Constituents and Pharmacological Activities of Myrcia (Myrtaceae): A Review of an Aromatic and Medicinal Group of Plants.

Myrcia is one of the largest genera of the economically important family Myrtaceae. Some of the species are used in folk medicine, such as a group known as "pedra-hume-caá" or "pedra-ume-caá" or "insulina vegetal" (insulin plant) that it is used for the treatment of diabetes. The species are an important source of essential oils, and most of the chemical studies on Myrcia describe the chemical composition of the essential oils, in which mono- and sesquiterpenes are predominant. The non-volatile compounds isolated from Myrcia are usually flavonoids, tannins, acetophenone derivatives and triterpenes. Anti-inflammatory, antinociceptive, antioxidant, antimicrobial activities have been described to Myrcia essential oils, while hypoglycemic, anti-hemorrhagic and antioxidant activities were attributed to the extracts. Flavonoid glucosides and acetophenone derivatives showed aldose reductase and α-glucosidase inhibition, and could explain the traditional use of Myrcia species to treat diabetes. Antimicrobial and anti-inflammatory are some of the activities observed for other isolated compounds from Myrcia.

1. Introduction

Myrtaceae Juss. is the ninth largest flowering plant family; it includes trees and shrubs with centers of diversity in the wet tropics, particularly in South America, Australia and Tropical Asia, distributed in 132 genera and 5671 species [1,2]. It also represents one of the largest families of the Brazilian flora, where 23 genera and 1034 species occur distributed in all regions and vegetal formations of the country [1,2,3,4]. Economically, Myrtaceae is a very important family; some species are cultivated, such as Eucalyptus spp., from which the wood is used to produce paper, lamppost and charcoal; other species are ornamental and some are used as spices, such as Syzygium aromaticum (L.) Merr. & L.M.Perry, known as “cravo-da-índia” or clove. Several species produce edible fruits that are used to make juice, jelly and sweets, such as Psidium guajava L. (“goiabeira” and “guava”), Myrciaria cauliflora (Mart.) O.Berg (“jabuticabeira”), Eugenia uniflora L. (“pitangueira”), Syzygium spp. (“jambo”), but not all are cultivated. Myrtaceae species are also used in folk medicine to treat several diseases, especially gastrointestinal disorders, hemorrhagic and infectious diseases with an action that is probably related to its astringents properties [5].

Myrcia sensu lato or Myrcia s.l. (sensu Lucas et al., 2011) is now considered a large genus taken in a loose sense, composed of four traditional genera (Myrcia DC., Marlierea Cambess, Calyptranthes Sw. and Gomidesia O.Berg), comprising 753 species [1], that are now in process of synonimization based on recent molecular findings [6,7,8]. According to Rosario and coworkers, many species of these four genera found in the Amazon still need phylogenetic analysis [9].

There are 260 listed Myrcia species in Brazil found in different biomes and in all five regions of the country [2]. Myrcia species are an important source of essential oils and some species have been used in folk medicine. In the present work, traditional uses, identified volatile and non-volatile compounds, and the pharmacological activities of crude extracts, essential oils and isolated compounds from Myrcia sensu stricto are reviewed.

2. Traditional Uses

Some Myrcia species have been used in folk medicine, usually as infusions, for a long time [10,11,12,13]. The most cited traditional use of Myrcia species is related to a small group of Myrtaceae known in Brazil as “pedra-hume-caá”, “pedra-ume-caá” or “insulina vegetal” (insulin plant). The leaves or whole plant infusions of these plants are used to treat diabetes; this group of plants includes Myrcia (M.) punicifolia (Kunth) DC., M. speciosa (Amsh.) Mc Vaugh, M. amazonica DC., M. citrifolia (Aubl.) Urb., M. guianensis (Aubl.) DC., M. multiflora (Lam.) DC., M. salicifolia DC., M. sylvatica (G. Mey) DC., M. uniflora DC. besides Eugenia punicifolia (Kunth) DC. [14,15]. Myrcia uniflora is sold as a dry extract in capsules or as tinctures for the treatment of diabetes. “Pedra-ume-caá” is also used to treat diarrhea, enteritis, hemorrhage and aphtha [10] and M. salicifolia is good for cold sores and mouth ulcers [16]. Other Myrcia species have traditional uses: Myrcia bracteata DC. is used to treat dyspepsia [13]; M. ovata Cambess. is used on the treatment of gastric illness, gastritis and diarrhea [17]; and the inhabitants of the Amazon region use the macerated leaves of M. guianensis to neutralize snake venoms [18].

3. Volatiles

Most chemical and biological studies on Myrcia deal with the essential oils obtained from these species [19]. Major compounds from the essential oils of Myrcia (>5%) are summarized in Table 1, together with the classes and the total of the identified compounds, in accordance to literature.

Table 1

Relative abundance (>5%) of the constituents in the essential oils from Myrcia species.

Species	Part of the Plant (Yield: v/w)	Compounds (Relative Abundance, %>5) Classes of Substances; Total	Ref.
M. acuminatissima O.Berg	Fresh leaves (0.12%)	β-pinene (5.0), linalool (22.3), terpinen-4-ol (5.2), β-caryophyllene (8.1), spathulenol (7.5), caryophyllene oxide (5.5) MH: 13.9%, OM: 35.1%, SH: 15.7%, OS: 28.0%, T: 97.0%	[20]
M. alagoensis O.Berg	Fresh leaves (0.3%)	β-caryophyllene (7.9), germacrene D (11.1), germacrene B (26.7), (2E,6E)-farnesoic acid (7.3) S: 79.9%, T: 80.5%	[21]
	Dry leaves (0.4%)	β-caryophyllene (7.8), germacrene D (6.4), δ-cadinene (5.4), selina-3,7(11)-diene (5.4), germacrene B (23.1) S: 75.4%, T: 75.5%	[21]
M. amazonica DC.	Fresh leaves (0.65%)	germacrene D (10.09), germacrene B (9.59), 1-epi-cubenol (20.22), α-muurolol (6.21)	[22]
	Dry leaves (0.96%)	germacrene D (16.56), germacrene B (11.09), 1-epi-cubenol (14.72)	[22]
M. arborescens O.Berg	Fresh leaves (0.2%)	α-muurolol (6.2), caryophyllene oxide (26.3), spathulenol (8.9), globulol (15.9), 5-epi-7-epi-α-eudesmol (5.9) S: 94.8%, T: 96.2%	[23]
M. bombycina (O.Berg) Nied.	Fresh leaves (0.95%)	α-pinene (23.9), β-pinene (12.4), limonene (7.0), γ-eudesmol (7.8) MH: 53.0%, OM: 5.4%, SH: 8.0%, OS: 24.0%, T: 93.5%	[20]
M. bracteata DC.	Leaves (0.71%)	α-bisabolol oxide (10.37), α-bisabolol (45.86) SH: 13.76%, OS: 63.49%, S: 77.25%	[24]
	Leaves and fine stems (0.1%) a	(E)-nerolidol (80.8)	[25]
	Leaves and fine stems (0.3%) a	(E)-β-farnesene (33.9), β-curcumene (9.8), β-bisabolol (8.2)	[25]
	Leaves and fine stems (0.1%) a	germacrene B (8.8), spathulenol (31.0)	[25]
M. cuprea (O.Berg) Kiaersk.	Leaves (<0.05%)	β-caryophyllene (9.57), α-humulene (7.03), γ-selinene (21.75), α-selinene (11.84), (Z)-α-bisabolene (9.51), (E,E)-α-farnesene (10.52) SH: 82.41%, S: 82.41%, OTH: 11.02%	[24]
	Leaves and fine stems (0.3%) a	myrcene (48.1), β-caryophyllene (19.9), δ-cadinene (6.9)	[25]
	Leaves and fine stems (0.1%) a	α-pinene (15.9), myrcene (19.2), β-caryophyllene (39.1)	[25]
	Leaves and fine stems (>0.1%) a	β-caryophyllene (38.1), germacrene D (21.8), germacrene B (19.5)	[25]
M. fallax (Rich.) DC.	Leaves (0.09%)	α-pinene (7.68), β-pinene (11.88), β-elemene (11.21), β-caryophyllene (5.55), selin-11-en-4α-ol (7.56) MH: 22.29%, M: 24.02%, SH: 41.83%, OS: 24.20%, S: 66.03%	[24]
	Leaves (0.25%)	α-pinene (7.7), β-pinene (6.9), β-caryophyllene (6.0), carotol (9.9), guaiol (31.0) T: 83.4%	[26]
	Flowers (0.30%)	α-pinene (6.0), guaiol (27.5), aristolene (24.5) T: 83.2%	[26]
	Fresh leaves (0.25%)	α-bisabolol (83.8) SH: 7.2%, OS: 86.5%, T: 94.3%	[20]
M. aff. fosteri Croat	Leaves	β-bisabolol oxide (19.2), α-bisabolol (19.2), bisabolol oxide B (7.0), undeca-4,6-diene (5.4) SH: 8.2%, OS: 65.9%, T: 76.7%	[27]
M. glabra (O.Berg) D.Legrand	Fresh leaves (0.11%)	α-copaene (6.1), β-caryophyllene (9.5), β-selinene (5.8), α-selinene (9.4), valerianol (13.2) SH: 54.4%, OS: 27.4%, OTH: 9.4%, T: 92.0%	[20]
M. hatschbachii D.Legrand	Fresh leaves (0.1%)	germacrene D (6.4%), γ-cadinene (8.1), α-cadinol (6.1), β-caryophyllene (23.3) S: 95.2%, T: 97.9%	[23]
M. lageana D.Legrand	Fresh leaves (0.3%)	(E)-nerolidyl acetate (25.3), germacrene D (23.4) S: 98.5%, T: 99.3%	[23]
M. laruotteana Camb.	Unripe fruits (0.3%)	spathulenol (5.4), globulol (6.3), α-bisabolol oxide B (11.5), α-bisabolol (23.6), globulol (6.3), (2E,6E)-methyl farnesoate (5.8) SH: 5.8%, OS: 75.8%, T: 82.8%	[28]
	Leaves (0.05%)	spathulenol (7.3), globulol (6.2), guaiol (6.1), 1-epi-cubenol (5.0), α-cadinol (8.0), α-bisabolol (20.7), 14-hydroxy-α-muurolene (19.9) SH: 10.2%, OS: 79.6%, T: 90.4%	[29]
	Flowers (0.07%)	spathulenol (8.6), globulol (6.6), guaiol (7.7), 1-epi-cubenol (5.0), α-cadinol (6.5), α-bisabolol (28.1), 14-hydroxy-α-muurolene (13.7) SH: 9.1%, OS: 83.1%, T: 95.5%	[29]
M. multiflora (Lam) DC.	Leaves (1.16%)	α-gurjunene (6.40), β-caryophyllene (10.72), γ-selinene (5.12), α-selinene (8.67), selin-11-en-4α-ol (10.67) MH: 6.14%, OS: 5.23%, M: 11.37%, SH: 53.91%, OS: 17.57%, S: 71.48%	[24]
	Fresh leaves (0.20%)	β-caryophyllene (7.5), germacrene D (8.7), bicyclogermacrene (6.3), δ-cadinene (5.2), MW 222 (7.4), cubenol (5.9) SH: 44.9%, OS: 32.3%, n.i.: 5.9%, T: 87.5%	[20]
M. myrtillifolia DC.	Leaves (0.14%)b	α-pinene (80.4), α-terpineol (7.0) MH: 85.4%, OM: 13.0%, T: 99.7%	[30]
	Flowers (0.26%) b	α-pinene (76.2) MH: 77.1%, OM: 9.9%, T: 88.8%	[30]
	Fruits (0.37%) b	α-pinene (88.1) MH: 91.9%, T: 96.8%	[30]
M. obtecta (O.Berg) Kiaersk.	Fresh leaves (0.1%)	α-pinene (7.2), ar-curcumene (19.0), β-bisabolene (8.5), α-copaene (8.0), α-humulene (6.2) M: 16.2%, S: 79.1%, T: 95.3%	[23]
M. obtecta (O.Berg) Kiaersk.	Leaves (0.01%) b	α-terpineol (11.2), α-guainene (5.8), trans-calamenene (29.3), 1-epi-cubenol (5.6) M: 16.7%, SH: 56.4%, OS: 20.9%, T: 95.6%	[31]
	Flowers (n.i.)	methyl salicilate (88.2) T: 97.9%	[31]
M. oligantha O.Berg	Fresh leaves (0.1%)	δ-cadinene (17.9), 1-epi-cubenol (7.2), cubenol (5.7), β-caryophyllene (6.5), caryophyllene oxide (5.4), bicyclogermacrene (8.3), spathulenol (10.2) S: 96.8%, T: 99.9%	[23]
M. ovata Cambess.	Leaves (0.9%)	neral (35.8), geranial (50.4) T: 92.1%	[17,32]
	Leaves (1.27%; w/w)	OM: 91.78%, T: 93.55%	[33]
M. pubiflora DC.	Fresh leaves (1.1%)	tricyclene (5.27), 1,8-cineole (5.35), caryophyllene oxide (22.16), mustakone (11.34) T: 72.7%	[34]
M. pubipetala Miq.	Fresh leaves (0.1%)	germacrene D (7.2), β-caryophyllene (13.3), bicyclogermacrene (25.2), spathulenol (31.7), n-heneicosane (14.9) OTH: 14.9%, S: 84.8%, T: 99.7%	[23]
M. richardiana (O.Berg) Kiaersk.	Fresh leaves (0.1%)	β-caryophyllene (20.6), caryophyllene oxide (19.3), α-humulene (5.1), bicyclogermacrene (5.7) S: 90.0%, T: 90.0%	[23]
M. rostrata DC.	Fresh leaves (0.2%)	δ-cadinene (5.7), τ-muurolol (5.1), caryophyllene oxide (13.1), bicyclogermacrene (6.8), spathulenol (17.3) S: 93.3%, T: 93.3%	[23]
M. rufipila McVaugh	Leaves (0.42%) a	β-caryophyllene (7.07), γ-elemene (10.49), germacrene D (9.09), bicyclogermacrene (7.49), δ-cadinene (7.36), germacrene B (6.70) SH: 72.35%, OS: 19.93%, S: 92.28%	[24]
	Leaves (0.18%) a	β-caryophyllene (5.66), germacrene D (10.31), δ-cadinene (10.12), α-cadinol (6.20) SH: 65.87%, OS: 23.69%, S: 89.56%	[24]
M. salzmanni O.Berg	Leaves (n.i.) b	β-caryophyllene (25.9), α-humulene(12.9), MW 222 (11.7), MW 220 (14.2), MW 222 (10.0) SH: 49.2%, OS: 10.1%, NI: 36.2%, T: 95.5%	[35]
	Flowers (n.i.)	β-caryophyllene (13.8), α-humulene (10.9), MW 222 (10.0), MW 220 (12.6), cis-β-elemone (6.2), MW 222 (7.1) SH: 36.4%, OS: 20.1%, NI: 38.6%, T: 95.4%	[35]
M. selloii (Spreng.) N.Silveira	Fresh leaves (0.5%)	germacrene D (6.7), δ-cadinene (14.5), τ-cadinol (9.3), α-cadinol (17.2), β-caryophyllene (9.0), bicyclogermacrene (10.2) S: 99.2%, T: 99.9%	[23]
M. splendens (Sw.) DC.	Fresh leaves (0.44%)	(Z)-α-bisabolene (79.65) SH: 94.54%, S: 98.34%, T: 98.34%	[36]
	Fresh stems (0.15%)	β-caryophyllene (23.8), germacrene D (25.3), bicyclogermacrene (7.1), caryophyllene oxide (10.5) T: 97.2%	[37]
	Leaves (n.i.)	trans-2-hexenal (9.5), germacrene D (35.9), δ-cadinene (5.8), epi-α-cadinol (6.8), valerianol (16.3) SH: 55.7%, OS: 31.8%, T: 96.9%	[38]
M. sylvatica (G.Mey) DC.	Leaves and fine stems (>0.1%) a	spathulenol (13.8), caryophyllene oxide (16.6), selin-11-en-4α-ol (24.7)	[25]
	Leaves and fine stems (0.3%) a	cis-calamenene (30.1), α-calacorene (11.5), spathulenol (18.7)	[25]
	Leaves and fine stems (>0.1%) a	β-bisabolene (14.7), spathulenol (40.2)	[25]
M. tomentosa (Aubl.) DC.	Aerial parts (0.54%) b	(E)-β-farnesene (6.94), γ-muurolene (18.04), bicyclogermacrene (11.51), (2E,6E)-methyl farnesoate (36.95) SH: 47.22%, OS: 52.02%, T: 99.24%	[39]
	Fresh flowers (0.31%)	spathulenol (7.36), globulol (5.97), (2Z,6Z)-farnesal (6.86), (2Z,6Z)-farnesol (10.65), (2E,6E)-farnesal (5.36), (2E,6E)-methyl farnesoate (14.28), benzyl salicylate (5.99) OS: 46.69%, OTH: 24.61%, T: 72.71%	[39]
	Stem bark (0.31%)	(2E,6E)-methyl farnesoate (14.39), hexadecanoic acid (22.05) SH: 6.26%, OS: 9.06%, OTH: 60.4%, T: 76.27%	[39]
	Leaves (0.1–0.8) b	spathulenol (18.35), globulol (7.66), (2E,6E)-methyl farnesoate (46.38)	[40]
	Leaves (0.1–0.8) b	γ-muurolene (14.20), bicyclogermacrene (14.38), δ-amorphene (18.83)	[40]
	Leaves (0.1–0.8) b	γ-muurolene (6.62), bicyclogermacrene (8.04), globulol (57.48)	[40]
	Leaves (0.1–0.8) b	γ-muurolene (7.67), bicyclogermacrene (5.85), (2E,6E)-methyl farnesoate (60.69)	[40]
	Leaves (0.1–0.8) b	β-caryophyllene (12.66), γ-muurolene (40.16), bicyclogermacrene (13.74), δ-amorphene (6.31)	[40]

M: Monoterpenes (hydrocarbons and oxygenated); S: Sesquiterpenes (hydrocarbons and oxygenated); MH: Monoterpene Hydrocarbons; OM: Oxigenated Monoterpenes; SH: Sesquiterpene Hydrocarbons; OS: Oxigenated Sesquiterpenes; OTH: Others; NI: not identified; T: total of the identified compounds; a Different site of collection for a same species in a same reference; b Studies of seasonal or circadian variations (oils with the highest T and measured yield is listed); n.i.: not informed; Ref.: Reference.

Leaves, flowers, stems, fruits of Myrcia can produce essential oils. Sesquiterpenes are the major compounds in most of these oils, although monoterpenes were identified in a higher amount than sesquiterpenes in the essential oil of M. acuminatissima and M. bombycina [20], one of the studied specimen of M. cuprea [25], M. myrtillifolia [30] and M. ovata [17,32,33]. The major compound of the essential oil of M. obtecta flowers of was methyl salicylate [31], and the most abundant compound of the essential oil of M. tomentosa stem bark was decanoic acid [39].

According to Alarcón and coworkers [26], the essential oils of M. fallax collected in Venezuela were different; leaves and flowers oils were rich on guaiol/carotol and guaiol/aritolone, respectively. Additionally, it was observed that the essential oils from M. falax collected in Venezuela were also different from the specimens from Brazil, in which those terpenes were not identified [20,24].

Siani and coworkers arranged the mono- and sesquiterpenes from 15 Neotropical Myrtaceae in accordance to their biosynthetic pathways; the species showed a heterogeneous composition, with a wide variation with respect to terpenoid structures, including bisabolene-type; no chemotaxonomical implications were found [41].

Seasonal variation studies have demonstrated that the essential oil of M. obtecta leaves did not exhibitet important differences on the composition, except for the flowering month, when α-terpineol and trans-calamenene were detected on the highest amounts [31]. The essential oil of the leaves of M. tomentosa exhibited seasonal variation; it was observed that only nine of 44 compounds were identified in all samples, indicating a significant correlation between the climatic data, foliar nutrients and essential oil composition [39]. Cluster and Principal Component analysis indicated a high chemovariability within the essential oils of M. tomentosa [39]. The oil from M. salzmannii leaves showed qualitative and quantitative variations in the composition; only two compounds, β-caryophyllene and α-humulene, were identified in all samples [35]. According to Zoghbi and coworkers, the essential oils of M. sylvatica show intraspecific variation [25].

4. Biological and Antioxidant Activities of the Essential Oils of Myrcia Species and Their Major Constituents

Several studies have shown the biological activities of Myrcia essential oils [19]. The number of published papers is growing every day.

4.1. Anti-Inflammatory and Antinociceptive Effect

Essential oils from M. ovata leaves (50–300 mg/kg of oral doses) showed significant effect in acute pain and inflammation tests with no adverse effects and intoxication during the assays; according to the authors, these results provided initial evidence of the traditional use of this species [33].

The essential oil from the fresh leaves of M. pubiflora (25, 50 and 100 mg/kg) significantly reduced the number of writhing induced by acetic acid and the nociception in the second phase of formalin test; it exhibited inhibitory effect on carrageenan-induced response, it was ineffective inhibiting the time for reaction to thermal stimulus and it did not show any motor performance alterations [34].

4.2. Antimicrobial Activity

The essential oil of M. ovata leaves shows antimicrobial action against several microorganisms [13]. The studies of Alarcón and coworkers [26] showed that the essential oil of M. fallax flowers from Venezuela is active only against the Gram positive bacteria and not against the Gram negative bacteria. The oil from M. aff. fosteri showed activity against two bacteria which was comparable to chloramphenicol [27]. The leaves essential oils of M. myrtillifolia showed antimicrobial activity against several microorganisms, with a moderate toxicity against Artemia salina [30]. The essential oils of M. alagoensis exhibited a broad spectrum of antibacterial action, on both Gram positive and Gram negative bacteria, and the former were more sensitive to the essential oil from the fresh leaves [21]. Antibacterial activity was observed when essential oil from the stems of M. splendens was tested [37].

4.3. Larvicidal Activity

The essential oil of M. ovata leaves, which is rich in citral (neral: 35.8%; geranial: 50.4%), showed larvicidal activity against Aedes aegypti [32]. According to these authors the essential and their major compounds may be potent source of natural larvicides.

4.4. Antiproliferative Activity

The essential oil from M. laruotteana fruits and the fraction rich in α-bisabolol when tested against in vivo human cancer cells (glioma, melanoma, breast, ovarian and ovarian-resistant, kidney, lung, prostate, colon and leukemia) showed antiproliferative activity against all cell lines, except for the lung cell line; the α-bisabolol rich fraction had a similar profile [28].

4.5. Antioxidant Capacity

The essential oil from M. amazonica leaves showed a higher antioxidant activity than BHT (buthyl-hydroxytoluene) and α-tocopherol when using the ORAC (oxygen radical absorbance capacity) method, but lower when the cation-radical ABTS (2,2ʹ-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid)) method was applied, using TROLOX as reference [22].

5. Activity of the Major Compounds from Myrcia Essential Oils

Some of the constituents of Myrcia essential oils show activities that could contribute to the biological properties, however, in all cases synergistic and antagonist influence of the various components should be considered.

Citral has a significant central and peripheral antinociceptive effect and anti-inflammatory activity [42]. In that way, citral, the major component of M. ovata essential oil, can contribute for the observed analgesic activity of the essential oil.

The sesquiterpene caryophyllene oxide exhibits antinociceptive activity [43]; the monoterpene 1,8-cineole also shows antinociceptive properties on hot plate and tail-flick tests, while β-pinene exerts supraspinal and antinociceptive actions in rats, but it reverses the effect of morphine [44]. These compounds were identified in several essential oils from Myrcia.

Terpinen-4-ol, linalool, α-terpineol and β-caryophyllene are known for their antimicrobial activities [45,46]. These compounds probably contribute to some of the observed activities.

6. Non-Volatiles

The chemical studies regarding to the non-volatile compounds identified from Myrcia species mostly describe the isolation of flavonol glucosides. Together with flavonoids, terpenoids, organic acids, acetophenones and related compounds have been isolated. A small number of species have been studied for their chemical composition on non-volatile compounds.

6.1. Flavonoids

The flavonoids isolated from Myrcia are mostly flavanones and flavonol-O-glycosides. The sugar units are usually galactose, glucose, xylose and rhamnose. Structures of the isolated flavonoids from Myrcia are in Figure 1, Figure 2 and Figure 3.

Figure 1

Structures of the flavanone glucosides Myrciacitrins.

Figure 2

Structures of the flavonols and their glucosides isolated from Myrcia.

Figure 3

Other flavonoids and derivatives isolated from Myrcia species.

The extracts of M. multiflora leaves contain the flavanone glucosides myrciacitrins I (1), II (2), III (3), IV (4) and V (5) [47,48]. To date, the flavanone glucosides have been isolated only from M. multiflora.

Myrcia multiflora extracts also contain the flavonol glucosides myricitrin (6), mearnsitrin (7), quercitrin (8), desmanthin-1 (9), guaijaverin (10) [47,48]. Myricitrin (6) was also isolated from M. bella Cambess. [49], M. splendens [50], M. palustris DC. [50] and M. uniflora [51], mearnsitrin (7) was also obtained from M. uniflora [52]. From the leaves of M. tomentosa, avicularin (11) and juglanin (12) were isolated [53]. Other flavonoids have been isolated from M. bella, such as myricetin (13), kaempferol-3-O-deoxyhexoside (14), kaempferol-3-O-hexoside (15), myricetin-3-O-β-d-galactopyranoside (16), myricetin-3-O-α-arabinofuranoside (17), myricetin-3-O-α-arabinopyranoside (18), myricetin-3-O-(O-galloyl)-hexoside (19), quercetin (20), quercetin-3-O-β-d-galactopyranoside (21), quercetin-3-O-β-d-xylofuranoside (22), quercetin-3-O-β-d-xylopyranoside (23), quercetin-3-O-α-l-arabinofuranoside (24), quercetin-3-O-(6ʹʹ-galloyl)-β-galactopyranoside (25), quercetin-3-O-(O-galloyl)-pentoside (26) [49]. Myrcia palustris also produced desmanthin-1 (9), myricetin (13), myricetin-3-O-β-d-galactopyranoside (16), quercetin (20), quercetin-3-O-β-d-xylopyranoside (23) and quercetin-3-O-α-l-arabinofuranoside (24) together with myricetin-(6ʹʹ-galloyl)-3-O-β-d-galactopyranoside (27), myricetin-3-O-β-d-xylopyranoside (28), quercetin-3-O-α-l-arabinopyranoside (29), quercetin-3-O-α-l-rhamnopyranoside (30) and kaempferol-3-O-β-d-galactopyranoside (31) [54]. Quercetin (20) was also isolated from M. myrtillifolia [55]. Flavonol glucoside is the major class of non-volatile secondary metabolites identified from Myrcia species.

Studies with the leaves of M. hiemalis Cambess. led to the isolation of 5-hydroxy-6,8-dimethyl-7-methoxyflavanone (32), 6,8-dimethyl-5,7-dimethoxyflavanone (33) and 2,7-dihydroxy-6,8-dimethyl-5-methoxyflavanone (34), together with the chalcones 2ʹ,4ʹ-dihydroxy-3ʹ,5ʹ-dimethyl-4,6ʹ-dimethoxychalcone (35), 2ʹ-hydroxy-3ʹ,5ʹ-dimethyl-4ʹ,6ʹ-dimethoxychalcone (36) and 2ʹ,6ʹ-dihydroxy-3ʹ,5ʹ-dimethyl-4ʹ-methoxychalcone (37) and the isoflavone 7-hydroxy-6,8-dimethyl-5-methoxy-isoflavone (38) [55]. Myrcia hiemalis was the only species from which chalcones, C-methylflavanones and isoflavones were isolated.

6.2. Terpenoids

Some Myrcia species produce terpenoids. 2α,3β,21α-Trihydroxy-28,20β-hydroxytaraxastanolide (39) was isolated from M. hiemalis [55], and betulinic acid (40), betulonic acid (41), betulinaldehyde (42), betulona (43), oleanolic acid (44), ursolic acid (45) were obtained from M. myrtillifolia [55]. The sesqui-, di- and tetraterpenoids eudesm-4-(15)-en-7α,11-diol (46) and geranylgeranyl acetate (47) and α-tocopherol (48), respectively, were also isolated from M. hiemalis [55]. Stigmasterol (49) was found in M. myrtillifolia [55]. Structures of the terpenoids identified from Myrcia are in Figure 4.

Figure 4

Terpenoids from Myrcia species.

6.3. Organic Acids

Some organic acids were isolated from Myrcia species (Figure 5). Gallic acid (50) was isolated from the leaves of M. bella [49] and M. guianensis [56]. Protocatechuic acid (51) was identified from M. guianensis [56] and M. palustris [54]. Caffeic acid (52), quinic acid (53) and the derivative ethyl gallate (54) were found in M. bella [49]. Cinnamic acid (55) was isolated from M. hiemalis [55] and ginkgoic acid (56) from M. multiflora [47].

Figure 5

Organic acids isolated from Myrcia species.

6.4. Acetophenones and Related Compounds

Myciaphenones A (57) and B (58) and phloroacetophenone (2ʹ,4ʹ,6ʹ-trihydroxyacetophenone) (59), were isolated from M. multiflora [47,57]; two derivatives (60–61) were identified in M. myrtillifolia [55]. Structures of compounds 57–61 are in Figure 6.

Figure 6

Acetophenones and derivatives from Myrcia species.

6.5. Tannins

Myrcia palustris produced the tannin casuarinin (62) together with 4-O-(4ʹʹ-O-acetyl-α-l-rhamnopyranosyl)-ellagic acid (63), 4-O-(2ʹʹ,4ʹʹ-O-diacetyl-α-l-rhamnopyranosyl)-ellagic acid (64), 4-O-(2ʹʹ,3ʹʹ-O-diacetyl-α-l-rhamnopyranosyl)-ellagic acid (65), 4-O-(3ʹʹ,4ʹʹ-O-diacetyl-α-l-rhamnopyranosyl)-ellagic acid (66) and 4-O-(2ʹʹ,3ʹʹ,4ʹʹ-O-triacetyl-α-l-rhamnopyranosyl)-ellagic acid (67) [54]. Structures of the tannins identified from Myrcia species are in Figure 7.

Figure 7

Tannins isolated from Myrcia species.

6.6. Alkaloid

Myrcia blanchetiana (O.Berg) Mattos was the only Myrcia species found to produce alkaloid; the nicotinic ester Myrciaine (68) was identified from this species [58] (Figure 8).

Figure 8

Strucuture of the alkaloid myrciaine.

7. Pharmacological Effects of Myrcia Extracts and Isolated Compounds

Several studies dealing with biological activities of Myrcia extracts and isolated compounds have been published.

7.1. Hypoglycemic Potential

The methanol extract and ethyl acetate-soluble portion from M. multiflora leaves, one of the species known as “pedra-ume-caá”, showed inhibitory activities on aldose reductase and α-glucosidase, on the increase of serum glucose level on sucrose-loaded rats and on alloxan-induced diabetic mice [47]. The flavanone glucosides myrciacitrins I–II (1–2), the flavonol glucosides myricitrin (6), mearnsitrin (7), quercetin (8), desmanthin-1 (9) and guaijaverin (10) and the acetophenone glucoside myrciaphenone B (58), all isolated from M. multiflora, showed potent inhibitory activity on aldose reductase and α-glucosidase and among them, desmanthin-1 showed the most potent activity on aldose reductase [47]. A further study with the same species confirms potent inhibitory activity on aldose reductase of myrciatrins, including III, IV and V [48]. When comparing the structures of the tested substances, it is observed that desmanthin-1 is the only flavonol glucoside with a galloyl group linked to the sugar unit.

Myrcia palustris produced five α-glucosidase inhibitors, the flavonol glucosides myricetin (13), quercetin (20), casuarinin (62), myricetin 3-O-β-d-(6ʹʹ-galloyl)-galactopyranoside (27) and kaempferol 3-O-β-d-galactopyranoside (31) [54]. The treatment of mice with the ethanol extract of M. bella leaves using 600 mg/kg reduced the fast blood glucose, total cholesterol and triglycerides and it increased hepatic glycogen; the authors conclude that the tested extract has exhibited hypoglycemic properties and possibly acts to regulate glucose uptake by the liver [59]. Although M. palustris and M. bella are not included in the group as species known as “pedra-ume-caá”, they show hypoglycemic potential.

The number of studies is still small, but it can be observed that flavonol glucosides and acethophenone derivatives are not restricted to species known as “pedra-ume-caá”.

7.2. Antiobesity and Mixed Hypolipidemic Effects

Phloroacetophenone (59) isolated from M. multiflora has hypolipidemic and antiobesity effects related to reduction of triglyceride intestinal absorption and pancreatic lipase activity inhibition [57].

7.3. Anti-Hemorrhagic Activity

The aqueous extract and the aqueous residue at 1:1 (w/w) of the leaves of M. guianensis completely inhibited the hemorrhagic effect produced by intradermic injections of crude venom of the snake Bothrops jararaca in Swiss mice; the ethyl acetate extract at 1:3 (w/w) inhibited 90.7%; the in vitro venom effect was analyzed by electrophoresis; according to the authors, these observations could explain the traditional use of M. guianensis to reduce snake venom effect [18].

7.4. Phytotoxic Effect and Allelophatic Potential

The ethyl acetate extract of M. guianensis leaves (1% w/v) showed phytotoxic activity when tested on seed germination and seedlings growth bioassays using the weeds Mimosa pudica and Senna obtusifolia as test plants; the isolated compounds gallic (50) and protocatechuic acids (51) showed concentration-dependent allelopathic effects and the strongest activity was observed at 60 ppm [56]. The fractions containing the flavonoids glucosides avicularin (11) and juglanin (12) isolated from M. tomentosa showed potent inhibition of coleoptiles growth using wheat seeds (Triticum aestivum) as the test plant [53].

7.5. Hepatoprotective Effect

Hydrolysis of phloroacetophenone glucoside (57), isolated from M. multiflora, gave its aglicone (59), which protected mouse liver from injury induced by CCl4, probably through its scavenging ability [60]. In the same study, it was observed that the pre-treatment with phloroacetophenone normalized the activities of antioxidant enzymes catalase, glutathione peroxidase, and superoxide dismutase, and increased the levels of reduced glutathione. In addition, it significantly prevented the elevation of serum enzymatic activities, as well as histological alteration.

7.6. Antioxidant Effects

The ethanol extracts of M. laruotteana and M. obtecta leaves showed antioxidant effects in the DPPH assays; these extracts were more active than quercetin [61]. The ethyl acetate and n-butanol phases of the hydroalcoholic extract of M. splendens and M. palustris leaves and stems showed antioxidant activity using DPPH radical and iron reduction assays; myricitrin (6) was isolated as the major constituent of the ethyl acetate phase of both species [50].

Studies with M. rostrata showed that the content of phenolic compounds (total, tannins, flavonoids) is influenced by environmental factors such as soil micronutrients, rainfall and pH [62], as well as the study with M. tomentosa leaves [63].

7.7. Others

The aqueous phase of the methanol extract of M. uniflora and the isolated flavonoids myricitrin (6) and mearnsitrin (7) were able to inhibit thyroid peroxidase in vitro; according to the authors, the indiscriminate consumption of M. uniflora pharmaceutical products (capsules or tinctures for treatment of diabetes mellitus), allied to the nutritional deficiency of iodine, might contribute to the development of hypothyroidism [52].

A US patent dealing with M. fallax extracts and its capacity of killing tumor cells derived from human carcinoma of the nasopharynx (KB) was deposited [64].

8. Concluding Remarks

Myrcia is an economically important genus. It is a rich source of essential oils and it is ornamental. Parts of the plant in natura, extracts and capsules of some Myrcia species are commercialized as phytomedicine. Myrcia species are used in the traditional medicine on the treatment of a variety of illnesses, including diabetes and stomach problems. The essential oils from Myrcia, are usually mixtures of sesquiterpenes with small concentrations of monoterpenes. These volatile oils have shown biological activities such as anti-inflammatory, antinociceptive, antimicrobial, among others. Chemical studies with the non-volatile compounds show that Myrcia species are a rich source of flavonoids, especially flavonol glucosides; triterpenoids, organic acids and acetophenone derivatives were also isolated from Myrcia. Some of the isolated flavonol and flavanone glucosides, their aglicones and acetophenone derivatives show hypoglycemic potential and could explain the traditional use of some of Myrcia species to treat diabetes. Acetophenone derivatives are also related to hypolipidemic effects. Therefore, Myrcia is a promising source of biologically active compounds. Several species have not been chemically and biologically studied, and others required further studies. As it is observed for other Myrtaceae, the similarity of the species is high and taxonomic and nomenclatural history is complex, resulting in difficulties in identification. Further comparison of chemical composition, biological activities and traditional uses taking into account all species of Myrcia s.l. will contribute to the chemosystematic of Myrtaceae.

Compound	R1	R2	R3
1	H	H	O-β-d-glucopyranosyl
2	CH3	H	O-β-d-glucopyranosyl
3	H	O-β-d-glucopyranosyl	H
4	H	H	(6ʹʹ-O-p-coumaroyl)-O-β-d-glucopyranosyl
5	H	H	(6ʹʹ-O-p-hydroxybenzoyl)-O-β-d-glucopyranosyl

Compound	R1	R2	R3	R4
6	OH	H	OH	O-α-l-rhamnopyranosyl
7	OH	CH3	OH	O-α-l-rhamnopyranosyl
8	OH	H	OH	O-α-l-rhamnopyranosyl
9	OH	H	OH	(2ʹʹ-O-galloyl)-O-α-l-rhamnopiranosyl
10	OH	H	H	O-α-l-arabinopyranosyl
11	OH	H	H	O-α-l-arabinofuranosyl
12	H	H	H	O-α-l-arabinofuranosyl
13	OH	H	OH	OH
14	H	H	H	O-Deoxyhexosyl
15	H	H	H	O-Hexosyl
16	OH	H	OH	O-β-d-galactopyranosyl
17	OH	H	OH	O-α-arabinofuranosyl
18	OH	H	OH	O-α-arabinopyranosyl
19	OH	H	OH	(O-galloyl)-O-hexosyl
20	H	H	OH	OH
21	H	H	OH	O-β-d-galactopyranosyl
22	H	H	OH	O-β-d-xylofuranosyl
23	H	H	OH	O-β-d-xylopyranosyl
24	H	H	OH	O-α-l-arabinofuranosyl
25	H	H	OH	(6ʹʹ-O-galloyl)-O-β-galactopyranosyl
26	H	H	OH	(O-galloyl)-pentosyl
27	OH	H	OH	(6ʹʹ-O-galloyl)-O-β-d-galactopyranosyl
28	OH	H	OH	O-β-d-xylopyranosyl
29	H	H	OH	O-α-l-arabinopyranosyl
30	H	H	OH	O-α-l-rhamnopyranosyl
31	H	H	H	O-β-d-galactopyranosyl

Compound	R1	R2	R3
63	H	H	Acetyl
64	Acetyl	H	Acetyl
65	Acetyl	Acetyl	H
66	H	Acetyl	Acetyl
67	Acetyl	Acetyl	Acetyl