Current state of knowledge on the traditional uses, phytochemistry, and pharmacology of the genus Hymenaea

Author’s Accepted Manuscript Current state of knowledge on the traditional uses, phytochemistry, and pharmacology of the genus Hymenaea Pone Kamdem Boniface, Sabrina Baptista Ferreira, Carlos Roland Kaiser www.elsevier.com/locate/jep

PII: DOI: Reference:

S0378-8741(16)31737-8 http://dx.doi.org/10.1016/j.jep.2017.05.024 JEP10865

To appear in: Journal of Ethnopharmacology Received date: 5 November 2016 Revised date: 4 April 2017 Accepted date: 16 May 2017 Cite this article as: Pone Kamdem Boniface, Sabrina Baptista Ferreira and Carlos Roland Kaiser, Current state of knowledge on the traditional uses, phytochemistry, and pharmacology of the genus Hymenaea, Journal of Ethnopharmacology, http://dx.doi.org/10.1016/j.jep.2017.05.024 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Current state of knowledge on the traditional uses, phytochemistry, and pharmacology of the genus Hymenaea Pone Kamdem Boniface*, Sabrina Baptista Ferreira and Carlos Roland Kaiser Department of Organic Chemistry, Institute of Chemistry, University of Rio de Janeiro, Avenida Athos da Silveira Ramos, Rio de Janeiro (RJ) 21949-900, Brazil. [email protected] [email protected] *

Corresponding author. Telephone: +55 2562-7001/2562-7002/98204-4129. Fax: +55 2562-

7106

Abstract Ethnopharmacological relevance: Plants of the genus Hymenaea (Fabaceae) are used in South American and Asian traditional medicines to treat a multitude of disorders, like cough, diarrhea, dysentery, intestinal colic, pulmonary weakness, asthma, anemia, sore throat, and for the treatment of kidney problems, viral related disorders, chronic cystitis, bronchitis, and bladder infections. Some Hymenaea species are also used as vermifuge, and for the treatment of arthritis, and inflammation conditions. This review deals with updated information on the traditional uses, phytochemistry and pharmacolgy of ethnomedicinally important Hymenaea species in order to provide an input for the future research prospects. Methods: Literature available in various recognized databases including Google Scholar, PubMed, SciFinder, Scopus, Springer, Wiley, ACS, Scielo and Web of Science, as well as from theses, dissertations, books, reports, and other relevant websites (www.theplantlist.org), are surveyed, analysed, and included in this review. Herein, the literature related to chemical constituents and pharmacological activities were searched in November 2016. Results: The literature provided information on ethnopharmacological uses of the South American and African species of the genus Hymenaea [e.g., H. courbaril, H. stigonocarpa, H. onblogifolia, H. martiana, H. parvifolia (South America) and H. verrucosa (African species)] for the treatment of multi-factorial diseases. From these plant species, more than 130 compounds,

including fatty acids, flavonoids, terpenoids and steroids, phthalides, phenolic acids, procyanidins and coumarins were identified. Experimental evidences confirmed that the Hymenaea spp. could be used in treating inflammatory disorders, asthma, diarrhea, and some microbial infections. However, reports on the toxicity of Hymenaea species remain scarce. Conclusion: Plants of this genus have offered bioactive samples, both from crude extracts and pure compounds, thus substantiating their effectiveness in traditional medicine. However, intensive investigations of all the species of Hymenaea spp. relating to phytochemical and pharmacological properties, especially their mechanism of action, safety and efficacy could be the future introspection. Graphical abstract Abbreviations: CNS: Central nervous system; DI: Diameter of inhibition; DPPH: 2,2-Diphenyl-1picrylhydrazyl; EC50: Half maximal effective concentration; HPLC: High-performance liquid chromatography; IC50: Half maximal inhibitory concentration; MIC: Minimum inhibitory

concentration;

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-

diphenyltetrazoliumbromide; NS: Not specified; ORACFL: Oxygen radical absorbance capacity;

TCID50: 50%

tissue

culture

infectious

dose

per

millilitre;

TNBS:

Trinitrobenzesulfonic acid. Keywords: Hymenaea spp.; Ethnomedicine; Phytochemistry; Pharmacology; Toxicology; Pharmacopeia. Chemical compounds cited in this article: δ-Amorphene (PubChem CID: 12306059); Arachidic acid (PubChem CID: 10467); Aromadendrene (PubChem CID: 11095734); allo-Aromadendrene (PubChem CID: 10899740); Astilbin (PubChem CID: 119258); Behenic acid (PubChem CID: 8215); α-transBergamotene (PubChem CID: 86608); Bicyclogermacrene (PubChem CID: 5315347); (-)(1'S,2S)-α-Bisabolol (PubChem CID: 1549992); β-Bourbonene (PubChem CID: 62566); αCadinene (PubChem CID: 12306048); δ-Cadinene (PubChem CID: 441005); γ-Cadinene (PubChem CID: 92313); trans-Cadina-1,4-diene (PubChem CID: 6430869); α-Calacorene (PubChem CID: 12302243); trans-Calamenene (PubChem CID: 6429022); Calarene

(PubChem CID: 15560278); Campesterol (PubChem CID: 173183); Camphoric acid (PubChem CID: 219463); Caprylic acid (PubChem CID: 379); (Z)-Caryophyllene (PubChem CID: 5322111); (-)-(E)-Caryophyllene (PubChem CID: 5354499); (-)-(E)- Caryophyllene oxide (PubChem CID: 1742210);

α-Copaene (PubChem CID: 92042749); β-Copaene

(PubChem CID: 21722369); Copalic acid (PubChem CID: 11162521); α-Cubebene (PubChem CID 86609); 1-epi-Cubenol (PubChem CID: 519857); Cyclosativene (PubChem CID: 16212927); Cyperene (PubChem CID: 12308843); (Z)-9-Eicosenoic acid (PubChem CID: 5312523); β-Elemene (PubChem CID: 6918391); δ-Elemene (PubChem CID: 89316); Engelitin (PubChem CID: 6453452); Eperuic acid (PubChem CID: 12309485); (-)Epicatechin (PubChem CID: 72276); Erucic acid (PubChem CID: 5281116); Eucryfin (PubChem CID: 5488575); (Z)-β-Farnesene (PubChem CID: 5281517); Fisetin (PubChem CID: 5281614); Fisetinediol (PubChem CID: 442397); Fustin (PubChem CID: 5317435); Germacrene B (PubChem CID: 9281519); Germacrene D (PubChem CID: 5317570); Globulol (PubChem CID: 12304985); Guamaic acid (PubChem CID: 101297672); αHimachalene (PubChem CID: 11830551); α-Humulene (PubChem CID: 5281520); βHumulene (PubChem CID: 5318102); Humulene epoxide II (PubChem CID: 10704181); 4Hydroxybenzoic acid (PubChem CID: 135); Ipomopsin (PubChem CID: 5491777); Isoozic acid (PubChem CID: 100983062); (-)-Kolavenic acid (PubChem CID: 6441458); Lauric acid (PubChem CID: 3893); Levomenol (PubChem CID: 442343); Linoleic acid (PubChem CID: 5820450); Linolenic acid (PubChem CID: 5280934); Margaric acid (PubChem CID: 10465); 7-Methoxy catechin (PubChem CID: 44257125); (-)-Methyl (-)-copalate (PubChem CID: 13858180); Methyl (-)-kolavenate (PubChem CID: 13918497); cis-Muurola-3,5-diene (PubChem CID: 6429206); α-Muurolene (PubChem CID: 12306047); γ-Muurolene (PubChem CID: 12313020); trans-Muurolol (PubChem CID: 3084331); Mustakone (PubChem CID: 102316377); Myristic acid (PubChem CID: 11005); Neoastilbin (PubChem CID: 442437); (E)-9-Octadecenoic acid (PubChem CID: 5282767); Oleic acid (PubChem CID: 445639); (-)-Ozic acid (PubChem CID: 12303813); Palmitic acid (PubChem CID: 985); Palmitoleic acid (PubChem CID: 445638); Pentadecanoic acid (PubChem CID: 13849); Quercetin (PubChem CID: 5280343); Quesnoin (PubChem CID: 101837763); Selina4(14),7-diene (PubChem CID: 524199); α-Selinene (PubChem CID: 10856614); β-Selinene (PubChem

CID: 442393); Selin-11-en-4-α-ol

(PubChem

CID:

15560330);

7-epi-

Sesquithujene (PubChem CID: 56927990); γ-Sitosterol (PubChem CID: 457801); Spathulenol (PubChem CID: 92231); Stearic acid (PubChem CID: 5281); Stigmasterol

(PubChem CID: 5280794); Taxifolin (PubChem CID: 439533); α-Ylangene (PubChem CID: 442409); Zanzibaric acid (PubChem CID: 101289556).

1. Introduction For centuries, plants have been widely used as food and for medicinal purposes in several cultures (Street and Prinsloo, 2013). In the last few years, interest in medicinal plants has increased worldwide (Ekor, 2014). Because of the immense diversity of flora around the world and because of cultural factors, the use of medicinal plants in the form of crude extracts, infusions, or plasters has experienced a revival as a common approach for the treatment of several diseases (Samuelsson, 2004; Samuelsson and Bohlin, 2004; Marques and Farah, 2009). The Hymenaea genus belongs to the family Fabaceae, subfamily Caesalpinoideae, and is considered a neotropical genus with approximately 16 species distributed from central Mexico through Central America and the West Indies to all South American countries, except Uruguay and Chile (Langenheim and Lee, 1974; Souza et al., 2014a). Indeed, all species but one are native to the tropics of the Americas, largely in Brazil, especially in the Brazilian biome called “cerrado” (savanna-like vegetation) (Minas Gerais, Bahia, Goias, and Tocantins) and the Amazon forest (Lee and Langenheim, 1975; Lorenzi, 1992; Lorenzi, 2000; Silva et al., 1994), with one additional species (Hymenaea verrucosa Gaertn.) on the east coast of Africa. Most species of the genus Hymenaea are large trees that are primarily evergreen, and different parts of these species have been used by indigenous peoples to treat various ailments, including diarrhea, dysentery, intestinal colic, pulmonary weakness, asthma, anemia, sore throat, kidney problems, and viral disorders (Panizza, 1997; Lorenzi and Matos, 2002a, 2002b; Cecílio et al., 2012; Bezerra et al., 2013). According to Walter et al. (2011), Hymenaea spp. are also used to treat chronic cystitis, bronchitis, and bladder infections and as a vermifuge. The traditional use of Hymenaea spp. in the treatment of arthritis and inflammation conditions has also been reported (Vale et al., 2013). The bark and sap of some species (Hymenaea courbaril L. and Hymenaea intermedia Ducke) are taken orally as tea or syrup for the treatment of lung problems, cough, and tuberculosis (Oliveira et al., 2011; Leitão et al., 2013). H. courbaril is a plant species mostly sold in northeast Brazil for medicinal purposes. The public market sellers mostly sell the bark, leaves, seeds, and roots of this plant for therapeutic use (Souza et al., 2014b; de Carvalho et al., 2015). Plants from the genus

Hymenaea have shown a great versatility with regard to their medicinal use, as indicated by the sellers from open-air markets of the State of Rio de Janeiro, Brazil (Leitão et al., 2013). With the increasing interest in pharmacologically active phytochemicals from Hymenaea spp., a number of studies related to phytochemical and pharmacological aspects of this genus have been conducted. In recent decades, phytochemical studies were conducted on H. courbaril, Hymenaea stigonocarpa Hayne, Hymenaea martiana Hayne, Hymenaea parvifolia Huber and Hymenaea verrucosa Gaertn. and have discovered the presence of terpenoids (Monteiro et al., 2015; Bandeira et al., 2015), fatty acids (Omaira et al., 2011), flavonoids (Bezerra et al., 2013; Da Costa et al., 2014; Monteiro, 2014), phenolics (Monteiro, 2014), coumarins (Fernandes et al., 2015), procyanidins (Sasaki et al., 2009) and polymers (Busato et al., 2005) in these plant species. From the available literature, two species, namely H. courbaril and H. stigonocarpa, have been the most investigated, although Hymenaea oblongifolia Huber, H. parvifolia, H. martiana, H. intermedia, and H. verrucosa have also been studied. Indeed, most of the traditional uses of Hymenaea spp. have been substantiated by modern pharmacological studies. The literature revealed that Hymenaea spp. contain various biological activities, including antibacterial (de Souza et al., 2010; Garcia et al., 2011; Dimech et al., 2013), antidiarrheal (Orsi et al., 2014), antifungal (Da Costa et al., 2014), antiinflammatory (Takagi et al., 2002), antileishmanial (Ribeiro et al., 2014), antinociceptive (Silva, 2011), antioxidant (Imai et al., 2008; Aguiar et al., 2010; Silva et al., 2012a; Maranhão et al., 2013), antiplasmodial (Köhler et al., 2002), antiproliferative (Lacerda et al., 2014; Monteiro, 2014), antiulcer (Orsi et al., 2012), antiviral (Cecílio et al., 2012), hepatoprotective (Closa et al., 1997), larvicidal (Aguiar et al., 2010; Valente et al., 2014) and myorelaxant (Bezerra et al., 2013) activities. In this review, the traditional uses, chemical constituents, pharmacological activities, and toxicology of the Hymenaea genus are highlighted. Critical evaluation of pharmacological studies in terms of their relation to ethnomedicinal use is also described.

2. Methodology 2.1. Literature search Scientific publications from the following electronic databases were searched up to November 2016: SciFinder, PubMed (National Library of Medicine), Science Direct, Wiley,

ACS, SciELO, Google Scholar, Springer, Scopus, and Web of Science. The search terms used for this systematic review included Hymenaea, H. courbaril, H. stigonocarpa, H. martiana, H. parvifolia, H. oblongifolia, H. verrucosa, toxicity, pharmacology, traditional uses, toxicity, and phytochemistry. “The Plant List” (www.theplantlist.org) was used to validate the scientific names of the Hymenaea spp. Moreover, dissertations, theses, books, and reports from classic literature; articles published in peer-reviewed journals; and unpublished materials related to Hymenaea spp. were also examined and searched. Reference lists of all the included reviews and other archives of the publications were hand searched for further relevant articles. No limitations were set for languages. 2.2. Data extraction and synthesis Potentially eligible reviews were assessed in full text, irrespective of the database. Study selection and data extraction were conducted by one author (PKB) and confirmed by the others (SBF and CRK). The extracted data were summarized in tables, and a narrative synthesis was used to provide a summary of the results. Graphical expression was used to express the chemical compounds identified from Hymenaea spp. 2.3. Results of the literature search From the database searches, ninety-nine potentially relevant records were identified, from which sixty-four were excluded after screening the titles or abstracts. The full reports of thirty-five articles were acquired: Six in vivo studies (Closa et al.,1997; Köhler et al., 2002; Orsi et al., 2012; Bezerra et al., 2013; Orsi et al., 2014; Martins et al., 2015), eleven ex vivo studies (Ishibashi et al., 1999; Braga et al., 2000a; Braga et al., 2000b; Rosário et al., 2008; de Souza et al., 2010; Cecílio et al., 2012; Dimech et al., 2013; Da Costa et al., 2014; Lacerda et al., 2014; Ribeiro et al., 2014; Valente et al., 2014), two toxicity studies (Vale et al., 2013; Santana et al., 2016), four ethnopharmacological surveys (Cartaxo et al., 2010; Souza et al., 2014a; Souza et al., 2014b; de Carvalho et al., 2015), and twelve phytochemical studies (Lima et al., 1995; Busato et al., 2000; Busato et al., 2001; Nogueira et al., 2001; AbdelKader et al., 2002; Nogueira et al., 2002a; Nogueira et al., 2002b; Busato et al., 2005; Jossang et al., 2008; Sasaki et al., 2009; Aguiar et al., 2010; Monteiro et al., 2015). To gather all the information on the genus Hymenaea, other data were accessed through manual search from books, dissertations, theses, government reports, unpublished materials, and other web machineries including Google and Google Scholar.

3. Ethnobotany of Hymenaea spp. 3.1. Origin and geographic distribution Fabaceae is widely distributed family and currently consists of 730 genera and 19,400 species

divided

into

three

subfamilies,

namely

Faboideae,

Mimosoideae,

and

Caesalpinioideae (Nofel, 2016). The genus Hymenaea belongs to the subfamily Caesalpinioideae. This genus is considered predominant and comprises 16 species that are distributed from Mexico to South and Central America, of which 13 are found in Brazil (Lee and Langenheim, 1975; Lewis, 2005; Kodama and Sartori, 2007) (Table 1). The species of the genus Hymenaea originated from the equatorial forests of Africa and, however, exhibit excellent ecosystem adaptation in South and Central America (Lee and Langenheim, 1975). The African species, H. verrucosa, is restricted to the continent’s eastern coast and the adjacent offshore islands, where it occurs in seasonally dry coastal forests. Lee and Langenheim (1975) assumed that Hymenaea spp. and its amphi-Atlantic distribution resulted from a West African rain forest ancestral stock that supplied, during the early Tertiary era, material through ocean currents to the rain forests of the New World. However, the wide distribution of most of the species from the Hymenaea genus in South and Central America and their quasi-absence in West Africa is controversial. Nonetheless, Hymenaea protera sp.n. which is an extinct species of this genus, grew in a large area, stretching from southern Mexico, through the Antilles and North and South America, to the African continent. The taxonomic DNA studies revealed that H. protera was more closely related to the only remaining Hymenaea spp. in East Africa than the more numerous American species (Willis and McElwain, 2002; Briggs and Crowther, 2003). H. courbaril, H. stigonocarpa, and H. martiana are the most useful species for people living in the northern, northeastern, and southeastern Brazil (Barroso, 1991; Joly, 1998; Judd et al., 2009). These species are widely used by the local population for construction and ornamental purposes, and for curing or ameliorating various diseases (Judd et al., 2009). 3.2. Economic relevance of Hymenaea spp. H. courbaril and H. stigonocarpa are mostly found in two Brazilian biomes (Cerrado and Caatinga), especially in the states of Bahia, Minas Gerais, Piauí, Goiás, Mato Grosso do Sul, and São Paulo (Brazil) where they are considered useful resources (Corrêa, 1984; Lorenzi, 2000; Pinto et al., 2000; Lorenzi and Matos, 2002b). The resin that exudes from the

stems of these plants is used for polishing canoes, and to manufacture varnishes (Embrapa, 2004). Found in numbers of 2-6 or more per fruit, the seeds of these plants produce edible flour of great nutritional value. The flour is used as a substitution of wheat flour to manufacture biscuits, bread, and porridges (Carvalho-Filho et al., 2003; Gorchov et al., 2004). The wood from these plants is decay-resistant and is used for civil constructions and boat building, while their canopy is used for decoration of public and private areas (Corrêa, 1984; Lorenzi, 2000; Alvino et al., 2005). Moreover, H. martiana, which can also be found in the Brazilian savanna-like vegetation, is of great economic importance because of its use in urban forestation and recovery programs in degraded natural areas (Lorenzi and Souza, 2005; Pestana, 2010). Hymenaea plant species are also used in pastures to provide shade and shelter for animals, especially on hot dry days (Reifsynder and Darnhofer, 1987). 3.3. Management, agro-climatic preference, and pests 3.3.1. Tree management H.courbaril seedlings grow at an angle with a drooping leader, a habit that may persist for 2 or 3 years. Open planting sites and good weed control until the seedlings reach about 2 m height is important for obtaining the best planting stock. The rate of growth is steady, and the yields are large, with some trees capable of producing several thousand pods a year (Orwa et al., 2009). The seeds germinate in 20-30 days with 40-90% success. Scarification of the seeds by nicking or soaking for 1 h in concentrated sulfuric acid increases the germination percentage and reduces the germination time (Wang et al., 2012). H. courbaril seeds can be stored for as long as 12 months in dry conditions with little loss of viability. The seeds that are to be stored for more than one year should be refrigerated at 2-4oC in a sealed container. The germination probability of seeds following two years in hermetic air-dry storage at 3-5oC is 29%. There are approximately 270 seeds/kg. H. courbaril may reach a height of 8 m in 5 years and 18.5 m in 16 years (Orwa et al., 2009). 3.3.2. Agro-climatic preference The Hymenaea genus occupies a wide range of habitats. The plants from this genus grow preferably in tropical wet and moist forests. They tolerate poor fertility of the soil, waterlogging and drought, with temperatures typical of the wet lowland tropics. The precipitation may be evenly distributed throughout the year or monsoonal. They grow best on ridges or slopes and high riverbanks (Orwa et al., 2009). 3.3.3. Pests and damage associated with the genus Hymenaea

Hymenaea spp. can be attacked by many pests. Weevils (Rhinocherus sp.) bore through the seedpods and eat the seeds, while other insects such as Hypothenmus buscki, Myelois decolour, and Acanthoscelides spp. feed inside the seedpods. Some leaf-cutter ants (Atta spp.) harvest the young leaves, and an unidentified insect cuts the twigs and branches after depositing its eggs. Nasutitermes costalis, a dampwood termite, eats dead wood, whereas the marine borers (Toredo spp.) attack the timber (Orwa et al., 2009).

4. Ethnopharmacological uses Plants belonging to the genus Hymenaea have been used traditionally for the treatment of multi-factorial diseases in many parts of the world, especially in South America and Africa (Table 2). The literature revealed that the most used species are H. courbaril, H. stigonocarpa, H. martiana, H. oblongifolia, H. parvifolia, and H. verrucosa. 4.1. Traditional uses of H. courbaril H. courbaril has a long history of use by the indigenous tribes of the rainforest and in South American traditional medicine where it is used in several ways. Plant parts such as bark, fruits, resin, leaves, seeds, and stems are involved in different traditional medications. 4.1.1. H. courbaril bark In the mid-1960s, the ethanol (EtOH) bark extract of H. courbaril, popularly called “Vinho de Jatobá”, was widely sold throughout Brazil as an energy tonic, and for the treatment of various diseases. The tea prepared from the bark remains a quite popular drink of lumberjacks working in the forests in Brazil because it is a natural energy tonic and helps them to work for long hours without any sign of fatigue. The tea of the bark is also used as a vermifuge, carminative, laxative, sedative, pectoral astringent, and to clean the stomach, whilst the bark oil is used to treat wounds (Lee and Langenhein, 1974; Ayensu, 1981; Garcia et al., 2010).

The bark is also recommended for the treatment of hematuria, diarrhea,

dysentery, general fatigue, dyspepsia, constipation, and hemoptysis (Bontempo, 2000). This plant part is macerated in hot water and taken orally as an anodyne, antiseptic, and purgative, and for the treatment of diarrhea, cystitis, laryngitis, hepatitis, prostatitis, tuberculosis, ulcers, and catarrh (Marsaioli et al., 1979). Duke and Wain (1981) indicated that the tea from the bark is used to treat malaria, beriberi, arthritis, asthma, bruises, fractures, sores, spasms, and venereal diseases. The infusion of the bark is taken orally to treat foot skin and nail fungi (Branch and Da Silva, 1983; Gupta, 1990; Schwontkowsi, 1996). In the United States, this plant part is used to make natural energy tonic, as a decongestant, and as a douche for yeast

infections, and for the treatment of hemorrhages, bursitis, bladder infections, arthritis, asthma, laryngitis, bronchitis, cystitis, prostatitis, and fungal infections (Duke et al., 2009). The Karaja Indians in Peru and the Creole people in Guyana macerate the bark to treat diarrhea, cystitis, hepatitis, prostatitis and coughs (Rutter, 1990; Vasquez, 1990). According to Ka'apor ethnobotany, it is taken orally to stop excessive menstrual discharge. It is applied to wounded or sore eyes, and is also used to expel intestinal worms and parasites (Duke et al., 2009). In Colombia, the aqueous bark extract is used for the treatment of high blood pressure (Leslie, 2002). Moreover, the bark decoction is taken orally by the indigenous peoples from Guatemala as a vermifuge, and for the treatment of rheumatism and mouth ulcers, while the same preparation is used in Venezuela and Suriname for the treatment of chest ailments, diarrhea and dysentery (Gupta et al., 1979; Cáceres et al., 1987; Duke et al., 2009; Mans et al., 2016). Haitians regularly use the bark decoction or infusion as a laxative or purgative, whereas Hondurans use the same preparation as a substitute for quinine to treat malaria (Timyan, 1996; Leslie, 2002). The tea of the bark is taken by Panamanians to relieve rheumatic pain, diabetes, gastrosis, oral ulcers, and hypoglycemia (Duke et al., 2009) (Table 2). 4.1.2. Resin In the Amazon, H. courbaril resin is dug up from the base of the tree and burned as incense, used as glaze for pottery, and used to manufacture varnishes. Indians who live in this area have long been using the resin in magic rituals, love potions, and wedding ceremonies (Gupta et al., 1979). It is also indicated for all types of upper respiratory and cardiopulmonary problems, in addition to debilitation (Marsaioli et al., 1979; Bontempo, 2000). According to Timyan (1996), Haitians apply powdered resin to arthritis, bruises, cramps, myalgia, rheumatism, sores and wounds. Mexicans inhale fumes of burning resin for asthma and hysteria treatment (Leslie, 2002). Smoke from the resin is similarly used for headaches and rheumatism (Lee and Langenhein, 1974). 4.1.3. Fruits, pulp, and seeds The dusty pulp around the seeds is edible and is often consumed by children, despite having an odor that may be considered offensive (Marrero, 1949; Liogier, 1978; ChavelasPolito and González-Vicente, 1985; Marcello et al., 2010). Irrespective of whether it is raw, roasted, or fermented, the pulp is used to prepare refreshments (Hueck, 1961; Lee and Langenhein, 1974; Chavelas-Polito and González-Vicente, 1985). The seed pulp is used as a laxative, whereas the fruit pulp is used as an antidiarrheal agent (Araiyo, 1930; Cruz, 1965;

Lee and Langenhein, 1974; Mors et al., 2000). Seedless pods are ground, and used to feed cattle and goats (Susano-Hernandez, 1981). Similarly, the fruits and seeds are used for the treatment of lung, kidney, prostate, and stomach problems (Cartaxo et al., 2010). In Panama’s traditional medicine, the fruit is used to treat mouth ulcers (Gupta et al., 1979). 4.1.4. Leaves and sap According to Leslie (2002), the leaf decoction is used to alleviate diarrhea and stomach ache. The leaf infusion is used for the treatment of bronchitis, especially in children (Di Stasi et al., 2002). In Venezuela and Suriname, the leaves are used to treat fractures, wounds, and lung problems, and in Panama, they are used to treat diabetes (Gupta et al., 1979; Duke et al., 2009; Mans et al., 2016). When mixed with bee honey, the sap is used to treat heart ailments. The sap is also used to treat blennorrhagia, cough, wounds, chronic cystitis and prostatitis (Van den berg, 1984; Gupta, 1990).

4.1.5. Stems and whole plant Haitians use the whole plant to treat asthma, catarrh, constipation, diarrhea, emphysema, enterosis, headache, respirosis and spasms (Timyan, 1996). In China, the whole plant is used as a decongestant and energizer, and to treat cystitis and bladder and prostate infections (Gainesville, 1993). Brazil’s forest community use the stem as decoction, infusion, tincture, and juice and by soaking or licking for the treatment of anemia, prostatitis, kidney, lung and stomach problems, influenza, cancer (leukemia), lice, throat inflammation, and herpes labialis and as an anticoagulant and expectorant (Cartaxo et al., 2010). 4.2. Traditional uses of H. stigonocarpa There are popular and pharmacological reports on the medicinal relevance of H. stigonocarpa (Jatobá-do-cerrado) in the treatment of stomach disorders (Martins et al., 2015). Moreover, there are several reports on the use of H. stigonocarpa in Brazilian folk medicine for the treatment of various ailments. According to Neto and Morais (2003), the bark infusion is used to treat fevers and the resin is boiled and administered orally to cure respiratory problems. The bark infusion is also taken orally as an anthelmintic, and to relieve stomach, chest, and back aches. Furthermore, the tea prepared from the bark is taken with honey to alleviate cough, bronchitis, phlegm, diarrhea, dysentery, intestinal cramps, asthma

and pulmonary weakness (Panizza, 1997; Carvalho, 2007). Similarly, the decoction of the bark is indicated for the treatment of hemoptysis and hematuria (Bontempo, 2000). Other reports indicate the use of the stem bark and fruit to treat stomach pain, stomach ulcers, diarrhea and inflammatory disorders (Grandi et al., 1989). The fruit pulp is also used as a laxative and the resin is consumed as an aphrodisiac. The leaf infusion is administered orally for the treatment of cystitis (Brandão, 1991). In Brazil, the fruit is mixed with local ethanol (commonly called “cachaça”), and used as a natural energy tonic. When administered orally as tea or syrup, the stem bark is used as a purifier, and for the treatment of cough and wounds (Barros, 1982). 4.3. Traditional uses of H. martiana, H. parvifolia, H. intermadia, and H. oblongifolia H. martiana known as “Jatoba-da-mata” is found in South America, especially in Mexico, Cuba, Paraguay, and Brazil (Goiás cerrado) (Almeida et al., 2012; Cipriano et al., 2014). This plant is of great economic importance, and its wood is commonly called “red wood” (Normative Instruction, 2008). H. martiana is used in popular medicine in the therapies for gastrointestinal, urinary, and respiratory tract infections. It is also used to treat inflammatory disorders (rheumatoid arthritis) and liver problems (Neves et al., 1993, Closa et al., 1997; Gazzaneo et al., 2005). The people of the Caetité-Bahia state (Brazil) use the infusion and decoction of the bark and stem bark of H. martiana to treat respiratory disorders, inflammation, and stomach and chest aches, while the resin is used as a healing agent (Corrêa, 1984; Silva et al., 2012b). H. parvifolia is commonly called “Jutaí do campo” or “Jutaí-mirim”, and its sap is popularly used in Brazil to alleviate weak memory (Rai et al., 2012; Shanley et al., 2002). The stem bark of this plant is also administered orally as a decoction for the treatment of anemia and cough, while the resin is used to treat sinusitis and abdominal spasms. Similarly, the syrup from its epicarp is used as an energy tonic, and for the treatment of anemia (Agra et al., 2007). H. intermadia is popularly known as “Jutaí”. The stem bark, epicarp, and resin of this plant are used in Brazilian ethnomedicine for the treatment of cough, anemia, sinusitis, and abdominal spasms (Agra et al., 2007). H. oblongifolia (commonly called Jatoba, Jatoba farinheira or Burundanga) is mostly found in northern parts of South America, including Bolivia, Brazil, Colombia, Guyana, Peru, Suriname and Venezuela. In these countries, the seed oil is used as a laxative and the trunk bark is used to relieve arthritis or rheumatism. The fruits of H. oblongifolia are used to

prepare beverages or eaten fresh. The trunk resin is also used as a fungicide (Groom, 2012). In Brazil, the epicarp of the fruit is used to treat anemia (Agra et al., 2007) (Table 2). The foregoing information indicates that, various parts of Hymenaea plant species are used for the traditional treatment of multi-factorial diseases. However, the sustainability of the plant parts involved in differents preparations is still questionable. Indeed, trees from the genus Hymenaea are harvested from the wild as a local source of food, medicines, and various commodities. They are exploited commercially for their timber and have also been planted for ornamental purpose all over the tropical world (Barwick, 2004). A survey conducted by Shanley and Luz (2003) revealed that 45% of households from the Eastern Amazonia (Brazil) obtain Hymenaea spp. by direct collection, cultivation, or swapping with friends and neighbors. In this area, the collectors bring their products to the city on trucks, boats, buses, and bicycles, where they sell their wares to wholesalers and retailers. Because of some changes in the forest composition and structure such as ranching (Uhl et al., 1988; Nepstad et al., 1991), selective logging (Martini et al., 1994), and shifting agriculture (Vieira et al., 1996), the members of the aforesaid communities relate that some tree parts such as exudates and barks that have been extracted from the forests are particularly difficult to find. However, these communities strip the bark from trees prior to shipping the logs downriver to the sawmill. The availability of Hymenaea spp. that are harvested for wood has also produced concentrated, albeit short-term, sources of bark (Shanley and Luz, 2003). 5. Chemical constituents of Hymenaea spp. 5.1. Fatty acids The chemical investigation of the seed gums from H. courbaril led to the identification of nine (1-9) saturated and seven (10-16) unsaturated fatty acids (Omaira et al., 2011). Similarly, Matuda and Maria (2005) identified four fatty acids (1, 2, 10, 13) from H. stigonocarpa seeds (Figure 1, Table 3). 5.2. Terpenoids and steroids 5.2.1. Terpenoids 5.2.1.1. H. courbaril Martin et al. (1972) identified ten sesquiterpenes (17-26) from the leaf pocket resin (leaf parenchyma cells lining rounded pockets into which the resin is secreted) (Figure 2) of H. courbaril. Moreover, Khoo and Oehlschlager (1973) reported the isolation of eleven terpenoids from the seed pod resin of H. courbaril. In their study, α-muurolene (28), βbourbonene (29), selina-4(14),7-diene (30), calarene (31), α-humulene (19), α-cadinene (87),

and α-calacorene (33) were elucidated as minor compounds, whereas α-himachalene (27), cyclosativene (32), (Z)-caryophyllene (17) and β-selinene (22) were identified as the major components (Figure 3). In another study, the chemical investigation of the trunk resin from H. courbaril led to the isolation of labd-13-en-8-ol-15-oic acid (34) (Cunningham et al., 1974). Marsaioli et al. (1975) isolated three diterpenes from the bark of this plant. The isolated compounds were characterized as epurua-7,13-dien-15-oic acid (35), labdan-8β-ol15-oic acid (labdanolic acid) (36), and lab-13-en-8β-ol-15-oic acid (37). In addition to these, five other diterpenes (38-40, 43, 48) were isolated from the seed pods of H. courbaril (Nogueira et al., 2001). One year later, Nogueira et al. (2002a) isolated nine terpenoids (41, 42, 44-50) from the bark of this plant. Moreover, Abdel-Kader et al. (2002) isolated three enthalimane diterpenoids (51-53) from the methanol (MeOH) extract of H. courbaril leaves, stems and twigs. Furthermore, Jayaprakasam et al. (2007) isolated and characterized seven terpenoids (34, 36, 54-58) from H. courbaril seeds (Figure 3). Costa et al. (2008) identified three compounds, namely α-humulene (2.3% v/w) (19), (-)-(E)-caryophyllene (60.5%) (59), and caryophyllene oxide (20.7%) (60), from the resin oil of this plant. From the peel of the ripe fruits of H. courbaril, Aguiar et al. (2010) isolated the diterpenes zanzibaric acid (61) and isoozic acid (39), along with the sequiterpene caryolane-1,9β-diol (62). The essential oils from the peel of ripe and unripe fruits of H. courbaril were also investigated by the same authors. From the oil of unripe fruit peel, six terpenoids were identified [21(11.1%), 22 (8.2%), 54 (10.1%), 59 (27.1%), 63 (31.9%), 64 (6.5%)], whereas forty-three terpenoids (19, 21, 22, 24, 33, 39, 54, 59-61, 63, 64, 65-95) were identified from the ripe fruit peel oil (Aguiar et al., 2010) (Table 3, Figure 3). In addition to these, copalic acid (96) and (5S,9S,10R)-ent-labd-8(17)-en-15 ethyl acetate (97) were isolated from H. courbaril resin (Bandeira et al., 2015). 5.2.1.2. H. stigonocarpa Five terpenoids were isolated from the EtOH extracts of H. stigonocarpa flowers (98) and leaves (37, 57, 99, 100) (Monteiro, 2014; Monteiro et al., 2015). In another study, Andreao (2010) isolated and characterized three terpenoids [kaur-16-en-18-ol (101), kauran16-α-ol (102) and kaur-16-en-3-α-ol (103)] from the fruit pericarp of this plant. Similarly, Domenech-carbo et al. (2009) reported the isolation of nine terpenoids (42, 44, 47, 104-109) from the trunk resin of the same species (Figure 3). 5.2.1.3. H. oblongifolia and H. verrucosa

Cunningham et al. (1973) isolated two compounds from the trunk resin of H. oblongifolia that were elucidated as ent-pinifolic acid (110) and guamaic acid (111). Moreover, quesnoin (112) (pentacyclic ent-diterpene) was isolated from the resin of this plant (Jossang et al., 2008). Martin and Langenheim (1974) isolated a terpenoid, namely ent-8(17),13(16),14-labda trien-18-oic acid (113), from the trunk resin of H. verrucosa (Figure 3). 5.2.2. Steroids Monteiro (2014) isolated a mixture of three steroids, namely γ-sitosterol (114), campesterol (115), and stigmasterol (116), from the leaves of H. stigonocarpa. In another experiment, Carneiro et al. (1993) isolated β-sitosterol-3-O-glycoside (117) from the bark of H. martiana (Figure 3). 5.3. Flavonoids The flavononol rhamnoside, namely astilbin (118) and (-)-epicatechin (119) were reported from H. courbaril leaves (Artavia et al., 1995). Astilbin (118) was isolated from the EtOH extract of H. courbaril stem bark (Bezerra et al., 2013). The fresh xylem sap extracted from a hole through the bark to the heartwood of this plant was chemically investigated by Da Costa et al. (2014). In their study, the insoluble brownish color of the xylem sap was identified as fisetin (120). Further, the filtrate of the fresh xylem sap was fractionated on silica gel to afford four compounds, characterized as fisetinediol (121), taxifolin (122), fustin (123), and 3-O-methyl-2,3-trans-fustin (124) (Figure 4). Four flavonoids, namely hultenin (125), taxifolin (122), 7-methoxycatechin (126) and quercetin (127), were isolated from the ethyl acetate (EtOAc) extract of H. stigonocarpa heartwood (Maranhão et al., 2013). Another flavonoid called 4’,5,7-trihydroxy-3’,5’dimethoxyflavone (128) was also isolated from the flowers of the same species (Monteiro, 2014). In another study, Carneiro et al. (1993) isolated three flavonoids, eucryphin (129), engelitin (130) and astilbin (118), from H. martiana bark (Figure 4, Table 3). Moreover, two dihydroflavonol rhamnosides (118, 131) were identified from the bark of H. parvifolia (Ishibashi et al., 1999). 5.4. Coumarins The phytochemical investigation of the seeds from H. courbaril led to the isolation of two biscoumarins: ipomopsin (132) and hymenain (133) (Simões et al., 2009). In addition to

these, Fernandes et al. (2015) isolated two biscoumarins (134, 135) from the EtOAc extract of the same plant part (Figure 5, Table 3). 5.5. Procyanidin Procyanidin 4-(benzylthio)-epicatechin (136) (Figure 5) was isolated from the EtOAc extract of H. courbaril bark (Sasaki et al., 2009). 5.6. Polymers A cellulose-type (1→4)-linked β-D-glucan backbone partially substituted with side chains of α-D-xylopyranose at O-6 was isolated from the seeds of H. courbaril (Lima et al., 1995). Similarly, Busato et al. (2000) isolated the acidic xylan hemicellulose A from the leaves of this plant through methylation analysis and periodate oxidation. Moreover, a fucosylated xyloglucan was isolated from the leaves of H. courbaril by alkaline extraction, followed by EtOH precipitation and ion-exchange chromatography (Busato et al., 2001). Four years later, a fucogalactoxyloglucan was also isolated from the same plant part (Busato et al., 2005). 5.7. Phenolic acids The phenolic acid 4-hydroxybenzoic acid (137) was isolated from the leaves of H. stigonocarpa (Monteiro, 2014). 5.8. Phthalide De Alvarenga et al. (1978) performed chemical investigation of the trunk wood of H. oblongifolia; 6-formyl-7-hydroxy-5-methoxy-4-methylphthalide (artifact) (138) was obtained and characterized (Figure 5). The literature survey revealed that the Hymenaea genus is mostly rich in terpenoids, steroids, fatty acids, flavonoids, phenolic acids and procyanidins. Nonetheless, most of these compounds have been identified from the leaves, bark, sap, trunk, resin, seeds and fruits of the plants from this genus. Consequently, further studies are suggested to identify the chemical constituents present in the gums of Hymenaea spp. as they are traditionally used for the treatment of external ulcers or rashes (Table 2). In addition, the connection between the activity and a specific compound is unclear. Therefore, more research is required to elucidate the relations between the isolated compounds and the therapeutic applications of Hymenaea spp. in ethnomedicine. 6. Pharmacology 6.1. Pharmacology of H. courbaril -Anti-inflammatory activity

The ethnomedicinal use of H. courbaril in the treatment of inflammatory disorders was evaluated through pharmacological investigations. One such study was performed by Keiji and Kenji (2000) who investigated the anti-inflammatory activity of the MeOH and aqueous acetone (AcOH) (70 % v/v) extracts of the fruit peel of H. courbaril by evaluating their tyrosinase inhibitory effects. H. courbaril extracts exhibited moderate inhibitory activity, with the percentage of inhibition between 2.5% and 87.1%. In another investigation, Keiji et al. (2002) reported the anti-inflammatory effects of 70% AcOH and hydro-ethanolic (HEtOH) (1:1) extracts of the pericarp of the same species. The extracts significantly inhibited carrageenan-induced edema in Wistar rats. The percent reductions in swelling were 36.67% and 50% for HEtOH and AcOH extracts, respectively. Furthermore, Bezerra et al. (2013) evaluated the anti-inflammatory activity of EtOAc extract of H. courbaril stem bark through ovalbumin-induced leukocytosis. Leukocytosis was significantly inhibited upon the pre-treatment of rats with 150 mg/kg EtOAc extract. Eosinophil (80% cell decrease) and neutrophil (67.34 % cell decrease) counts had significantly decreased after treatment with this extract (Table 4). Indigenous peoples from Brazil use the decoction, infusion, or maceration of H. courbaril (leaves, resin, bark) for the treatment of various inflammatory disorders. Hence, it is suggested to study the anti-inflammatory properties of water extract and aqueous formulations as commonly used traditionally. -Antileishmanial activity To evaluate the antileishmanial activity of H. courbaril leaves, Ribeiro et al. (2014) assayed the hexane (Hex) and EtOH extracts of this plant against stationary-phase promastigotes of Leishmania amazonensis. H. courbaril leaves displayed moderate antileishmanial activity with IC50 values of 44.10 and 35.84 μg/ml for Hex and EtOH extracts, respectively. Further investigation of this plant may provide new mechanisms and treatments for leishmaniasis. -Myorelaxant activity Bezerra et al. (2013) investigated the myorelaxant activity of EtOH, Hex, chloroform (CHCl3), dichloromethane (DCM), EtOAc, and MeOH extracts of H. courbaril stem bark on rat tracheal smooth muscle. The contractions of the rat tracheal rings in the presence of carbachol (Cb) and potassium chloride (KCl) were significantly relaxed after treatment with the EtOH extract at a concentration of 1000 µg/ml. Irrespective of the muscle contractive agent (Cb or KCl) used, the DCM, MeOH and mixture Hex-DCM (1:1) extracts exhibited partial relaxing activities, whereas the EtOAc extract fully relaxed the tracheal rings (Table

4). The maximal relaxation induced by astilbin, a flavonoid isolated from the EtOAc extract, reached a value of 49.87% for the contraction induced by 60 mM KCl. These results suggested that extracts and astilbin from H. courbaril stem bark might yield valuable adjunctive therapy for the reduction of muscle tension (Table 4). -Antiplasmodial activity Köhler et al. (2002) assessed the antimalarial activity of the lipophilic fraction and the MeOH extract of H. courbaril stems against two strains of Plasmodium falciparum. The lipophilic fraction (IC50: 11.8 µg/ml) was found to be effective against the tested strains, although cytotoxicity test of the plant extract was not performed. -Larvicidal activity Essential oils from ripe and unripe fruit peels of H. courbaril were tested for their larvicidal activity against Aedes aegypti larvae. H. courbaril exhibited larvicidal effects with LC50 values of 14.8 and 28.4 µg/ml for ripe and unripe fruit oils, respectively (Aguiar et al., 2010). Moreover, the acaricidal activity of the EtOH extract of H. courbaril leaves was evaluated against Rhipicephalus microplus with mean larval mortality of 0.68 % at 10 to 30% concentration (Valente et al., 2014). -Antioxidant activity Two compounds, namely fisetinediol and taxifolin, isolated from the EtOAc extract of H. courbaril heartwood were reported to possess antioxidant activity after evaluating them by 2,2-diphenyl-1-picrylhydrazyl (DPPH) test. The EC50 (amount of oxidant required for 50% consumption of the initial DPPH radical concentration) values were 28 (102) and 48 (158) μg/ml (μM) for fisetinediol and taxifolin, respectively. The activity was comparable to that of α-tocopherol (51 μg/ml or 118 μM) (Imai et al., 2008). The biscoumarins ipomopsin and hymenain (Isolated from germinated seeds of H. courbaril) were evaluated for antioxidant activity by the DPPH method. The EC50 values were 100 and 300 µM for ipomopsin and hymenain, respectively compared with catechin (7 µM) and quercetin (6 µM) (Simões et al., 2009) (Table 5). Contreras-Calderón et al. (2011) evaluated the antioxidant activity of the acidic HEtOH extract of H. courbaril fruits by the ABTS (free radical-scavenging capacity) and FRAP (ferric reducing antioxidant power) methods. The extract showed promising activity with FRAP and ABTS values of 7.60 and 26.7 μmol trolox equivalents per gram of fresh weight of fruits, respectively. Murillo et al. (2012) reported moderate antioxidant activity of the extract of H. courbaril fruits by the DPPH test. The antioxidant activities of

EtOH, EtOAc, and MeOH extracts of the leaves of the same plant species were also described by the DPPH (60 mM) method, with trolox as the positive control (Bezerra et al., 2013) (Table 4). Antioxidant activities of HEtOH (70% v/v) and MeOH extracts (250 µg/ml) of leaves, fruit rind, pulp, and seeds of H. courbaril were evaluated by DPPH, FRAP and ORACFL assays. Except the pulp extracts, all other plant extracts showed effective antioxidant activity. For the DPPH test, gallic acid was used as the positive control, whereas trolox was used for FRAP and ORACFL tests (Figueiredo, 2014) (Table 4). -Antiviral activity The antiviral activity of the EtOH extract of H. courbaril leaves was evaluated against rotavirus. This extract (50 µg/ml) significantly inhibited the cytopathic effect of rotavirus and prevented viral replication at 10 and 20 TCID50 (Cecílio et al., 2012). -Immunomodulatory activity Xyloglycans from the seeds of H. courbaril were assessed for immunomodulatory activity on peritoneal macrophages. After 24 h of intraperitoneal injection, the polysaccharide promoted an increase in the number of peritoneal macrophages in mice treated at 100 and 200 mg/kg. The increase was as high as 576% at 200 mg/kg. Moreover, xyloglycans enhanced nitric oxide (NO) production. At concentrations of 25 and 50 µg/ml, NO production was enhanced from 68% to 92% (Rosário et al., 2008). -Antihypertensive activity The antihypertensive activity of H. courbaril was assessed with the inhibition of angiotensin l-converting enzyme. H. courbaril resin exhibited 10% inhibition of this enzyme (Braga et al., 2000a). -Antiasthmatic activity The inhibitory effect of H. courbaril resin on 5-lipoxygenase (LO) was evaluated to determine the antiasthmatic activity of this plant. The resin of the plant showed 100 % inhibition of 5-LO at a concentration of 19 µg/ml (Braga et al., 2000b) (Table 6). Further investigation is required to determine the specific mechanisms involved in the growth inhibition. -Cytotoxicity The insoluble fraction of H. courbaril xylem sap and its major constituent (fisetin) were evaluated for their cytotoxicity against a mouse cell line (Balb/c 3T3-A31 fibroblast cell line). Fisetin and the fresh xylem sap showed IC50 values of 158 and 109 μg/ml, respectively (Da Costa et al., 2014). In another investigation, the cytotoxicity of the EtOH extract of H.

courbaril leaves was evaluated against rhesus monkey kidney cell line MA-104. The extract was toxic to these cells at 5000 µg/ml, but showed no cytotoxicity at 50 and 500 µg/ml (Cecílio et al., 2012). Furthermore, the cell viability of a xyloglycan isolated from the seeds of H. courbaril was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay at different concentrations (1-500 µg/ml). The xyloglycan did not show any cytotoxic effect as the percent cell viability was as high as 85% at 50 µg/ml (Rosário et al., 2008). Lately, Figueiredo (2014) reported the cytotoxic effects of the HEtOH extract of H. courbaril seeds on murine melanoma B16F10-Nex2 cells (Table 6). -Antimicrobial activity Fernandes et al. (2005) evaluated the antibacterial activity of the HEtOH (70 % v/v) extract of H. courbaril stem against a range of bacterial strains. At a concentration of 2.5 mg/ml, 54.0 % Staphylococcus spp. isolates were inhibited by H. courbaril, whilst 35.0 % Streptococcus mutans isolates were inhibited at 1.25 mg/ml. However, these concentrations of extracts are generally too high to be considered as active antimicrobial substances (Scorzoni et al., 2007). In another experiment, the susceptibility of a wide range of bacterial strains was evaluated using the HEtOH (70%) extract of H. courbaril leaves. The extract was effective against Pseudomonas aeruginosa (DI: 28 mm) and Staphylococcus aureus (DI: 23 mm) (Gonçalves et al., 2005; Gonçalves et al., 2011; Sarah de Jesus and Fabiana, 2012). Similarly, the antibacterial activity of the EtOH extracts of exocarp and farinaceous pulp of H. courbaril were assessed against standard bacteria, including gram-positive and gramnegative clinical isolates at concentrations of 300 and 500 mg/ml. Penicillin and gentamicin (50 µg/ml) were considered as standard antibacterial agents (Martins et al., 2010). According to Scorzoni et al. (2007) report (active extracts: MIC<250 µg/ml), these extracts exhibited weak antibacterial activity against S. aureus, Enterococcus faecalis, and Shigella flexineri (ATCC 12022) as the MIC values ranged from 350 to > 400 µg/ml. The EtOH extract of the bark of H. courbaril trunk was tested for its antibacterial activity against a wide range of pathogens of veterinary interest. The extract showed significant antibacterial activity against the tested bacterial strains with MIC ranging from 62.5 to 208.33 µg/ml (de Sá et al., 2011) (Table 7). The IC50 value (3.33 mg/ml) of the HEtOH extract of H. courbaril leaves was also reported after testing this extract against S. aureus (Garcia et al., 2011; Garcia, 2011). Aleixo et al. (2013) described the antibacterial activity of the HEtOH extract of H. courbaril leaves (MIC: 500 µg/ml) against a clinical strain of methicillin resistant S. aureus. However, the concentrations of the extracts obtained in both the studies were too high and are not generally considered active plant extracts (Scorzoni et al., 2007). In another experiment, the

antibacterial activity of the essential oil from the fruit rind of H. courbaril was evaluated against two oxacillin susceptible S. aureus strains. The extract inhibited the bacterial growth with a MIC value of 0.28% (v/v) extract for both strains (Sales et al., 2014; Sales, 2014). Furthermore, Aleixo et al. (2015) investigated the antibacterial activity of the EtOH, Hex, DCM, EtOAc and HEtOH (70% v/v) extracts of H. courbaril bark against the bacterial pathogens Acinetobacter baumannii, Klebsiella pneumonia, P. aeruginosa, Escherichia coli, S. aureus and E. faecalis. The EtOH, Hex, EtOAc and HEtOH extracts were found to be active against E. faecalis with a MIC value of 125 µg/ml (Table 7). EtOAc (MIC: 125 µg/ml), HEtOH (MIC: 250 µg/ml), and EtOH (MIC: 250 µg/ml) extracts were also active against E. coli. In this study, the synergistic antibacterial activity of EtOH extracts of the bark of H. courbaril and Stryphnodendron adstringens (1:1) was also evaluated. The combination of both extracts exhibited strong antibacterial activity against A. baumannii (31.25 µg/ml), E. coli (31.25 µg/ml), S. Aureus (31.25 µg/ml) and E. faecalis (125 µg/ml). Three protein fractions [precipitated with ammonium sulfate into three saturation ranges: 0-30% (F1), 30-60% (F2), and 60-90% (F3)] obtained from the seeds of H. courbaril were tested against three bacterial strains, namely S. aureus, Vibrio parahaemolyticus, and E. coli, while tetracycline was used as the standard antibacterial agent. Among the fractions tested, only two (F1, F2) were found to significantly inhibit V. parahaemolyticus. The diameters of inhibition were 17 and 14 mm for F1 and F2, respectively, compared to 30 mm by tetracycline (Brito et al., 2016). Da Costa et al. (2014) evaluated the antifungal activity of the insoluble fraction of fresh xylem sap from H. courbaril and its constituents against Cryptococcus neoformans species complex and dermatophytes. The insoluble fraction (MIC: <256 μg/ml) was found to be active, whilst fisetin (MIC: 128 μg/ml) emerged as the most potent among the compounds tested. Hubbell et al. (1983) observed and reported that leaf-cutter ants (Atta cephalotes) do not attack H. courbaril in Costa Rica and discovered that the leaves contain the terpenoid caryophyllene epoxide which inhibits the growth of the fungus cultivated by the leaf-cutter ants. Additional tests determined that this terpenoid has a broad spectrum fungicidal effect. Irrespective of the country of use, H. courbaril (leaves, bark, sap) is administered in the form of decoction, infusion, or maceration in water to traditionally treat various infectious diseases. Consequently, pharmacological studies on aqueous preparations rather than only organic extracts should be conducted in future. Moreover, there would be a problem with the

conservation of decoction, infusion, or maceration used by traditional healers as water-based preparations cannot be conserved like those from ethanol or oil. 6.2. Pharmacology of H. stigonocarpa -Anti-inflammatory activity Orsi et al. (2014) investigated the anti-inflammatory activity of the stem bark (100, 200, and 400 mg/kg) and fruit pulp (10% and 5% in diet) of H. stigonocarpa in TNBS model of intestinal inflammation in rats. Treatment with 100, 200 and 400 mg/kg of the stem bark extract and 10% fruit pulp flour exhibited significant protective effects in TNBS-induced colon damage related to myeloperoxidase and alkaline phosphatase inhibitory activities; in addition, reduction of colon malondialdehyde content and counteraction of colon gluthatione depletion were also observed. Prednisolone (2 mg/kg) and sulphasalazine (25 mg/kg) were used as positive controls, while phosphate buffer saline was used as negative control (Table 6). H. stigonocarpa showed anti-inflammatory effects and could be a potential source for the development of new lead molecules against inflammation. -Antitermitic activity The antitermitic activity of the EtOAc extract of H. stigonocarpa heartwood and its constituents (hultenin, taxifolin, quercetin and 7-methoxycatechin) was evaluated. The results revealed that both the EtOAc extract, and the compounds possessed antitermitic activity. Among the compounds tested, quercetin presented the highest activity, with acetone as negative control (Maranhão et al., 2013). -Antioxidant activity Maranhão et al. (2013) reported the antioxidant activity of the EtOAc extract (IC50: 9.95 µ/ml) of H. stigonocarpa heartwood and its constituents (Quercetin: 30.78 µg/ml; 7methoxycatequin: 54.85 µg/ml; taxifolin: 61.65 µg/ml and hultenin: 78.80 µg/ml) by the DPPH test, while using ascorbic acid (IC50: 7.38 µg/ml) as positive control. The report of Orsi et al. (2014) highlighted the antioxidant (lipid peroxidation assay in rat brain membranes) activity of the stem bark extract (IC50: 5.25 μg/ml) and fruit pulp flour (IC50: 27.34 μg/ml) of H. stigonocarpa. Quercetin (IC50: 0.3 μg/ml) was used as the positive control. -Antimutagenic effects Santana et al. (2016) assessed the mutagenic effect of the HEtOH extract of H. stigonocarpa bark by using Allium cepa meristematic root cells as a test system. The extract potentiated the antiproliferative effect of the cells at all the concentrations (0.5 or 1.0

or 1.5 mg/ml) tested. In combination with paracetamol at 0.008 mg/ml, the plant extract reduced the number of cell aberrations compared to the number of aberrant cells obtained when treated only with paracetamol (0.008 mg/ml).

-Antidiarrheal activity Orsi et al. (2012) investigated the antidiarrheal activity of the MeOH extract of stem bark of H. stigonocarpa and its fruit pulp in diet through castor oil-induced diarrhea in mice. The percentages of inhibition of diarrhea in treated mice were 61%, 50%, and 53 % at 100, 150, and 200 mg/kg, respectively, whereas loperamide, the standard antidiarrheal agent exhibited 88% inhibition. Two years later, the antidiarrheal activity of the stem bark (100, 200, and 400 mg/kg) and fruit pulp (10% and 5% in diet) of H. stigonocarpa was also reported in rats (Orsi et al., 2014) (Table 6). Further investigation of H. stigonocarpa may provide new mechanisms and treatments for diarrhea. Despite the relief obtained from H. stigonocarpa in the traditional treatment of diarrhea, it is difficult to successfully administer the decoction, infusion, or maceration to patients whose purging episodes are accompanied by vomiting (Casburn-Jones and Farthing, 2004). -Antiulcer activity Orsi et al. (2012) depicted the antiulcer activity of the MeOH extract of stem bark of H. stigonocarpa, and its fruit pulp in a rat model. The activity was comparable to that of lansoprazole, the standard antiulcer agent (Table 6). -Antiproliferative activity Lacerda et al. (2014) reported the antiproliferative activity of the aqueous extracts of the rhytidome of H. stigonocarpa on Allium cepa meristematic root cells after 24 and 48 h of exposure. Similarly, the cytotoxic effects of the EtOH extracts of the leaves, flowers, roots and stem of H. stigonocarpa against normal (L-929) and tumor (Sarcoma 180) cell lines were described (Monteiro et al., 2014). The EtOH stem extract exhibited moderate cytotoxic effects, with IC50 value of 20.2 µg/ml. -Cysteine protease inhibition The EtOH extract of and compounds from H. stigonocarpa leaves, flowers, stem, and roots were evaluated for their cysteine inhibitory effects toward three proteases Cat K, Cat L,

and Cat V. The extracts and compounds showed significant inhibitory effects toward cysteine proteases. The percentages of inhibition varied from 79% to 99% (Monteiro, 2014). -Antibacterial activity Dimech et al. (2013) investigated the antibacterial activity of cyclohexane, EtOAc, EtOH, HEtOH and water extracts of H. stigonocarpa bark against S. aureus and E. faecalis strains. The fractions from the HEtOH extract were also individually evaluated for antibacterial activity. The extracts and fractions exhibited promising antibacterial activity, with MIC ranging from 64 to 1024 µg/ml (Table 7). 6.3. Pharmacology of H. martiana The traditional use of H. martiana in the treatment of various disorders such as rheumatoid arthritis, pathogenic infections, and liver problems has been established by some modern pharmacological studies (Neves et al., 1993; Closa et al., 1997; Gazzaneo et al., 2005). -Antinociceptive activity Antinociceptive activity of EtOH, Hex, and EtOAc extracts of the stem bark of H. martiana were evaluated in mice through acetic acid-induced abdominal contortion method. At 100 mg/kg, the extracts showed significant antinociceptive activity with 53.4%, 93.19% and 91.26% for EtOH, Hex, and EtOAc extracts, respectively. The inhibitory activities were compared with those of morphine (100%) and acetyl salicylic acid (87.36 %), which were used as positive controls (Silva et al., 2011). These results suggested that H. martiana could be used to relieve pain. -Hepatoprotective activity The hepatoprotective effect of astilbin, isolated from the crude extract of H. martiana, was evaluated by using tetrachloride-induced liver damage in rats. The positive effects of astilbin on superoxide dismutase, lipoperoxides, and protanoid profiling helped to conclude on its hepatoprotective activity (Closa et al., 1997). -Antioxidant activity Silva et al. (2012a) reported the antioxidant activity of the EtOH extract (IC50: 0.84 µg/ml) of H. martiana trunk bark by the DPPH test. -Agonistic and antagonistic effects Carneiro (1989) investigated the antagonistic effects of the EtOAc extract of H. Martiana bark and its constituents. In isolated rat uterus, the crude extract competitively antagonized the contractions induced by bradykinin, lysyl-bradykinin, and acetylcholine. Responses of the uterus to angiotensin II, prostaglandin F2α, and oxytocin and of the guinea-

pig ileum to bradykinin and acetylcholine were antagonized by the extract. The purified compounds (eucryphin, astilbin, and engelitin; 20-240 µM) promoted slight modifications in the responses of the rat uterus to bradykinin and acetylcholine. These results demonstrated the effects of extract and compounds from H. martiana bark on neurotransmitter-induced contractions in nonvascular smooth muscles of rats (Carneiro, 1989; Carneiro et al., 1993). In another investigation, Calixto et al. (1992) reported the antagonistic effects of the HEtOH extract (50-200 µg/ml) of H. martiana, and its agonist-induced contractions on isolated uterus and ileum of rat and guinea pig, respectively. Treatment of these tissues with the HEtOH extract (50-200 µg/ml) for 20 min caused a concentration-dependent rightward displacement of bradykinin-, lysyl-bradykinin-, and acetylcholine-induced contractions in the rat uterus, which resulted in a discrete but significant reduction of maximal responses to the latter two agonists. The extract also antagonized the contractions in a concentrationdependent manner. Prostaglandin F2α and oxytocin-induced contractions were inhibited at extract concentrations higher than 200 μg/ml. H. martiana (200 μg/ml) caused a marked depression in bradykinin- and acetylcholine-induced maximal responses. -Antimicrobial activity The antimicrobial activities of Hex, ethyl ether, MeOH, butanol, and hydromethanol extracts of H. martiana (trunk and bark) were evaluated against various human pathogenic fungi. Sterile (only medium) and growth (medium and inoculum suspension) controls were used in each experiment. The extracts were active against Trichophyton rubrum, Trichophyton mentagrophytes, Microsporum canis and Cryptococcus neoformans (MIC: from 4 to 512 µg/ml) (de Souza, 2008; de Souza et al., 2010) (Table 7). Da Silva et al. (2014) investigated the antimicrobial activity of the EtOH extract of H. martiana leaves against gram-negative bacilli, including E. coli, Enterobacter sp., Acinetobacter sp. and Klebsiella sp. The extract showed MIC values of 542.5-4167 µg/ml, and might be considered inactive according to Scorzoni et al.’s (2007) criteria (active crude extract: MIC<250 µg/ml). Moreover, the EtOH extract from H. martiana leaves was active against S. aureus 25923, with MIC value of 125.3 μg/ml (De Santana, 2015). Similarly, Peixoto et al. (2015) evaluated the in vivo antistaphylococcal activity of the EtOH extract of H. martiana bark. After 32 days post infection, the extract exhibited significant reduction (93.99%) of S. aureus stock in milk collected from the treated goat (Table 7). A common mechanism or specific mode of action has not been determined and the diversity of extracts makes data interpretation difficult.

6.4. Pharmacology of H. parvifolia -Protease inhibitor effects In a previous study, the inhibitory effect of neoastilbin and astilbin isolated from H. parvifolia bark on casein kinase II (CK-II) activity was determined by standard methods. Both compounds inhibited CK-II activity with IC50 values of 7 and 9 µM for neoastilbin and astilbin, respectively (Ishibashi et al., 1999) (Table 5). In fact, more than a dozen studies focused on the antimicrobial activity of different plant parts (leaves, stem, pulp, trunk, bark, fruits, and seeds) of Hymenaea spp. However, except for a few studies (de Souza et al., 2010; de Sá et al., 2011; Da Costa et al., 2014; Aleixo et al., 2015),

most of these reports indicate antimicrobial activity at in vitro

concentrations >250 µg/ml, which is not practical. The most relevant anti-inflammatory effects of Hymenaea spp. include those against carrageenan-induced edema (Keiji et al., 2002) and ovalbumin-induced leukocytosis (Bezerra et al., 2013) and TNBS model of intestinal inflammation (Orsi et al., 2014) as the responses of the plant extracts were obtained with doses<300 mg/kg. Antileishmanial (Ribeiro et al., 2014; IC50 values: 35.84-44.10 μg/ml), antifungal (Da Costa et al., 2014; Fisetin; MIC: 128 μg/ml) larvicidal (Aguiar et al., 2010; LC50 values: 14.8-28.4 µg/ml), anti-asthmatic (Braga et al., 2000b; inhibitory concentration: 19 µg/ml) and antidiarrheal (Orsi et al., 2012; 61% reduction of diarrhea at 100 mg/kg) studies were also relevant in terms of the effective doses recorded. Although several investigations have focused on the pharmacology of plants from the Hymenaea genus, there are some plant parts such as the gums that have not yet been studied. Indeed, the gum from Hymenaea spp. is used traditionally to treat external ulcers (Table 2). Thus, future studies should be conducted on the pharmacological activity of gums from Hymenaea spp. so as to assess their ethnomedicinal use in the treatment of skin rashes. Above and beyond, there is a need for rigorous pharmacological studies and, more importantly, the mechanism of action for such a widely used species in traditional medicine. 6.5. Correlation of traditional use with bioactivity of crude extracts and isolated compounds The ethnomedicinal use of H. courbaril and H. stigonacarpa has a clear correlation with the biological activities highlighted across the literature (Table 8). Thus, chemical and pharmacological studies of resin, bark, seeds and fruits (parts preferentially used for medicinal preparations) of other plant species of the genus Hymenaea is recommended. Indeed, H. martiana, H. parvifolia, H. oblongifolia, and H. intermedia are used in traditional medicine to relieve wounds, pain, inflammation, arthritis and rheumatism, respiratory disorders, and so on (Table 2), while there are no reports highlighting their pharmacological

use. Except fisetin which is reported to significantly inhibit Cryptococcus neoformans, fisetinediol, taxifolin and ipomopsin (antioxidant activity), the test compounds identified from Hymenaea species were not effective enough to emerge as potential leads for drug development. Among the Hymenaea species studied, only two were biologically tested in accordance with their traditional use. This may be because of the scarcity of laboratory equipments for biological tests or because the plants were studied separately by a chemist, pharmacologist or biologist. Hence, an innovative and interdisciplinary approach combining phytochemistry, biology, and pharmacology should be followed to comprehensively conduct research work on plants from the genus Hymenaea. 7. Toxicological studies 7.1. Toxicological studies of H. courbaril Vale et al. (2013) reported the toxic and genotoxic effects of the sap from H. courbaril trunk. To perform the genotoxicity test, three doses of the sap (5, 10, and 15 ml/kg body weight) were orally administered to groups of five animals for each treatment at the doses 5, 10, and 15 ml/kg body weight. To evaluate the antigenotoxicity, groups of five animals were orally treated with three doses of the sap (5, 10, and 15 ml/kg BW) simultaneously with mitomycin C (4 mg/kg). Mitomycin C and sterile distilled water were used as positive and negative controls, respectively. After the treatment period (24 and 48 h), the mice were euthanized, their femurs were dissected and opened, and the bone marrow cells were gently flushed out with fetal calf serum and centrifuged (300 g, 5 min). The bone marrow cells were smeared on glass slides, air-dried, and fixed with absolute methanol. The smears were stained with Giemsa solution for the detection and scoring of poly- and monochromatic erythrocytes observed under microscope. The frequency of both type of erythrocytes helped in evaluating the genotoxic and antigenotoxic effects. The results indicated that H. courbaril sap was not toxic, clastogenic, aneugenic, mutagenic, and/or recombinogenic at the doses tested. In contrast, the plant sap protected the cells against clastogenic, aneugenic, mutagenic and/or recombinogenic effects of mitomycin C and doxorubicin in mouse bone marrow cells and in Drosophila melanogaster somatic cells, respectively. 7.2. Toxicological studies of H. stigonocarpa The MeOH extracts of the bark (5000 mg/kg) and fruit pulp (10% in diet) of H. stigonocarpa were evaluated for their acute toxicity in rats for 14 days after submitting them to gastric lesions induced by acetic acid. The extracts did not induce any significant change in the biochemical parameters of toxicity such as aspartate aminotransferase, alanine

aminotransferase, gamma glutamyltransferase, creatinine, urea, and glucose (Orsi et al., 2012). Reports on the toxicity of Hymenaea spp. are relatively few. At present, none of the research has reported any side effects of plant extracts from the Hymenaea genus, although their resin might exhibit mild allergic effects when used externally (Duke et al., 2009). Indeed, most of the reports are directed toward the adverse effects of crude extracts of Hymenaea spp. rather than their constituents. In future, the toxicity profile of active constituents of Hymenaea spp. should be investigated. The possible adverse effects following the short- or long-term oral administration of Hymenaea spp. are not yet reported. We therefore recommend that sub-chronic and chronic toxicity studies should be conducted to support the safe use of the plants from this genus. Nonetheless, attention should be paid with regard to the external application of Hymenaea spp.

8. Conclusions Hymenaea plant parts have been consumed in varied quantities and forms by many populations across the world over a long period, and no toxicity has been reported. The major edible part of Hymenaea spp., the seeds, produce edible flour of great nutritional value that is used to manufacture biscuits, bread, and porridges and can be used in the development of food products. Moreover, the modern pharmacological studies mainly focused on six Hymenaea spp. namely H. courbaril, H. stigonocarpa, H. oblongifolia, H. martiana, H. parvifolia, and H. verrucosa. From these species, a total of more than 130 compounds, including fatty acids, terpenoids, flavonoids, phenolic acids, steroids, procyanidins, and coumarins were identified. Except fisetin (antifungal activity), fisetinediol, taxifolin, and ipomopsin (antioxidant activity), the test compounds identified from Hymenaea spp. were not found effective enough to emerge as potential leads for drug development. Nonetheless, other bioactive constituents of Hymenaea spp. need further investigations to evaluate the various pharmacological claims and explore their potential use in the development of drugs. Ongoing research should also make use of available technology to understand the pharmacokinetics and mechanism of action of the identified isolates. In addition to medicinal uses, Hymenaea spp. are endowed with other great economically important properties: they are used for urban forestation, while their wood is used in civil construction and for boat building. Indeed, plants from the Hymenaea genus have been reported to possess diverse pharmacological activities. However, among the Hymenaea spp. studied, only two species (H. courbaril and

H. stigonacarpa) were biologically tested in accordance with their traditional use. Thus, the pharmacological studies of the other species should be carried out in respect of their involvement in traditional medicine. Previous research of the genus Hymenaea has focused mostly on the leaves, stems, bark, seeds and fruits with little or no attention on the other morphological parts, such as resin, trunk and gums. Expansion of research materials would provide more chances for the discovery of new bioactive principles. Additionally, effective polyherbal formulations with Hymenaea-containing extracts as major ingredients can also be successfully developed. Furthermore, there are little reported data focusing on toxicity or adverse effects following the long-term oral administration of Hymenaea spp. Hence, subchronic and chronic oral toxicity studies are desired to support the safe use of Hymenaea spp. in ethnomedicine.

Conflict of interest The authors declare no conflicts of interest. Acknowledgments This work was supported by CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior) foundation under the Grant Number 88881.067994/2014-01 while PKB is availing a postdoctoral fellowship at the Federal University of Rio de Janeiro (Institute of Chemistry)Brazil.

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Vale, C.R., Silva, C.R., Oliveira, C.M., Silva, A.L., Carvalho, S., Chen-Chen, L., 2013. Assessment of toxic, genotoxic, antigenotoxic, and recombinogenic activities of Hymenaea courbaril (Fabaceae) in Drosophila melanogaster and mice. Genet. Mol. Res. 12, 2712-2724. Valente, P.P., Amorim, J.M., Castilho, R.O., Leite, R.C., Ribeiro, M.F., 2014. In vitro acaricidal efficacy of plant extracts from Brazilian flora and isolated substances against Rhipicephalus microplus (Acari: Ixodidae). Parasitol. Res. 113, 417-423. Van den berg, M.A., 1984. Ver-o-peso: The ethnobotany of an Amazonian market. Advances in economic botany, ethnobotany in the neotropics. GT Prance & JA Kallunki (Eds) New York BOTA 149 (1984). Vasquez, M.R., 1990. Useful plants of Amazonian Peru. Second draft. Filed with USDA’S National Agricultural Library. 1990. Walter, da S.C., Agostinho, L.de S., Priscila, B. de S., 2011. Jatobá (Hymenaea courbaril L.): Espécies nativas da Mata Atlântica. Projeto: Prospecção do conhecimento científico de espécies florestais nativas (Convênio de cooperação técnica FAPEMIG / FUNARBE) Polo de excelência em florestas, Universidade Federal de Viçosa, Viçosa-MG. 2 (2011), pp. 21. Vieira, I.C., Nepstad, D., Salomão, R.P., Rosa, N.A., Roma, J.C. 1996. O renascimento da floresta no rastro da agricultura. Ciência Hoje. 20, 38-44. Wang, X.X., Sun, H.J., Liu, Y., Chen, Y.T., Feng, D.L., Li, S., 2012. Effects of treating with concentrated sulphuric acid on the seed germination of ten Hibiscus hamabo provenance families. Ying Yong Sheng Tai Xue Bao. 23, 2968-2974. Willis, K.J., McElwain, J.C., 2002. The evolution of plants. Annals of Botany Company. Oxford: Oxford University Press. pp. 378.

Figure 1: Fatty acids of Hymenaea spp. Figure 2: Cross section of H. courbaril leaves. (A): Pockets of developing leaf in bud, enclosed in stipules; (B): Section of mature leaf showing location of pocket in spongy mesophyll below palisade tissue and (C): Pocket in young leaf. Source: Langenheim et al. (1982). Figure 3: Terpenoids of the Hymenaea genus Figure 4: Flavonoids of Hymenaea spp. from previous studies Figure 5: Coumarins, procyanidins, phenolic acids and phthalides of the genus Hymenaea

Table 1: Species of the genus Hymenaea (Lee and Langenheim, 1975; Frank, 1994; The Plant List, 2013) Hymenaea species (Accepted names) Hymenaea aurea Lee & Langenh. Hymenaea courbaril L.

Hymenaea eriogyne Benth. Hymenaea intermedia Ducke

Hymenaea maranhensis Lee & Langenh. Hymenaea martiana Hayne Hymenaea oblongifolia Hube r

Synonyms

Country

Hymenaea candolleana Kunth; Hymenaea chapadensis Barb.Rodr.; Hymenaea confertifolia Hayne; Hymenaea correana Barb.Rodr. Hymenaea courbaril var. courbaril; Hymenaea courbaril var. obtusifolia Ducke; Hymenaea courbaril var. altissima (Ducke) Lee & Langenh.; Hymenaea courbaril var. stilbocarpa (Hayne ) Lee & Langenh.; Hymenaea davisii Sandwith

Brazil

Hymenaea floribunda Kunth Hymenaea intermedia var. intermedia; Hymenaea intermedia var. adenotricha (Duc ke) Lee & Langenh.; Hymenaea latifolia Hayne NS Hymenaea multiflora Kleinhoonte Hymenaea oblongifolia var. davisii (Sandwit h) Lee & Langenh.; Hymenaea oblongifolia var. oblongifolia; Hymenaea oblongifolia var. palustris (Ducke ) Lee & Langenh.; Hymenaea olfersiana Hayne;

Brazil, Guatemala, Peru, Guyana, Panama, Colombia, Mexico, Haiti, United states, Venezuela, China, Belize, El Salvador, Costa Rica, Suriname, Nicaragua, Honduras, Dominican Republic, Jamaica, Porto Rico, Trinidad and Tobago Brazil Brazil

Brazil Brazil, Argentina, Paraguay Bolivia, Brazil, Colombia, Guyana, Peru, Suriname,

Hymenaea palustris Ducke Hymenaea parvifolia Huber

Hymenaea resinifera Salisb.

Hymenaea reticulata Ducke

Hymenaea retusa Hayne; Hymenaea rotundata Hayne; Hymenaea rubriflora var. rubriflora Hymenaea sellowiana Hayne; Hymenaea splendida Vogel; Hymenaea splendida var. longifolia Benth. Hymenaea stigonocarpa var. pubescens Bent h.; Hymenaea stigonocarpa var. stigonocarpa; Hymenaea stilbocarpa Hayne NS NS Hymenaea venosa Vahl NS

Hymenaea rubriflora Ducke Hymenaea sagittipetala Rizzi ni Hymenaea stigonocarpa Hay ne Hymenaea torrei Leon Hymenaea travassii L.E.Paes Hymenaea velutina Ducke Hymenaea verrucosa Gaertn.

Venezuela, French Guiana Brazil, Bolivia, Colombia, Peru, Venezuela Brazil, Peru Brazil NS Brazil, Paraguay Cuba Bolivia Brazil Ghana, Kenya, Mozambique , Tanzania, India, Java, Sri Lanka, Madagascar Mauritius, Seychelles, Reunion

Table 2: Ethnomedicinal uses of Hymenaea spp. Country Plant part Traditional uses used and route of administration Brazil -The bark is -Lack of appetite macerated in hot water and -Diarrhea taken orally -Haematuria -Debilitation -Astringent, tonic and energizer -Catarrh of respiratory and urinary tract -Cystitis, hepatitis, prostatitis and tuberculosis

Species

Common Reference (s) name

jatobá, jutaí, jutaí-açu, jutaíbravo, jutaígrande, jataípeba, jataí-uba, jataí-uva, jataíba, H. jataúba, courbaril jatioba, jatiuba ou jupati

Lee and Langenhein, 1974; Leslie, 2002; Raul, 1994; Marsaioli et al., 1979; Lorenzi, 2000; Pinto et al., 2000; Lorenzi and Matos, 2002a, 2002b

-Hemoptysis, hematuria, diarrhoea, dysentery, colic, to fortify the system and to improve appetite - Balsamic, vermifuge and hemostatic -Bronchitis and coughs, bladder and prostate problems and as an astringent -The infusion of the bark is taken orally

-Athlete’s foot and foot fungus -Laryngitis, bronchitis -Hemorrhage, bursitis, bladder infections, cystitis, arthritis and prostatitis

Branch and Da Silva, 1983; Gupta, 1990; Schwontkowsi, 1996

Table 2 (Continued) Country Plant part used and route of administration -The decoction of the bark is administered orally

Traditional uses

-Prostatitis -For painful urination and dribbling and for pain in the testicles or prostate

Species

Common name

Reference (s) Lee and Langenhein, 1974; Caribe and Campos, 1997

-For inflammatory problems -Decongestant -Diarrhea and dysentery -The decoction of the bark is also used for bath

Seeds pulp are taken orally The sap is taken orally

-Inflammation conditions -Blennorrrhagia -Sedative and carminative -Dyspepsia -Skin diseases -Asthma and pulmonary problems -Skin diseases -Laxative -Cough -Wound healing -Chronic cystitis, -Urine retention, -Anaemia, -Prostatitis, -Blennorrhagia -Chronic bronchitis.

Mors et al., 2000 Van den berg, 1984; Gupta, 1990

Table 2 (Continued) Country Plant part Traditional uses used and route of administration -Debilitation -The resin is taken orally -Pulmonary affections, coughs, bronchitis and asthma -Hemoptysis -Worms -Lack of appetite, -Acute and chronic cystitis, dysuria, anuria, prostatitis and blennorrhagia,

Species Common Reference name (s) Araiyo, 1930; Marsaioli et al., 1979; Cruz, 1965; Mors et al., 2000; Caribe and Campos, 1997; Raul, 1994

-Tonic -The resin is applied externally

-Bronchitis, laryngitis and dyspepsia - Urethritis

-The leaves are macerated in hot water and administered orally Decoction of the leaves are also taken orally

-Aches and pains -Bronchitis and coughs, -Bladder and prostate problems -As astringent -Diarrhea, dysentery and intestinal colic. -Coughs, bronchitis, catarrh, asthma and pulmonary weakness. -Affections of the urinary system, chronic cystitis and prostatitis.

Leslie, 2002

Leslie, 2002

Table 2 (Continued) Country

China

Colombia

Plant part Traditional uses used and route of administration NS -Decongestant of the urinary tract, -Cystitis, bladder and prostate infections, -Fortifier, energizer, -Respiratory problems. -The bark -Diarrhea and stomach decoction is ache taken orally

-The leaf infusion is administered orally. Guatemala The bark is macerated in hot water and taken orally The fruit is also taken orally: three fruits are eaten daily for ten days Guyana The bark is macerated and administered orally Haiti -The infusion of the bark is taken orally

Mexico Panama

-A liniment made with powdered gum and bark The resin is burned and the fume is inhaled The fruit are taken orally The leaves are macerated in hot water The leaves and

Species

Common name

Reference (s)

NS

Gainesville, 1993

H. courbaril

Algarrobo Leslie, 2002

-High blood pressure

Vermifuge, febrifuge, sudorific and as an antirheumatic

NS

Gupta et al., 1979; Cáceres et al., 1987

-Diarrhea

Locust

- Treatment of intestinal parasites, -Indigestion -Cure urinary infections.

NS

Rutter, 1990; Vasquez, 1990 Timyan, 1996

-Mouth ulcers

-External ulcers or rashes -Asthma and hysteria

NS

Leslie, 2002

-Mouth ulcers

NS

Gupta et al., 1979; Gupta, 1990

-As hypoglycemic agent -Diabetes

the cortex are infused and administered orally The decoction of the leaves is administered orally

- Stomach ailments and diarrhea

Table 2 (Continued) Country

Peru

United states

Plant part Traditional uses used and route of administration The bark -Diarrhea decoction is -Cystitis, hepatitis, taken orally prostatitis and coughs The bark is -As a decongestant, and taken internally for systemic candida in the stomach and intestines. - The bark is also applied topically

Venezuela - The bark is also applied topically

Brazil

-The decoction is taken orally - The decoction of the stem bark is taken orally -The resin is also administered orally

Species

H. courbaril

Common Reference name (s) Azucarhuayo

Rutter, 1990; Vasquez, 1990

NS

Duke et al., 2009

NS

Leslie, 2002

-Hemorrhages, bursitis, bladder infections, arthritis, prostatitis, yeast and fungal infections, cystitis -Skin and nail fungi. -Fracture -Vermifuge and lung related problems -Anemia and tosses

H. jutaí intermedia

Agra et al., 2007

-Sinusitis and abdominal spasms -Tonic against anemia

-Syrup from the epicarp is taken orally -The decoction and infusion of barks and stem barks is taken orally

-Inflammation, stomach and chest aches -Respiratory disorders -Wound healing -Bronchitis

H. martiana

jatobada-mata

Silva et al., 2012b; Marsaioli et al., 1979; Corrêa, 1984

-The resin is locally applied

-Stomach disorder

Table 2 (Continued) Country

Plant part Traditional uses Species used and route of administration Bolivia, -The decoction -Anemia and tosses H. Brazil, of the stem oblongifolia Colombia, bark is taken Guyana, orally -Sinusitis and Peru, abdominal spasms Suriname -The resin is and also Venezuela administered -Tonic against anemia orally

Brazil

-Syrup from the epicarp is taken orally

-Arthritis or rheumatism

-Trunk bark decoction is taken orally

-Laxative

-Seed oil is administered orally -The decoction of the stem bark is taken orally -The resin is also administered orally

Brazil

-Syrup from the epicarp is taken orally -The bark infusion is taken orally

-Anemia and cough -Sinusitis and abdominal spams

H. parvifolia

Common Reference name (s) jatobá

Agra et al., 2007; Groom, 2012.

jutaí do campo, jutaímirim

Agra et al., 2007

-Tonic against anemia

-Fever, stomach pain, chest and back aches, and as an anthelminthic

-The resin is boiled and administered orally

-Respiratory problems

-The decoction

-Hemoptysis and

H. jatobástigonocarpa docerrado, jatobácapão, jatobáda-cascafina, jatobáaçu,

Neto and Morais, 2003; Panizza, 1998; Carvalho , 2007; Bontempo, 2000

of the bark is administered orally -The tea is prepared from the bark and taken in association with honey

hematuria -Cough, bronchitis, phlegm, asthma and pulmonary weakness, diarrhea, dysentery and intestinal cramps.

jatobeiro, jatobádocampo, jataí-depiauí, jatobádevaqueiro and jatobai

Table 3: Chemical constituents of the Hymenaea.genus Phytochemical Serial classification number (1) Fatty acids

Terpenoids and steroids

Constituent name Palmitic acid

Part of plant Seed gums, seeds

Plant species H. courbaril, H. stigonocarpa

(2)

Stearic acid

Seed gums, seeds

H. courbaril, H. stigonocarpa

(3)

Lauric acid

Seed gums H. courbaril

(4)

Behenic acid

Seed gums H. courbaril

(5)

Margaric acid

Seed gums H. courbaril

(6)

Arachidic acid

Seed gums H. courbaril

(7)

Myristic acid

Seed gums H. courbaril

(8)

Seed gums H. courbaril

(9)

Pentadecanoic acid Caprylic acid

(10)

Linoleic acid

Seed gums, seeds

(11) (12)

(E)-9Seed gums H. courbaril Octadecenoic acid Palmitoleic acid Seed gums H. courbaril

(13)

Oleic acid

(14)

Erucic acid

(15)

Linolenic acid

(16)

(Z)-9Eicosenoic acid (Z)Caryophyllene

(17) (18)

(-)-α-Selinene

Seed gums H. courbaril H. courbaril, H. stigonocarpa

Reference (s) Omaira et al., 2011; Matuda and Maria, 2005 Omaira et al., 2011; Matuda and Maria, 2005 Omaira et al., 2011 Omaira et al., 2011 Omaira et al., 2011 Omaira et al., 2011 Omaira et al., 2011 Omaira et al., 2011 Omaira et al., 2011 Omaira et al., 2011; Matuda and Maria, 2005 Omaira et al., 2011

Omaira et al., 2011 Seed H. courbaril, Omaira et al., gums, H. 2011; Matuda seeds stigonocarpa and Maria, 2005 Seed gums H. courbaril Omaira et al., 2011 Seed gums H. courbaril Omaira et al., 2011 Seed gums H. courbaril Omaira et al., 2011 Leaf H. courbaril Martin et al., pocket 1972 resin Leaf H. courbaril Martin et al., pocket 1972

(19)

(±)-αHumulene

(20)

(±)-βHumulene

(21)

α-Copaene

resin Leaf pocket resin, bark resin Leaf pocket resin Leaf pocket resin, fruits

H. courbaril

Martin et al., 1972; Costa et al., 2008

H. courbaril

Martin et al., 1972

H. courbaril

Martin et al., 1972; Aguiar et al., 2010

Table 3 (continued) Phytochemical Serial Constituent classification number name (22) (+)-β-Selinene (23)

(-)-α-Cubebene

(24)

(+)-δ-Cadinene

(25)

β-Copaene

(26)

γ-Muurolene

(27)

(-)-αHimachalene (-)-αMuurolene

(28) (29)

(-)-βBourbonene

(30)

Selina-4(14),7diene

(31)

(+)-Calarene

(32)

Cyclosativene

(33)

(+)-αCalacorene

(34)

Labd-13-en-8ol-15-oic acid

(35)

Eperua-7,13-

Part of plant Leaf pocket resin Leaf pocket resin, fruits Leaf pocket resin Leaf pocket resin Leaf pocket resin Seed pod resin Seed pod resin

Plant species H. courbaril H. courbaril H. courbaril H. courbaril H. courbaril H. courbaril H. courbaril

Reference (s) Martin et al., 1972 Martin et al., 1972, Aguiar et al., 2010 Martin et al., 1972 Martin et al., 1972 Martin et al., 1972

Seed pod resin

Khoo and Oehlschlager, 1973 Martin et al., 1972; Khoo and Oehlschlager, 1973 H. Khoo and courbaril Oehlschlager, 1973

Seed pod resin

H. Khoo and courbaril Oehlschlager, 1973

Seed pod resin Seed pod resin Seed pod resin, fruit

H. courbaril H. courbaril H. courbaril

Trunk resin, bark, fruits Bark

dien-15-oic

Khoo and Oehlschlager, 1973 Khoo and Oehlschlager, 1973 Khoo and Oehlschlager, 1973; Aguiar et al., 2010 H. Cunnigham et al., courbaril 1974; Marsaioli et al., 1975; Jayaprakasam et al., 2007 H. Marsaioli et al., courbaril 1975

acid (36)

Labdan-8-β-ol15-oic acid

(37)

Lab-13-en-8beta-ol-15-oic

H. Marsaioli et al., courbaril 1975; Jayaprakasam et al., 2007 Bark, leaves H. Marsaioli et al., courbaril 1975 Bark, fruits

acid (38)

Ozic acid

Seed pods

H.

Nogueira et al., 2001

Iso-ozic acid

Seed pods, fruits

(-)-Kolavenic acid

Seed pods

(39) (40)

courbaril H. Nogueira et al., courbaril 2001; Aguiar et al., 2010 H. Nogueira et al., 2001 courbaril

Table 3 (continued) Phytochemical Serial Constituent classification number name (41) Methyl (-)(5R,8S,9S,10R)clerod-3-en-15-oate (42) Methyl (-)-copalate

(43) (44)

Part of plant Bark

Plant species Reference (s) Nogueira et al., 2001; Nogueira et al., 2002a H. Nogueira et al., stigonocarpa, 2002a; H. courbaril Domenechcarbo et al., 2009 H. courbaril Nogueira et al., 2001 H. courbaril

Bark, trunk resin

(5R*,8S*,9S*,10R*)- Seed cleroda-3,13E-dien- pods 15-oic acid Bark, Methyl (-)-eperuate trunk resin

H. courbaril, H. stigonocarpa

(45)

Methyl (-)-isoozate

Bark, trunk resin

H. courbaril, H. stigonocarpa

(46)

Methyl (-)-ozate

Bark

H. courbaril

(47)

Methyl (-)kolavenate

Bark,

H. courbaril, t H. r stigonocarpa u n k

Nogueira et al., 2002a; Domenechcarbo et al., 2009 Nogueira et al., 2002a; Domenechcarbo et al., 2009 Nogueira et al., 2002a Nogueira et al., 2002a; Domenechcarbo et al., 2009

r e s i n

(48)

(49)

(50) (51)

Methyl (5S*,8S*,9S*,10R*)clero-3,13-dien-15oate Methyl (5R*,8S*,9S*,10R*)clero-3,13-dien-15oate Methyl (-)zanzibarate (13R)-2-Oxo-13-

Seed pods, bark

H. courbaril

Nogueira et al., 2002a

Bark

H. courbaril

Nogueira et al., 2002a

Bark

H. courbaril

Nogueira et al., 2002a Abdel-Kader et al., 2002

Leaves, H. courbaril stems

14- and twigs ent-halimadien-18hydroxy-1(10), oic acid (52)

(13R)-13-Hydroxy1(10),14-enthalimadien-18-oic

Leaves, H. courbaril stems and twigs

Abdel-Kader et al., 2002

Leaves, H. courbaril stems and twigs

Abdel-Kader et al., 2002

Jayaprakasam et al., 2007 Jayaprakasam et al., 2007 Jayaprakasam et al., 2007

acid (53)

(2S,13R)-2,13Dihydroxy-1(10), 14-ent-halimadien18-oic acid

(54)

(+)-Spathulenol

Seeds

H. courbaril

(55)

Crotomachlin

Seeds

H. courbaril

(56)

Labd-13E-en-8-ol-

Seeds

H. courbaril

Seeds, leaves

H. courbaril

15-oic acid methyl ester (57)

(13E)-Labd-7,13dien-15-oic acid

Jayaprakasam et al., 2007

Table 3 (continued) Phytochemical Serial Constituent name Part of classification number plant (58) Labd-8 (17), 13E- Seeds

Plant species H. courbaril

Reference (s)

Resin

H. courbaril

Costa et al., 2008

Resin

H. courbaril

Costa et al., 2008 Aguiar et al., 2010 Aguiar et al., 2010 Aguiar et al., 2010 Aguiar et al., 2010 Aguiar et al., 2010 Aguiar et al., 2010 Aguiar et al., 2010 Aguiar et al., 2010 Aguiar et al., 2010

dien-15-oic acid (59)

(-)-(E)Caryophyllene

(60)

(-)-Caryophyllene oxide

(61)

Zanzibaric acid

Fruits

H. courbaril

(62)

Caryolane-1,9βdiol Germacrene D

Fruits

H. courbaril

Fruits

H. courbaril

(+)Bicyclogermacrene cis-Muurola-3,5diene (+)-δ-Amorphene

Fruits

H. courbaril

Fruits

H. courbaril

Fruits

H. courbaril

Fruits

H. courbaril

(68)

(+)-7-epiSesquithujene 1-epi-Cubenol

Fruits

H. courbaril

(69)

trans-Cadina-1,4-

Fruits

H. courbaril

Fruits

H. courbaril

Fruits

H. courbaril

(63) (64) (65) (66) (67)

diene (70) (71)

Amorpha-4,7 (11)diene trans-Muurola4(14),5-diene

(72)

Camphoric acid

Fruits

H. courbaril

(73)

Amorpha-4,9-dien-

Fruits

H. courbaril

2-ol (74)

(+)-α-Ylangene

Fruits

H. courbaril

(75)

trans-Cadina-

Fruits

H. courbaril

1(6),4-diene (76)

Germacrene B

Fruits

H. courbaril

(77)

Selin-11-en-4-α-ol

Fruits

H. courbaril

Jayaprakasam et al., 2007

Aguiar et al., 2010 Aguiar et al., 2010 Aguiar et al., 2010 Aguiar et al., 2010 Aguiar et al., 2010 Aguiar et al., 2010 Aguiar et al., 2010 Aguiar et al.,

2010 Aguiar et al., 2010 Aguiar et al., 2010

(78)

trans-Muurolol

Fruits

H. courbaril

(79)

(-)-Humulene

Fruits

H. courbaril

Fruits

H. courbaril

Aguiar et al., 2010 Aguiar et al., 2010 Aguiar et al., 2010 Aguiar et al., 2010

epoxide II (80)

α-transBergamotene

(81)

δ-Elemene

Fruits

H. courbaril

(82)

β-Elemene

Fruits

H. courbaril

(83)

(Z)-β-Farnesene

Fruits

H. courbaril

Table 3 (continued) Phytochemical Serial classification number

Constituent name

Part of plant

Plant species

Reference (s) Aguiar et al., 2010 Aguiar et al., 2010 Aguiar et al., 2010

(84)

α-Cadinene

Fruits

H. courbaril

(85)

(±)-γ-Cadinene

Fruits

H. courbaril

(86)

allo-

Fruits

H. courbaril

Salvial-4(14)-en- Fruits

H. courbaril

Aguiar et al., 2010

Fruits

H. courbaril

Aguiar et al., 2010 Aguiar et al., 2010 Aguiar et al., 2010 Aguiar et al., 2010 Aguiar et al., 2010

Aromadendrene (87)

1-one (88)

transCalamenene

(89)

γ-Muurolene

Fruits

H. courbaril

(90)

β-Copaen-4 α-ol

Fruits

H. courbaril

(91)

Mustakone

Fruits

H. courbaril

(92)

(+)-

Fruits

H. courbaril

Aromadendrene (93)

(-)-Globulol

Fruits

H. courbaril

(94)

(-)-Cyperene

Fruits

H. courbaril

(95)

Levomenol

Fruits

H. courbaril

(96)

(-)-Copalic acid

Resin

H. courbaril

(97)

(5S,9S,10R)-ent-

Resin

H. courbaril

Labd-8(17)-en-

Aguiar et al., 2010 Aguiar et al., 2010 Aguiar et al., 2010 Bandeira et al., 2015 Bandeira et al., 2015

15 ethyl acetate (98)

18-Hydroxy-enthalima-1(10),13E-dien-15-oic

Flowers H. Monteiro, stigonocarpa 2014; Monteiro et al., 2015

acid (99)

ent-Δ13,14Labd-8-β-ol-15oic acid

Leaves

H. Monteiro, stigonocarpa 2014; Monteiro et al., 2015

(100)

Labd-7-en-15-

Leaves

oic acid (101) (102) (103)

Kaur-16-en-18ol (-)-Kauran-16-αol Kaur-16-en-3-αol

Fruit epicarp Fruit epicarp Fruit epicarp

H. Monteiro, stigonocarpa 2014; Monteiro et al., 2015 Andreao, 2010 H. stigonocarpa Andreao, 2010 H. stigonocarpa Andreao, 2010 H. stigonocarpa

Table 3 (continued) Phytochemical Serial Constituent name classification number (104) (-)-(1'S,2S)-αBisabolol (105)

Part of plant Trunk resin Trunk resin

(106)

5 β-9β-H-10αLabd-8(20)-en-15oic acid, 19methoxy-, methyl ester Eperuic acid

(107)

Methyl cativate

Trunk resin

(108)

Labd-8-en-15-oic acid, methyl ester

Trunk resin

(109)

Trunk resin

(110)

Labda-8,13-dien15-oic acid, methyl ester ent-Pinifolic acid

(111)

Guamaic acid

(112)

Quesnoin

(113)

Trunk resin

(114)

ent-8 (17), 13(16), 14-Labda trien-18oic acid γ-Sitosterol

(115)

Campesterol

Leaves

(116)

Stigmasterol

Leaves

(117)

β-Sitosterol-3-O-

Bark

Trunk resin

Trunk resin Trunk resin Resin

Leaves

glycoside Flavonoids

Plant Reference (s) species H. Domenechstigonocarpa carbo et al., 2009 H. Domenechstigonocarpa carbo et al., 2009 H. Domenechstigonocarpa carbo et al., 2009 H. Domenechstigonocarpa carbo et al., 2009 H. Domenechstigonocarpa carbo et al., 2009 H. Domenechstigonocarpa carbo et al., 2009 H. Cunningham et oblongifolia al., 1973 H. Cunningham et oblongifolia al., 1973 H. Jossang et al., oblongifolia 2008 H. verrucosa Martin and Langenheim, 1974 H. Monteiro, 2014 stigonocarpa H. Monteiro, 2014 stigonocarpa H. Monteiro, 2014 stigonocarpa H. martiana Carneiro et al., 1993

(118)

Astilbin

Bark, leaves and stem bark

H. martiana and H. parvifolia, H. courbaril

(119)

(-)-Epicatechin

Leaves

H. courbaril

(120)

Fisetin

Xylem sap

H. courbaril

Carneiro et al., 1993; Ishibashi et al., 1999; Artavia et al., 1995; Bezerra et al., 2013 Artavia et al., 1995 Da Costa et al., 2014

(121)

Fisetinediol

Xylem sap

(122)

Taxifolin

(123)

Fustin

Xylem sap, heartwood Xylem sap

(124)

3-O-Methyl-2,3-

Xylem sap

trans-fustin (125) (126) (127) (128)

Hultenin

Da Costa et al., 2014 H. courbaril, Da Costa et al., H. 2014; Maranhão stigonocarpa et al., 2013 H. courbaril Da Costa et al., 2014 H. courbaril Da Costa et al., 2014 H. courbaril

Heartwood H. stigonocarpa 7-Methoxy catechin Heartwood H. stigonocarpa Quercetin Heartwood H. stigonocarpa 4',5,7-trihydroxyFlowers H. stigonocarpa 3',5'dimethoxyflavone

Maranhão et al., 2013 Maranhão et al., 2013 Maranhão et al., 2013 Monteiro, 2014

Table 3 (continued) Phytochemical Serial classification number

Coumarins

(129)

Eucryphin

Part of plant Bark

(130)

Engelitin

Bark

H. martiana

(131)

Neoastilbin

Bark

H. parvifolia

(132)

Ipomopsin

Seeds

H. courbaril

(133)

Hymenain

Seeds

H. courbaril

(134)

Hymenain 7-O-beta-

Seeds

H. courbaril

Seeds

H. courbaril

Constituent name

Plant species

Reference (s)

H. martiana

Carneiro, 1989; Carneiro et al., 1993 Carneiro, 1989; Carneiro et al., 1993 Ishibashi et al., 1999 Simões et al., 2009 Simões et al., 2009 Fernandes et al., 2015

glucopyranosyl-(1′′′ → 2′′)O-alpha-apiofuranosyl(1′′′′ → 2′′′)-O-alphagalactopyranoside (135)

Hymenain 7-O-betaglucopyranosyl-(1′′′ → 2′′)-

Fernandes et al., 2015

O-alpha-apiofuranoside Procyanidin

(136)

Phenolic acid

(137)

Phthalide

(138)

Sasaki et al., 2009 4-Hydroxybenzoic acid Leaves H. Monteiro, stigonocarpa 2014 Trunk H. De 6-Formyl-7-hydroxy-5wood oblongifolia Alvarenga methoxy-4-methylphthalide et al., 2008 4-(Benzylthio)-epicatechin

Bark

H. courbaril

Table 4: Summary of antileishmanial, antioxidant, myorelaxant, antinociceptive and antiinflammatory effects of extracts from Hymenaea genus. Activity

Extrac ts

Antileishmani al activity

HEXE and EtOHE

EtOHE, DCMF, DEAF, EtOAc F and MeOH F

Test system Promastigot es of Leishmania amazonensi s

DPPH test

Antioxida nt activity

EtOHE and EtOAc E

DPPH test

AHME

ABTS (free radicalscavenging capacity) and FRAP (ferric reducing antioxidant power) methods

MeOH E

DPPH assay

Effects

Stud y

Dosag Specie e s

IC50: 44.10 and 35.84 μg/mlαforα HEXE and EtOHE, respectivel y IC50: 3, 66.3, 34, 5.05, 5.12 and 2.6 µg/ml for EtOHE, DCMF, DEAF, EtOAcF and MeOHF, respectivel y. EC50: 500 µg/ml and 100 µg/ml for EtOHE and EtOAcE, respectivel y. 7.60± 0.35 μmolαTEsα (trolox equivalent s) /g of FW and 26.7± 1.89 μmolα TEs/g of FW for ATBS and FRAP, respectivel y TEAC: 240.74 mg TE/100g

In vitro

1.56200 µg/ml

In vitro

11000 µg/ml

Plant part

H. Leave courbar s il

Stem bark

H. courbar il Seeds

Referen ce (s) Ribeiro et al., 2014

Bezerra et al., 2013

In vitro

NS

Simões et al., 2009

In vitro

0 and 500 µM

Fruits

Contreras Calderón et al., 2011.

In vitro

NS

Fruits

Murillo et al., 2012

MeOH E DPPH assay

HEtOH E

MeOH E

HEtOH E

FW EC50: 392.05, 395.44, 179.43 μg/mlαforα leaf, fruit In and seed vitro extracts, respectivel y

EC50: 415.8, 428.1 and 149.43 μg/mlαforα leaf, fruit and seed extracts, respectivel y 1112.63, 614.31 FRAP and (Antioxidan 2797.9 t power µM reduction of Trolox iron assay) Equivalent (TE)/ g of dried extract from leaves, fruits and seeds, respectivel y

632.64, 1274.42 and 3073.51 µM Trolox Equivalen t (TE)/ g of dried extract from leaves, fruits and

253000 μg/ml

500 µg/ml

Leave s, fruits and seeds

Figueired o, 2014

seeds, respective ly

Table 4 (Continued) Activity

Antioxidan t activity

Extrac Test ts system MeOH E ORACFL (Oxygen Radical Absorba nce Capacity assay) HEtO HE

Myorelaxa nt activity

EtOHE , DCMF , DEAF, EtOAc F and MeOH F

Effects

0.34, 0.16 and 0.12 Trolox Equivalen t for leaf, fruit and seed extracts, respective ly 0.34, 0.128 and 0.25 Trolox Equivalen t for leaf, fruit and seed extracts, respective ly Carbacho Maximum l-induced relaxation contractio values: n on 43.7, 60.5, tracheal 76.6, 95.2 rings and 40.8 from rats. % for EtOHE, DCMF, DEAF, EtOAcF and MeOHF, respective ly KCl52.5, 71.9, induced 79.1, 100 contractio and 35.9 n on % for tracheal EtOHE, rings DCMF, from rats DEAF, EtOAcF and MeOHF, respective

Stud Dosa y ge

Species

In vitro

1.56- H. 25 courbaril μg/ml

In vivo

1000 µg/ml

Plant part

Referen ce (s)

Leave Figueire s, do, 2014 fruits and seeds

H.

Stem

Bezerra

courbaril

bark

et 2013

al.,

Antinociceptiv e activity

Antiinflammat ory activity

Acetic EtOHE acid , induced HEXE abdomin and al EtOAc contracti E on in mice (Percenta ge of inhibitio n)

MeOH E

-Wistar rats (Extensio n of colon lesion) -(Colonic weight length ratio)

ly -At the dose of 100 mg/kg: 53.40, 93.19 and 91.26 % for EtOHE, HEXE and EtOAcE, respective ly. -At the dose of 200 mg/kg: 92.25, 100 and 82.53 % for EtOHE, HEXE and EtOAcE, respective ly. -At the dose of 400 mg/kg: 87.36 % for EtOHE - 2.94, 2.60 and 3.44 cm at 100, 200 and 400 mg/kg, respective ly against the negative control TNBS (5 cm) - 140.84,

In vivo

100, 200 and 400 mg/k g

H. martiana

Stem bark

Silva et al., 2011

In vivo 100, 200 and 400 mg/k g

Stem bark H. stigonoca rpa

Orsi et al., 2014

-Wistar rats (Extensio n of colon lesion) -(Colonic weight length ratio)

143.21 and 134.70 g/cm at 100, 200 and 400 mg/kg, respective ly against the negative control TNBS (159.6 g/cm) - 4.44 and 3.20 cm at 5 and 10 % diet, respective ly against the negative control TNBS (5 cm) - 158.17 and 152.38 g/cm at 5 and 10 % diet, respective ly compared to the negative control TNBS (159.6 g/cm)

In vivo

5 and 10% in Diet

Fruits

Table 4 (Continued) Activity

Extrac Test system ts

MeOH E Antioxid ant activity

-Increase of the colon glutathione (GSH) content -Decrease of the colon myeloperoxi dase (MPO) activity -Alkaline phosphatase

Effects

-1800, 1900 and 1780 nmol/g of tissue at 100, 200 and 400 mg/kg, respectiv ely compare d to the negative control TNBS (1400 nmol/g) - 240, 260 and 420 U/g of tissue at 100, 200 and 400 mg/kg, respectiv ely compare d to the negative control TNBS (480U/g of tissue) - 7.5, 6 and 7 mU/mg of protein at 100, 200 and 400

Stud Dosa y ge

100, 200 and 400 mg/k g In vivo

Species

Pla Referen nt ce (s) part

Ste Orsi et m al., bark 2014 H. stigonoca rpa

MeOH E

-Increase of the colon glutathione (GSH) content -Decrease of the colon myeloperoxi dase (MPO) activity -Alkaline phosphatase

mg/kg, respectiv ely compare d to the negative control TNBS (11mU/ mg of protein) -1600 and 1750 nmol/g of tissue at 5 and 10% in diet, respectiv ely compare d to the negative control TNBS (1400 nmol/g) -300 and 220 U/g of tissue at 5 and 10% in diet, respectiv ely compare d to the negative control TNBS (480U/g of tissue) -12 and 9 mU/mg of protein at 5 and 10% in

5 and 10% in diet

Frui ts

Orsi et al., 2014

diet, respectiv ely compare d to the negative control TNBS (11mU/ mg of protein) AHME: Acidic hydro-methanol extract; DEAF: Dichloromethane-ethyl acetate fraction; DCMF: Dichloromethane fraction; EtOAcF: Ethyl acetate fraction; EtOHE: Ethanol extract; HEtOHE: Hydro-ethanol extract; HEXE: Hexane extract, MeOHF: Methanol fraction; TEAC: Trolox antioxidant capacity.

Table 5: Summary of in vitro antioxidant, myorelaxant and casein kinase inhibitor activities of compounds from Hymenaea genus. Activity

Compoun ds

Antioxidan THMIF t activity

Test system

Effects

Dosag Species e

DPPH test

EC50: 50 µg/ml

0.01, 0.05, 0.1, 0.5, and 1.0 mg/ml 0.01, 0.05, 0.1, 0.5, and H. 1.0 courbar mg/ml il 0.01, 0.05, 0.1, 0.5, and 1.0 mg/ml 0.01, 0.05, 0.1, 0.5, and 1.0 mg/ml NS

THDMIF

DPPH test

EC50: 70 µg/ml

FISEL

DPPH test

EC50: 28 µg/ml

TAX

DPPH test

EC50: 48 µg/ml

IPO

DPPH test

EC50: 100 µM

Plant part

Imai et al., 2008

Heartwo od Imai et al., 2008

Imai et al., 2008

Imai et al., 2008

Seeds

Myorelaxa nt activity

HYM

DPPH test

EC50: 300 µM

AST

KClinduced contracti on on tracheal rings from rats

49.87% contractio n at 100 µg/ml

NS

100 µg/ml

Referen ce (s)

Stem bark

Simões et al., 2009 Simões et al., 2009 Bezerra et al., 2013

Casein kinase inhibitory activity

NAST and AST

Percenta ge of inhibition of casein kinase

ED50: 7 and 9 µM for NAST and AST, respective ly

NS

H. Bark parvifoli a

Ishibashi et al., 1999

AST: Astilbin; EC50: Oxidant concentration required for 50% consumption of the initial 1,1diphenyl-2-picrylhydrazyl radical concentration; FISEL: (−)-Fisetinidol; HYM: Hymenain; IPO: Ipomopsin, NAST: Neoastilbin; THDMIF: (+)-(3R)-8,2′,3′-Trihydroxy-7,4′dimethoxyisoflavan; THMIF: (−)-(3R)-7,2′,3′-Trihydroxy-4′-methoxyisoflavan and TAX: (+)-Taxifolin.

Table 6: Summary of antiasmathic, antihypertensive, antiviral, immunomodulatory, antidiarrhoeal, antiulcer, cysteine protease inhibitor and cytotoxic effects of extracts and compounds from Hymenaea spp. Activity

Anti asthmatic activity

Extracts/ Compou nds Resin

Resin Antihypertens ive activity

EtOHE Antiviral activity

FIS Cytotoxicity FZS

EtOHE

Test system

Effects

5lipoxygena se (LO) enzyme assay

Percent inhibition: 100 % at the concentrat ion tested

Inhibition of the angiotensi n lconverting enzyme (ACE) Ability of the extracts to inhibit the cytopathic effect (CPE) of rotavirus MTT assay (Bal/c 3T3-A31 fibroblast cell line) MTT assay(Bal/ c 3T3-A31 fibroblast cell line) Maximum non-toxic concentrati on based on morpholog ical alterations (Rhesus monkey kidney cell line MA-

Stu dy

Dosag Specie e s

Plan t part Resi n

Referen ce (s)

19 µg/ml

H. courba ril

NS

H. courba ril

Resi n

Braga et al., 2000a

50 µg/ml

H. courba ril

Leav es

Cecílio et al., 2012

Percent inhibition: 10%

Braga et al., 2000b

In vitro 10 and 20 TCID50 at the concentrat ion tested

IC50: 158α μg/ml

NS

IC50: 109 μg/ml

-At 50 and 500 µg/ml: No alteration -At 5000 µg/ml: Presence of cytotoxici ty

Xyle m sap

da Costa et al., 2014

H. courba ril 50, 500 and 5000 µg/ml

da Costa et al., 2014

Leav es

Cecílio et al., 2012

Xyloglyc an

HEtOHE

Immuno modulato ry activity

Xyloglyc an

104) MTT assay (Mouse peritoneal macrophag es)

MTT method (Murine melanoma B16F10Nex2) Proliferati on of peritoneal macrophag es in mice

NO production

85 and 91% of cell viability at 50 µg/ml after 24 and 48 hours of cell incubation , respective ly >50% reduction of cell viability

1-500 µg/ml

Seed s

Rosário et al., 2008

50μg/ ml

Seed s

Figueire do, 2014

Percent increase of macropha ge cells: 92 and 576% at 50 and 200 mg/kg, respective ly Percent increase of NO productio n: 68% to 92% at 25 and 50 µg/ml, respective ly

50 and 200 H. mg/kg courba ril

Seed s

Rosário et al., 2008

In vivo

25 and 50 µg/ml

Table 6 (Continued) Activity Extracts/ Compou nds Antidiarrhe MeOHE al activity

Antiulc er activity MeOHE

Test system

Effects

Wistar rats (Percent reduction of diarrheal condition)

43, 14 and 15 % reduction of diarrhoea at 100, 200 and 400 mg/kg, respective ly. 0 and 29% reduction of diarrhea at 5 and 10% in diet, respective ly -80 % protection at 200 mg/kg compared to lansopraz ole (89%) at 30 mg/kg.

Gastroprotec tive effects of lesions induced by ischemia/ reperfusion in rats. Gastroprotec tive effect of duodenal injury induced by cysteamine in rats

-Gastric healing effect after injury induced by acetic acid -Duodenal

-98 % protection at 200 mg/kg compared to lansopraz ole (89%) at 30 mg/kg. - After 7 days: 53 % of lesion protection at 200

Stud Dosa y ge In vivo

100, 200 and 400 mg/kg

Species

Plan t part

H. stigonoca rpa

Stem bark

5 and 10% in diet

In vivo

50, 100, 150 and 200 mg/kg ; 5 and 10% in diet

H. stigonoca rpa

Referen ce (s) Orsi et al., 2014

Fruits

Orsi et al., 2014

Bark

Orsi et al., 2012

healing effect after injury induced by acetic acid

Cystein e proteas e [Cathep sin K (Cat K), Catheps in L (Cat L) and Catheps in V (Cat V)] inhibito ry activity

EtOHE

Percentage of Cat K inhibition:

mg/kg compared to lansopraz ole (83%) at 30 mg/kg. - After 14 days: 61 and 60 % of lesion protection at 100 and 200 mg/kg compared to lansopraz ole (83%) at 30 mg/kg - After 7 days: 61 % of lesion protection with 10 % in diet compared to lansopraz ole (71%) at 30 mg/kg. -At 50 µg/ml: 79, 96, 79 and 80 % for leaf, flower, root and stem extracts, respective ly -At 125 µg/ml: 82, 98, 91 and 84 % for leaf, flower, root and stem

In vitro

50 and 125 µg/ml

H. stigonoca rpa

Leave s, stem, flowe rs and roots

Monteiro , 2014

extracts, respective ly

Table 6 (Continued) Activity

Extracts/ Compou nds EtOHE

Test system Percentag e of Cat L inhibition :

Percentag e of Cat V inhibition :

A, B, C, D and E

Percentag e of Cat

Effects -At 50 µg/ml: 79, 87, 92 % and ND for leaf, flower, root and stem extracts respective ly. -At 125 µg/ml: 94, 95, 92 % and ND for leaf, flower, root and stem extracts, respective ly -At 50 µg/ml: 98, 98, 97 and 95 % for leaf, flower, root and stem extracts respective ly. -At 125 µg/ml: 98, 99, 97 and 97 % for leaf, flower, root and stem extracts, respective ly

65, 12, 2, 12 and

Stu dy

Dosa ge

Species

50 and 125 µg/ml

Plant part

Refere nce (s)

Leaves, stem, flowers and roots H. stigonoca rpa Monteir o, 2014

In vitro

50 and 125 µg/ml

25µM Leaves

21 % for compoun ds A, B, C, D and E, respectiv ely Percentag 43, 47, e of Cat L 33, 57 inhibition and 3 for : compoun ds A, B, C, D and E respectiv ely Percentag 91, 0, 88, e of Cat 95, and V 71 for inhibition compoun : ds A, B, C, D and E, respectiv ely K inhibition :

A, B, C, D and E

A, B, C, D and E

EtOHE

Cytotoxi city

MTT assay: Normal (L- 929) and tumor (Sarcoma 180) cell lines

-For tumor (Sarcoma 180) cell line; IC50: 20.02, 87.8 µg/ml, nd and nd for stem, root, flower and leaf extracts, respective ly -For normal (L- 929) cell line; IC50: 1220, 855.3, 73.1 and 965.4 µg/ml for stem,

(A, B, C, D) and flowers (E)

25µM

25µM

0.1, 1.0, 10, 100 and 1000 μg/ml

H. stigonoca rpa

Leaves, stem, flower and roots

AE

Microsco pic examinati on of the mitotic division of Allium cepa meristem atic root cells

root, flower and leaf extracts, respective ly -Mitotic index after 24 hours of exposure: 14.6, 16 and 14.2 % at 0.082, 0.164 and 0.328 mg/ml, respective ly -Mitotic index after 48 hours of exposure: 13.5, 17.2 and 11.5 % at 0.082, 0.164 and 0.328 mg/ml, respective ly

0.082, 0.164 and 0.328 mg/ml

Rhytido me

Lacerda et al., 2014

A: labd-7,13-dien-15-oic acid; AE: Aqueous extract; B: labd-7-en-15-oic acid; C: ent-Δ13,14labd-8-β-ol-15-oic acid; D: 4-hydroxybenzoic acid; E: 18-hydroxy-ent-halima-1(10),13-E-dien15-oic acid; EtOHE: Ethanol extract; FIS: Fisetin; FZS: Fresh xylem sap; HEtOHE: Hydroethanol extract; MeOHE: Methanol extract; ND: Not determined; TCID50: 50% tissue culture infectious dose.

Table 7: Summary of in vitro antimicrobial activities of extracts and compounds from Hymenaea genus Species

Plant part

Extracts/ Test system Compounds Aeromonas spp., Bark of the EtOHE Corynebacterium spp., trunk Edwadisiella spp., Enterococcus faecalis, H. E. coli, Klebsiella courbaril spp., Listeria spp., Micrococcus spp., Nocardia spp., Proteus spp., P. aeruginosa, Rhodococcus equi, Salmonella spp., S. aureus, Staphylococcus caprie, Staphylococcus epidermidis, Staphylococcus intermedius, Streptococcus agalactiae, Streptococcus suis, Vibrio spp., Yersinia enterocolitica. Fruits EtOHE E. coli (ATCC 14948 (Exocarp & Clinical isolate), E. and faecalis (ATCC 19433 farinaceous & Clinical isolate), P. pulp) aeruginosa (ATCC 27853& Clinical isolate), S. aureus (ATCC 9144 & Clinical isolate), S. choleraesuis (ATCC 14028& Clinical isolate) and S. flexineri (ATCC 12022 & Clinical isolate) EtOHE, A. baumannii, E. Bark HEXE, K. faecalis, DCME, EtOAcE, pneumonia, P. HEtOHE aeruginosa, E. coli

MIC 62.5-291 µg/ml

Reference (s) de Sá et al., 2011

350 to >400 µg/ml

Martins et al., 2010

125-1000 µg/ml

Aleixo et al., 2015

and S. aureus. Fruits

ESOI

Leaves

HEtOHE

FXSBK

FXSBK and FIS

Leaves

HEtOHE

Stem bark

S. aureus (Strains ATCC 6538P & ATCC 14458) S. aureus ATCC 25923 C. gattii, C. neoformans, M. gypseum, T. mentagrophytes, T. rubrum and T. tonsurans. Methicillin-resistant Staphylococcus aureus (MRSA) Staphylococcus spp.

HEtOHE

S. mutans

0.28 % v/v

Sales et al., 2014

3.33 mg/ml

Garcia et al., 2011 Da Costa et al., 2014

32-128 µg/ml

500 µg/ml At MIC 2.5 mg/ml: 54.0 % of 14 isolates tested were inhibited At MIC 1.25 mg/ml: 35.0 % of 7 isolates tested were inhibited

Aleixo et al., 2013 Fernandes et al., 2005

Table 7 (Continued) Species H. Stigonocarpa

H. martiana

Plant part Bark

Extracts/ Compounds CE, EtOAcE, EtOHE, AE, HEtOHE, AF and EtOAcF

Trunk and bark

HEtOHE, MeOHE, ButOHE and LHEtOHF

Leaves EtOHE

Test system

E. faecalis (Strains LFBM 02, LFBM 07, 64-1024 µg/ml LFBM 08 & LFBM 18); S. aureus ( Strains ATCC 25293, ATCC 33591, LFBM 05, LFBM 11, LFBM 13, LFBM 15, LFBM 16, LFBM 25, LFBM 26, LFBM 28, LFBM 29 & LFBM 30) Crytococcus gattii 4-16αμg/mlα and Crytococcus neoformans Microsporum canis, Trichophyton mentagrophytes and Trichophyton rubrum. E. coli 35218, Salmonella enterica 10708 and S. aureus 25923 E. coli (14 strains)

Leaves EtOHEE and EtOHEW Enterobacter spp. (10 strains) Acinetobacter spp. (10 strains)

Klebsiella spp. (9 strains)

Bark

EtOHE

MIC

S. aureus

16-1024 μg/mlα

Reference (s) Dimech et al., 2013

de Souza, 2008; de Souza et al., 2010 de Souza, 2008; de Souza et al., 2010

125.3-1562.5 μg/mlα

De Santana, 2015

1302.1 µg/ml and NA for EtOHEE and EtOHEW, respectively 542.5 µg/ml and NA for EtOHEE and EtOHEW, respectively 1302.1 and 1042 µg/ml for EtOHEE and EtOHEW, respectively 954.9 and 4167 µg/ml for EtOHEE and EtOHEW, respectively -Somatic cell count test: Percentage of

da Silva et al., 2014

da Silva et al., 2014 da Silva et al., 2014

da Silva et al., 2014

Peixoto et al., 2015

reduction of somatic cells after 32 days treatment: 91.66% - California mastitis test: Reduction of bacterial cell stock after 32 days of goat mammary ointment: 99.39 % AF: Aqueous fraction; CE: cyclohexanic extract; DCME: Dichloromethane extract; EA: Aqueous extract; ESOI: Essential oil; EtOAcE: Ethylacetate extract, EtOHE: Ethanol extract; EtOHEE: Ethanol extract dissolved in ethanol; EtOHEW: Ethanol extract dissolved in water; FIS: Fisetin; FXSBK: Fresh xylem sap from the trunk bark; HEXE: Hexane extract; HEtOHE: Hydroethanol extract; NA: Not active.

Table 8: Correlation of ethnomedicinal use with bioactivity of crude extracts and isolated compounds from Hymenaea genus Plant name

Ethnomedicinal use The infusion of the bark is taken orally in Brazil to cure bladder and urinary infections.

H. courbaril

In Haiti, the infusion of the bark is taken orally to treat urinary infections, while the same preparation is used in China to treat bladder and prostate infections. The bark is topically applied in United states and Brazil, for the treatment of skin and nail fungi. It is also taken orally to relief systemic Candida and for the treatment of yeast and other fungal infections.

In Brazil, the bark is administered orally to treat bursitis, arthritis, prostatitis and cystitis. The resin is applied externally for ache and pain reliefs. Likewise, the bark decoction is taken orally in Columbia to treat stomach ache and other inflammatory disorders. The resin, as well as the bark decoction is taken orally in Brazil to cure pulmonary affections, coughs, bronchitis and asthma. In Mexico, the resin is burned and the fume is inhaled to relieve asthma. H. The bark infusion is taken stigonocarpa orally in Brazil, to treat stomach pain, chest and back aches. In Brazil, the tea is prepared

Bioactivity of extracts and compounds related to the traditional use EtOH extract from the bark of H. courbaril trunk exhibited antibacterial activity.

Reference (s)

Branch and Da Silva, 1983; Gupta, 1990; Schwontkowsi, 1996; de Sá et al., 2011. Extracts and fractions Timyan, 1996; from H. courbaril bark Aleixo et al., 2015; and seeds showed Brito et al., 2016. antibacterial activity against E. faecalis, E. coli and V. parahaemolyticus. The insoluble fraction Branch and Da of fresh xylem sap Silva, 1983; Duke from H. courbaril and et al., 2009; Da the compound thereof Costa et al., 2014. (fisetin) displayed antifungal activity against Cryptococcus neoformans. Extracts from fruit Lee and peels exhibited antiLangenhein, 1974; inflammatory activity Caribe and ex vivo and in vivo. Campos, 1997; Moreover, the stem Keiji and Kenji, bark extract showed 2000; Keiji et al., significant anti2002; Leslie, inflammatory activity. 2002; Duke et al., 2009; Bezerra et al., 2013. The resin exhibited ex Marsaioli et al., vivo anti-asmathatic 1979; Leslie, activity. 2002; Braga et al., 2000b.

Stem bark and fruit pulp displayed antiinflammatory activity in rat model. Stem bark extract and

Neto and Morais, 2003; Orsi et al., 2014. Panizza, 1998;

from the bark, and taken in association with honey to treat diarrhea.

fruit pulp in diet showed moderate antidiarrheal activity in rat model.

Carvalho , 2007; Orsi et al., 2012; Orsi et al., 2014.

Graphical Abstract