Zanthoxylum Genus as Potential Source of Bioactive Compounds

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).


Introduction
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,

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.

Fruits
Used as carminative, stomachic and as a remedy for toothache.
Mixed with salt for dyspepsia and headache.

All parts of the plant
To treat rheumatic conditions, toothaches, sore throats and burns, and as a tonic for various ailments.
Local and oral routes (macerated or decoction powder, paste, sticks).

Branches and stems
Stomach tonic, to treat snake bites.

Stem bark
Used for treating dyspepsia and some forms of diarrhea.
Oral route (aqueous extract of the leaves) Oral route (bark juice).Local and oral routes (decoction powder, paste, sticks, juice).

Fruits
Used in treatment of coughs.

Root bark
To treat snakebite, severe coughs and colds and chest pains.
Used for infected wounds.
Used for mouth ulcers, sore throats and as aphrodisiac.
Tonic both for man and animals and to treat toothache.
Local and oral routes (macerated or decoction).
Local and oral routes (macerated or decoction).

Leaves and roots
For malaria, in vaginal washes and to relieve toothache.

Leaves, fruits and seeds
Used as sedative and sudorific.

All parts of the plant
Commonly used as a spice in Japan.
Used to heal vomiting, diarrhea, and abdominal pain.

Seeds
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.
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, paste).

Leaves and ripe pericarp
Used as culinary applications and drugs for epigastric pain.

Wood
Used for treat tumors, swellings, inflammation and gonorrhea.

Used as a toothbrush
House and boatbuilding, joinery, decorative paneling and in the paper and pulp industry.
Cleaning the teeth.Used against cough, fever, colds, toothache and snake bite.
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.
Oral route (crushed seeds) Local and oral routes (infusion material, paste).
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).Kassim et al., 2009Ngassoum et al., 2003Ngane et al., 2000 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).

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).

Lignans
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).

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).

Amides
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 thesanshool 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).

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).

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

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Zanthoxylum Genus as Potential Source of Bioactive Compounds 201

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.

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 . ) B e a u v .) .A t 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).

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 www.intechopen.com Bioactive Compounds in Phytomedicine 202 purified alkaloids of the root bark of Z. xanthoxyloides have anti-prostaglandin synthetase activity (Prempeh & Mensah-Attipoe, 2008).

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).

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).

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).

Antimicrobial 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 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 Grampositive 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 Grampositive 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 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).

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).

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 IC 50 values of 16 and 18 µM, respectively (Yamazaki et al., 2007).

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.
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.
Zanthoxylum chalybeum root bark (IC 50 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 IC 50 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 IC 50 (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).
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).

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 IC 50 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.

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 (humulene, -caryophyllene, -pinene and -pinene) were investigated in vitro and in vivo using the Ehrlich ascites tumor model.Volatile oil and -caryophyllene exhibited little direct activity against Ehrlich tumor cells in vitro, while -humulene, -pinene and -pinene did not such activity.Additionally, volatile oil exhibits anti-tumor efficacy and significative immunomodulatory action in vivo, which may be related to -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

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Z. rhoifolium permitted to confirm that the essential oil is cytotoxic against tumoral cells (CD 50 = 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 due to its selective cytotoxic activity against tumoral cell lines (Da Silva et al., 2007b).
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 IC 50 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 IC 50 value in the range of 46.76-79.43nM (Chou et al., 2011).
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., 2010).
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 thirteen cell lines (Chen et al., 1994b).
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 (McManus, et al., 2007).

Conclusions
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 fields of ethnobothany, pharmacology and natural products chemistry.