antifungal activity. All of the extracts assayed showed activity against common dermatophytes of domestic animals, the one being most significant is that exhibited by the ethanolic extract of the bark of *Z. fagara* (Diéguez-

Leaf, fruit, stem, bark and root extracts of *Z. americanum* were investigated for antifungal activity with 11 strains of fungi. All extracts demonstrated a broad spectrum of antifungal activity and inhibited at least eight fungal species, being the fruit and leaf extracts the most

models of inflammation (Saleem, 2009).

bacteria (Panthi & Chaudhary, 2006).

Hurtado et al, 2003).

and *Aspergillus flavus* (Tatsadjieu et al., 2003).

**5.6 Antimicrobial activity**

purified alkaloids of the root bark of *Z. xanthoxyloides* have anti-prostaglandin synthetase activity (Prempeh & Mensah-Attipoe, 2008).

## **5.3 Anticonvulsant activity**

The reports on anticonvulsant activity of *Zanthoxylum* species are few. A recent study of anticonvulsant activity was carried out with the methanol and aqueous extracts from leaves of *Z. capense*. In this report was investigated the effect of both extracts on seizures induced by pentylenetetrazole, bicuculline, picrotoxin, N-methyl-DL-aspartic acid and strychnine in mice. Both extracts showed significant activity in the tests carried out with the five seizures inducing agents, finding that these substances in some cases delay seizures and in some cases act as agonists (Amabeoku & Kinyua, 2010).

## **5.4 Antihelmitic activity**

Antihelmitic activity studies have been advanced mainly in the specie *Z. xanthoxyloides*. Two recent studies reveal that acetone: water (70:30) and ethanol extracts from leaves of *Z. xanthoxyloides* showed promising activity against *Asaris lumbricoides*, *Haemonchus contortus*, *Trichostrongylus colubriformis*, three nematodes that of these nematodes provokes production losses, clinical signs and even can lead to deaths in sheep or goats worldwide (Azando et al., 2011; Barnabas et al., 2011).

## **5.5 Anti-inflamatory activity**

The anti-inflammatory effects of the extracts and isolated compounds of some *Zanthoxylum*  species have been evaluated employed mainly four methods: 1) paw edema induced by carragenin in rats; 2) ear edema induced by phorbol myristate acetate (PMA), arachidonic acid (AA) and 12-o-tetradecanoyl-phorbol acetate (TPA) in mice; 3) inhibition of superoxide anion generation and 4) elastase release in fMLP/CB-activated human neutrophils in a concentration-dependent manner. In different studies, ethanolic extracts of bark from *Z. elephantiasis*, *Z. fagara*, *Z. martinicense* and *Z. coriaceum*, and hexane, ethyl acetate and ethanolic extracts of leaf from *Z. chiloperone* have presented promising results of antiinflammatory activity (Villalba et al., 2007; Márquez et al., 2005; Bastos, 2001).

Other studies involving phytochemical and biological activity reported the isolation of various secondary metabolites with anti-inflammatory activity. From the hexane extract of *Z. naranjillo* was isolated a dibenzylbutirolactonic lignan (cubebin) with antiinflammatory properties (Bastos et al., 2001). In the methanol extract of stem wood from *Z. nitidum* were identified benzophenanthridine alkaloids, quinolone alkaloids, lignans and coumarins with promising anti-inflammatory activity (Chen et al., 2011). For the methanol extract of stem wood of *Z. integrifoliolum* and *Z. avicennae* have been reported the presence of phenylpropenoids, lignans, coumarins, quinolone alkaloids and quinoline alkaloids with anti-inflammatory potential (Chen et al., 2008; Chen et al., 2007).

One compound which has gained wide attention of medical professionals, pharmaceutical marketers and researchers all around the world is a dietary triterpene knows as lupeol. This compound is found in most species of the genus presented *Zanyhoxylum*, and has been extensively studied for its inhibitory effects on inflammation under in vitro and in animal models of inflammation (Saleem, 2009).

## **5.6 Antimicrobial activity**

202 Bioactive Compounds in Phytomedicine

purified alkaloids of the root bark of *Z. xanthoxyloides* have anti-prostaglandin synthetase

The reports on anticonvulsant activity of *Zanthoxylum* species are few. A recent study of anticonvulsant activity was carried out with the methanol and aqueous extracts from leaves of *Z. capense*. In this report was investigated the effect of both extracts on seizures induced by pentylenetetrazole, bicuculline, picrotoxin, N-methyl-DL-aspartic acid and strychnine in mice. Both extracts showed significant activity in the tests carried out with the five seizures inducing agents, finding that these substances in some cases delay seizures and in some

Antihelmitic activity studies have been advanced mainly in the specie *Z. xanthoxyloides*. Two recent studies reveal that acetone: water (70:30) and ethanol extracts from leaves of *Z. xanthoxyloides* showed promising activity against *Asaris lumbricoides*, *Haemonchus contortus*, *Trichostrongylus colubriformis*, three nematodes that of these nematodes provokes production losses, clinical signs and even can lead to deaths in sheep or goats worldwide (Azando et al.,

The anti-inflammatory effects of the extracts and isolated compounds of some *Zanthoxylum*  species have been evaluated employed mainly four methods: 1) paw edema induced by carragenin in rats; 2) ear edema induced by phorbol myristate acetate (PMA), arachidonic acid (AA) and 12-o-tetradecanoyl-phorbol acetate (TPA) in mice; 3) inhibition of superoxide anion generation and 4) elastase release in fMLP/CB-activated human neutrophils in a concentration-dependent manner. In different studies, ethanolic extracts of bark from *Z. elephantiasis*, *Z. fagara*, *Z. martinicense* and *Z. coriaceum*, and hexane, ethyl acetate and ethanolic extracts of leaf from *Z. chiloperone* have presented promising results of anti-

Other studies involving phytochemical and biological activity reported the isolation of various secondary metabolites with anti-inflammatory activity. From the hexane extract of *Z. naranjillo* was isolated a dibenzylbutirolactonic lignan (cubebin) with antiinflammatory properties (Bastos et al., 2001). In the methanol extract of stem wood from *Z. nitidum* were identified benzophenanthridine alkaloids, quinolone alkaloids, lignans and coumarins with promising anti-inflammatory activity (Chen et al., 2011). For the methanol extract of stem wood of *Z. integrifoliolum* and *Z. avicennae* have been reported the presence of phenylpropenoids, lignans, coumarins, quinolone alkaloids and quinoline alkaloids with

One compound which has gained wide attention of medical professionals, pharmaceutical marketers and researchers all around the world is a dietary triterpene knows as lupeol. This compound is found in most species of the genus presented *Zanyhoxylum*, and has been

inflammatory activity (Villalba et al., 2007; Márquez et al., 2005; Bastos, 2001).

anti-inflammatory potential (Chen et al., 2008; Chen et al., 2007).

activity (Prempeh & Mensah-Attipoe, 2008).

cases act as agonists (Amabeoku & Kinyua, 2010).

**5.3 Anticonvulsant activity**

**5.4 Antihelmitic activity**

2011; Barnabas et al., 2011).

**5.5 Anti-inflamatory activity**

Most reports of biological activity of the *Zanthoxylum* genus are related to the evaluation of antimicrobial activity. This activity has been evaluated mainly using human pathogenic strains, with few cases in which phytopathogenic strains are used. Most studies of antimicrobial activity have been made using disk diffusion method. Here are some examples of antimicrobial activity studies performed with species of the genus *Zanthoxylum*.

The antifungal and antibacterial activities of some compounds isolated from *Z. tessmannii* were determined against *Bacillus subtilis, Escherichia coli, Staphylococcus aureus, Streptomyces viridochromogenes, Mucor miehei, Candida albicans, Chlorella vulgaris, Chlorella sorokiniana and Scenedesmus subspicatus*. 2,6-dimethoxy-1,4-benzoquinone showed activities against seven of the nine strains employed, while *3β*-acetoxy-*16β*-hydroxybetulinic acid showed weak activities against *Bacillus subtilis* and *Escherichia coli*, and *3β, 16β*-hydroxybetulinic acid showed weak activities against *Bacillus subtili*s and *Candida albicans* (Mbaze et al., 2007).

The fruits extract of *Z. armatum* has been tested for their antibacterial activity against *S. aureus*, *E. coli, Pseudomonas aeruginosa* and *Shigella boydii*. This ethanolic extract was inactive against *P*. *aeruginosa*, while showed positive activity on the other three strains. These results indicate that the ethanolic extract from fruits of *Z. armatum* may have broad spectrum antibacterial activity because it shows activity against *Gram*-positive and *Gram*-negative bacteria (Panthi & Chaudhary, 2006).

The essential oils of *Z. xanthoxyloides* and *Z. leprieurii*, two Cameroonian plants used as spices in local food, showed antibacterial and antifungal activity against *E. coli*, *S. aureus*, *Klebsiella pneumoniae*, *Enterococcus faecalis*, *Corynebacterium glutamicum*, *B. cereus*, *B. subtilis* and *Aspergillus flavus* (Tatsadjieu et al., 2003).

Aqueous, hexane and methanol extracts of leaves, roots and stem bark obtained from *Z. chalybeum* and *Z. usambarense* were screened for in-vitro antibacterial activity using *Gram*positive bacteria (*B. subtilis*, *Micrococcus luteus* and *S. aureus*). The root and stem-bark extracts of the two *Zanthoxylum* species showed high antibacterial activity (Matu & Staden, 2003).

Aqueous, hexane and methanol extracts of leaves, roots and stem bark obtained from *Z. chalybeum* and *Z. usambarense* were screened for in vitro antibacterial activity using *Gram*positive bacteria (*B. subtilis*, *Micrococcus luteus* and *S. aureus*). The root and stem-bark extracts of the two *Zanthoxylum* species showed high antibacterial activity (Matu & Staden, 2003).

Ethanolic extracts of bark of *Z.fagara*, *Z. elephantiasis* and *Z.martinicense* were evaluated against *C. albicans*, *Saccharomyces cerevisiae*, *Aspergillus niger*, *A. flavus*, *Microsporum canis* and *Trichophyton mentagrophytes* to determined their antifungal activity. All of the extracts assayed showed activity against common dermatophytes of domestic animals, the one being most significant is that exhibited by the ethanolic extract of the bark of *Z. fagara* (Diéguez-Hurtado et al, 2003).

Leaf, fruit, stem, bark and root extracts of *Z. americanum* were investigated for antifungal activity with 11 strains of fungi. All extracts demonstrated a broad spectrum of antifungal activity and inhibited at least eight fungal species, being the fruit and leaf extracts the most

*Zanthoxylum* Genus as Potential Source of Bioactive Compounds 205

The information on the frequently utilized antimalarial plant species is an important lead to the species that can be targeted for pharmacological, toxicological and phytochemical tests. The most important antimalarial properties have been observed in alkaloids, sesquiterpene lactones, coumarins, triterpenoids and limonoids. *Z. chalybeum*, *Z. syncarpum*, *Z. zanthoxyloides*, *Z. gilletii*, *Z. limonella*, *Z. rhoifolium* and *Z. usambarense*, among others, are some of the species of

*Zanthoxylum chalybeum* root bark (IC50 of 4.2µg/ml) and some quinoline alkaloids isolated from this species have been exhibited strong antiplasmodial activity on chloroquine resistant *Plasmodioum falciparum* strain (Nguta et al., 2010). Syncarpamide and decarine, two compounds isolated from *Z. syncarpum* have showed strong in vitro antiplasmodial activity against D6 (chloroquine sensitive clone) and W2 (chloroquine resistant clone) *P. falciparum*  strains, having IC50 values lower than 6.1 µM (Kaur *et al*., 2009; Ross et al., 2005; Ross et al., 2004). The crude alkaloid extract obtained from the bark of *Z. zanthoxyloides* and fagaronine, a benzophenanthridine alkaloid derived from the root extract of *Z. zanthoxyloides*; inhibited *P. falciparum* growth in vitro at low IC50 (Adebayo & Krettli, 2011; Gansane et al., 2010). Also have been reported positive results of antimalarial activity for the ethanolic extract from stem bark of *Z. guilletti* (Zirihi et al, 2009) and for the chloroform crude extract from fruits of

Anti-plasmodial activity of stem bark extracts from *Z. usambarense* was performed against *P. knowlesi* and *P. berghei*. The aqueous extract was remarkably active against the two parasites, while all organic solvents extracts being inactive. These results suggest that the antiplasmodial activity of *Z. usambarense* is due mainly to polar substances (Were et al.,

A study of antimalarial properties of *Z. rhoifolium* bark carried out in order to validate its use and confirm the previously detected in vivo activity, lead to the isolation of antimalarial compounds. The antiplasmodial activity of *Z. rhoifolium* bark was concentrated in the alkaloid fractions showed approximately 44% inhibition of *P. falciparum* growth at 10µg/mL, using LDH micromethod. Three of the seven isolated compounds from alkaloidal fraction displayed antiplasmodial activity, ranging from good (nitidine, the most potent compound) to moderate (avicine and fagaridine) (Jullian et al., 2006). In other research of the antiplasmodial activity of *Z. rhoifolium* was determined that the water infusion from bark inhibited more than 50% the *P. falciparum* development with doses higher than 500 mg/kg

Recently, has been reported the trypanocidal effect of ethanolic extracts of leaves, fruits, stem bark and root bark, canthin-6-one alkaloids and some of its analogs obtained from *Z. chiloperone*, using *in vitro* methods and the mouse model of acute or chronic infection to evaluate the trypanocidal activity. These results demonstrate the anti-*Trypanozoma* activity of canthinones. Additionally, considering the low toxicity of canthin-6-one, is possible to propose this natural product as a possible advantageous phytotherapeutic compared to the current chemotherapy of Chagas disease (Ferreira et al., 2011; Ferreira et al., 2007). In a study carried out with the hexane extract from leaves of *Z. naranjillo* seven lignans were isolated and evaluated as trypanocidals. Four of the seven lignans showed trypanocidal activity in an *in vitro* assay, being (-)-methylpluviatolide the most active compound (Bastos

*Zanthoxylum* genus that have showed interesting antimalarial properties.

*Z. limonella* (Charoenying et al., 2008)*.*

2010).

(Bertani et al, 2005).

et al., 1999).

active in general. The results provide a basis for the very widespread use of *Z. americanum* in indigenous North American ethnomedical tradition for conditions that may be related to fungal infections (Bafi-Yeboa et al., 2005).

Chelerythrine, N-methyltetrahydrocolumbamine, N-methyltetrahydropalmatine and berberine, four alkaloids isolated from *Z. quinduense*, have exhibited promising antibacterial activity against different *Gram-*positive and *Gram-*negative bacteria, being chelerythrine the most active compound, showing an antibacterial activity comparable to that of the antibiotics kanamycine, tetracycline and anthracycline (Patiño et al., 2011).

## **5.7 Antinociceptive activity**

In order to contribute towards the pharmacological knowledge about *Zanthoxylum* genus, as well as demonstrate the popular uses of some species as a painkiller, have been advanced antinociceptive activity studies with extracts of hexane, ethyl acetate and ethanol obtained from leaves of *Z. chilipirone* and with stem bark ethanolic extract (EtOH), its fractions of partition (hexane, ethyl acetate, aqueous) and lupeol obtained of *Z. rhoifolium*, employing animal models of chemically induced acute pain. The study carried out with *Z. chilipirone* shows that with doses of 100 and 200 mg/kg of each extract is possible to detect significantly inhibition in the paw lick, results that suggest that the extracts from *Z. chiloperone* possess constituents with antinociceptive activity (Villalba et al., 2007). Moreover, the study with extracts of *Z. rhoifolium* sought to confirm its popular use, and shows for the first time that ethanol extract of *Z. rhoifolium* stem bark, its fractions and one of the major constituents (lupeol) have antinociceptive activity when administered orally in different models of chemical nociception in mice (Pereira et al., 2010).

## **5.8 Antioxidant activity**

To determine the antioxidant activity of substances isolated from species of *Zanthoxylum* genus have been used more than ten methods, most based on the determination of free radical scavenging activity. The most common methods are: 1) Total phenolic content; 2) DPPH radical scavenging assay; 3) ABTS radical scavenging activity and 4) superoxide anion scavenging assay.

Studies of antioxidant activity of *Zanthoxylum* species have been advanced mainly extracts from fruits and seeds. For example, the essential oil of seeds of *Z. bungeanum* (Xia et al., 2011), the ethanol extract of fruits of *Z. alatum* (Batool et al., 2010); extracts of hexane, ethyl ether, ethyl acetate and methanol obtained from fruits of *Z. piperitum* (Lee & Lim, 2008; Hisatomi et al., 2000), as well as extracts of hexane, acetone and ethanol from fruits of *Z. achanthopodium* (Suryanto et al., 2004), have demonstrated an interesting antioxidant power.

In a study made by Yamazaki and co-workers shows the isolation of two glycosylated flavonoids (hyperoside and quercitrin) of methanol extract from fruits of *Z. piperitum*, these substances scavenged DPPH radical strongly with IC50 values of 16 and 18 µM, respectively (Yamazaki et al., 2007).

## **5.9 Antiparasitary activity**

In the frame of the search for new leads against the most neglegted parasitic diseases, it is of particular interest to evaluate the antimalarial, trypanocidal and antileishmanial potencial of some of the most frequently traditional drugs used.

active in general. The results provide a basis for the very widespread use of *Z. americanum* in indigenous North American ethnomedical tradition for conditions that may be related to

Chelerythrine, N-methyltetrahydrocolumbamine, N-methyltetrahydropalmatine and berberine, four alkaloids isolated from *Z. quinduense*, have exhibited promising antibacterial activity against different *Gram-*positive and *Gram-*negative bacteria, being chelerythrine the most active compound, showing an antibacterial activity comparable to that of the

In order to contribute towards the pharmacological knowledge about *Zanthoxylum* genus, as well as demonstrate the popular uses of some species as a painkiller, have been advanced antinociceptive activity studies with extracts of hexane, ethyl acetate and ethanol obtained from leaves of *Z. chilipirone* and with stem bark ethanolic extract (EtOH), its fractions of partition (hexane, ethyl acetate, aqueous) and lupeol obtained of *Z. rhoifolium*, employing animal models of chemically induced acute pain. The study carried out with *Z. chilipirone* shows that with doses of 100 and 200 mg/kg of each extract is possible to detect significantly inhibition in the paw lick, results that suggest that the extracts from *Z. chiloperone* possess constituents with antinociceptive activity (Villalba et al., 2007). Moreover, the study with extracts of *Z. rhoifolium* sought to confirm its popular use, and shows for the first time that ethanol extract of *Z. rhoifolium* stem bark, its fractions and one of the major constituents (lupeol) have antinociceptive activity when administered orally in different

To determine the antioxidant activity of substances isolated from species of *Zanthoxylum* genus have been used more than ten methods, most based on the determination of free radical scavenging activity. The most common methods are: 1) Total phenolic content; 2) DPPH radical scavenging assay; 3) ABTS radical scavenging activity and 4) superoxide

Studies of antioxidant activity of *Zanthoxylum* species have been advanced mainly extracts from fruits and seeds. For example, the essential oil of seeds of *Z. bungeanum* (Xia et al., 2011), the ethanol extract of fruits of *Z. alatum* (Batool et al., 2010); extracts of hexane, ethyl ether, ethyl acetate and methanol obtained from fruits of *Z. piperitum* (Lee & Lim, 2008; Hisatomi et al., 2000), as well as extracts of hexane, acetone and ethanol from fruits of *Z. achanthopodium* (Suryanto et al., 2004), have demonstrated an interesting antioxidant power. In a study made by Yamazaki and co-workers shows the isolation of two glycosylated flavonoids (hyperoside and quercitrin) of methanol extract from fruits of *Z. piperitum*, these substances scavenged DPPH radical strongly with IC50 values of 16 and 18 µM, respectively

In the frame of the search for new leads against the most neglegted parasitic diseases, it is of particular interest to evaluate the antimalarial, trypanocidal and antileishmanial potencial of

antibiotics kanamycine, tetracycline and anthracycline (Patiño et al., 2011).

models of chemical nociception in mice (Pereira et al., 2010).

fungal infections (Bafi-Yeboa et al., 2005).

**5.7 Antinociceptive activity**

**5.8 Antioxidant activity**

anion scavenging assay.

(Yamazaki et al., 2007).

**5.9 Antiparasitary activity**

some of the most frequently traditional drugs used.

The information on the frequently utilized antimalarial plant species is an important lead to the species that can be targeted for pharmacological, toxicological and phytochemical tests. The most important antimalarial properties have been observed in alkaloids, sesquiterpene lactones, coumarins, triterpenoids and limonoids. *Z. chalybeum*, *Z. syncarpum*, *Z. zanthoxyloides*, *Z. gilletii*, *Z. limonella*, *Z. rhoifolium* and *Z. usambarense*, among others, are some of the species of *Zanthoxylum* genus that have showed interesting antimalarial properties.

*Zanthoxylum chalybeum* root bark (IC50 of 4.2µg/ml) and some quinoline alkaloids isolated from this species have been exhibited strong antiplasmodial activity on chloroquine resistant *Plasmodioum falciparum* strain (Nguta et al., 2010). Syncarpamide and decarine, two compounds isolated from *Z. syncarpum* have showed strong in vitro antiplasmodial activity against D6 (chloroquine sensitive clone) and W2 (chloroquine resistant clone) *P. falciparum*  strains, having IC50 values lower than 6.1 µM (Kaur *et al*., 2009; Ross et al., 2005; Ross et al., 2004). The crude alkaloid extract obtained from the bark of *Z. zanthoxyloides* and fagaronine, a benzophenanthridine alkaloid derived from the root extract of *Z. zanthoxyloides*; inhibited *P. falciparum* growth in vitro at low IC50 (Adebayo & Krettli, 2011; Gansane et al., 2010). Also

have been reported positive results of antimalarial activity for the ethanolic extract from stem bark of *Z. guilletti* (Zirihi et al, 2009) and for the chloroform crude extract from fruits of *Z. limonella* (Charoenying et al., 2008)*.*

Anti-plasmodial activity of stem bark extracts from *Z. usambarense* was performed against *P. knowlesi* and *P. berghei*. The aqueous extract was remarkably active against the two parasites, while all organic solvents extracts being inactive. These results suggest that the antiplasmodial activity of *Z. usambarense* is due mainly to polar substances (Were et al., 2010).

A study of antimalarial properties of *Z. rhoifolium* bark carried out in order to validate its use and confirm the previously detected in vivo activity, lead to the isolation of antimalarial compounds. The antiplasmodial activity of *Z. rhoifolium* bark was concentrated in the alkaloid fractions showed approximately 44% inhibition of *P. falciparum* growth at 10µg/mL, using LDH micromethod. Three of the seven isolated compounds from alkaloidal fraction displayed antiplasmodial activity, ranging from good (nitidine, the most potent compound) to moderate (avicine and fagaridine) (Jullian et al., 2006). In other research of the antiplasmodial activity of *Z. rhoifolium* was determined that the water infusion from bark inhibited more than 50% the *P. falciparum* development with doses higher than 500 mg/kg (Bertani et al, 2005).

Recently, has been reported the trypanocidal effect of ethanolic extracts of leaves, fruits, stem bark and root bark, canthin-6-one alkaloids and some of its analogs obtained from *Z. chiloperone*, using *in vitro* methods and the mouse model of acute or chronic infection to evaluate the trypanocidal activity. These results demonstrate the anti-*Trypanozoma* activity of canthinones. Additionally, considering the low toxicity of canthin-6-one, is possible to propose this natural product as a possible advantageous phytotherapeutic compared to the current chemotherapy of Chagas disease (Ferreira et al., 2011; Ferreira et al., 2007). In a study carried out with the hexane extract from leaves of *Z. naranjillo* seven lignans were isolated and evaluated as trypanocidals. Four of the seven lignans showed trypanocidal activity in an *in vitro* assay, being (-)-methylpluviatolide the most active compound (Bastos et al., 1999).

*Zanthoxylum* Genus as Potential Source of Bioactive Compounds 207

*Z. rhoifolium* permitted to confirm that the essential oil is cytotoxic against tumoral cells (CD50 = 82.3, 90.7 and 113.6 μg/ml for A-549 (human lung carcinoma), HeLa (human cervical carcinoma) and HT-29 (human colon adenocarcinoma) cell lines, respectively), while it did not show cytotoxicity against non-tumoral cells (Vero and mice macrophages). Thus, the essential oil from *Z. rhoifolium* leaves seems to present a possible therapeuthic role

The chloroform-soluble fraction of the crude extract of leaves from *Z. ailanthoides* showed cytotoxic activity against human promyelocytic leukemia (HL-60) and myelomonocytic leukemia (WEHI-3) cells with IC50 values of 73.06 and 42.22 µg/mL, respectively. From this fraction were obtained four pheophorbide derivatives, where three of these compounds showed cytotoxic activities against both leukemia cells with IC50 value in the range of 46.76–

The chemical investigation carried out with roots and fruits of *Z. leprieurii* led to the isolation of four acridone derivatives alkaloids were found to be moderately active against lung carcinoma cells (A549), colorectal adenocarcinoma cells (DLD-1) and normal cells (WS1) with IC50 values ranging from 27 to 77 µM (Kuete et al., 2011; Ngoumfo et al.,

A chemical and citotoxic studies of the root bark of *Z. simulans* led the isolation of two citotoxic pyranoquinoline alkaloids (zanthosimuline and huajiaosimulin). These compounds were evaluated against thirteen cultured human cancer cell lines, where zanthosimuline was active against all cell lines employed, while huajiaosimulin only was active against six of the

Benzophenanthridine alkaloids are secondary metabolites commonly isolated from species of *Zanthoxylum* genus and are characterized by their potent antitumor activity, being fagaronine and nitidine the most active substances (Tillequin, 2007). Hexahydrobenzophenanthridine alkaloids are also of interest for its cytotoxic activity. Currently the alkaloid chelidonin is used in experimental oncology as the main component of Ukrain ®, an anti-cancer medicament

Berberine, an alkaloid isolated from the bark of *Z. monophyllum* showed activity against HT-29 (colorectal cancer), MCF-7 (breast cancer), HEp-2 (larynx cancer) and MKN-45 (gastric cancer) cell lines (Cordero et al., 2004). Nitidine chloride and 6-methoxy-5,6-dihydronitidine, two benzophenanthridine alkaloids isolated from *Z. macrophylla* seeds also have exhibited

*Zanthoxylum* genus has proven to be a very valuable genus to the discovery and utilization of medicinal and agrochemical natural products. The collected information provides a means to understand the latest developments in the biological activity and phytochemistry of the genus. The potential for development of leads from *Zanthoxylum* continues to grow, particularly in the development of new antiparasitary, antitumor and antimicrobial agents. The information summarized here is intended to serve as a reference tool to people in all

antitumor activity against different human cell lines (Kuete et al., 2011).

fields of ethnobothany, pharmacology and natural products chemistry.

due to its selective cytotoxic activity against tumoral cell lines (Da Silva et al., 2007b).

79.43 nM (Chou et al., 2011).

thirteen cell lines (Chen et al., 1994b).

(McManus, et al., 2007).

**6. Conclusions**

2010).

Canthin-6-one alkaloids have exhibited interesting antileishmanial activity. For example, in a study carried out with the alkaloidal extract of *Z. chiloperone* stem bark reported that this extract inhibited the growth of *Leishmania braziliensis*, *L. amazonensis* and *L. donovani* at 100 µg/mL and mentioned that the compounds canthin-6-one and 5-methoxy-canthin-6-one were the two major active constituents (Ferreira et al., 2002). Also has been reported that meglumine antimonate isolated from *Z. chiloperone* showed activity against *L. amazonensis* at dose of 28 mg/kg (Sen & Chatterjee, 2011).

## **5.10 Antiplatelet activity**

The methanolic extract of the stem of *Z*. *beecheyanum* showed strong antiplatelet activity in vitro using the turbidimetric method. In washed rabbit platelets, thrombin (0.1 U/mL), arachidonic acid (AA 100 M), collagen (100 g/mL), and PAF (2 ng/mL) all caused about 90- 95% aggregation.

## **5.11 Antiviral activity**

*Zanthoxylum* species were used in experiments to test their influence on inhibition of multiplication of porcine epidemic diarrhea virus (PEDV). The extracts of *Z. coreanum* root, *Z. planispinum* leaf and stem, *Z. schinifolium* leaf exhibited antiviral activity with the IC50 of 1.0, 6.4, 7.5 and 3.7 μg/mL against PEDV, respectively.

In an anti-HIV screening program, three *Zanthoxylum* species, including the root bark of *Z. ailanthoides*, the root wood of *Z*. *integrifoliolum*, and the stem bark of *Z*. *scandens* showed anti-HIV activity. The anti-HIV principles of *Z*. *ailanthoides* have already been proved to be two alkaloids (decarine and fagarine) and an aromatic amide ((+)-tembamide). Thus, the former two constituents, decarine and fagarine, also isolated of *Z*. *integrifoliolum*, can be considered as the anti-HIV constituents of the root wood of this species.

## **5.12 Citotoxic activity**

Cancer is the leading cause of death worldwide. Finding a cure for this disease is always an important objective for human endeavor. Natural products have long been considered as potential drug candidates for cancer prevention and treatment (Chou et al., 2011). *Zanthoxylum* species are potential sources for find new antitumor agents, because diverse substances obtained from some of this species have showed strong citotoxic activity against different tumor cell lines. Following are some examples of reports about citotoxic activity of some species of *Zanthoxylum* genus.

The anti-tumor properties of the volatile oil from *Z. rhoifolium* leaves and some terpenes (αhumulene, β-caryophyllene, α-pinene and β-pinene) were investigated in vitro and in vivo using the Ehrlich ascites tumor model. Volatile oil and β-caryophyllene exhibited little direct activity against Ehrlich tumor cells in vitro, while α-humulene, α-pinene and β-pinene did not such activity. Additionally, volatile oil exhibits anti-tumor efficacy and significative immunomodulatory action *in vivo*, which may be related to β- caryophyllene associated to the synergism of other natural compounds presented in volatile oil from *Z. rhoifolium* leaves (Da Silva et al., 2007a). Other study about the citotoxic activity of essential oil from leaves of

Canthin-6-one alkaloids have exhibited interesting antileishmanial activity. For example, in a study carried out with the alkaloidal extract of *Z. chiloperone* stem bark reported that this extract inhibited the growth of *Leishmania braziliensis*, *L. amazonensis* and *L. donovani* at 100 µg/mL and mentioned that the compounds canthin-6-one and 5-methoxy-canthin-6-one were the two major active constituents (Ferreira et al., 2002). Also has been reported that meglumine antimonate isolated from *Z. chiloperone* showed activity against *L. amazonensis* at

The methanolic extract of the stem of *Z*. *beecheyanum* showed strong antiplatelet activity in vitro using the turbidimetric method. In washed rabbit platelets, thrombin (0.1 U/mL), arachidonic acid (AA 100 M), collagen (100 g/mL), and PAF (2 ng/mL) all caused about 90-

*Zanthoxylum* species were used in experiments to test their influence on inhibition of multiplication of porcine epidemic diarrhea virus (PEDV). The extracts of *Z. coreanum* root, *Z. planispinum* leaf and stem, *Z. schinifolium* leaf exhibited antiviral activity with the IC50 of