Introduction
The Myrtaceae family is a group of dicotyledonous plants comprising approximately 130 genera and 3800 – 5800 species of shrubs or trees. It has been found in all continents except Antarctica, with predominance in the tropical and subtropical regions of the world [1], [2], [3]. Approximately one-third of the species in this family belong to the genus Eugenia, with around 1000 species distributed from southern Mexico to northern Argentina. It is estimated that 350 species are native to Brazil, with a small number of species being found in Africa. The plants of this genus are perennial trees or shrubs with spherical and edible fruits [4], [5] that have diverse pharmacological activities, including antidiabetic, antirheumatic, antidiarrheal, antipyretic, anti-inflammatory, antifungal, antibacterial, antioxidant, and cytotoxic properties. In addition, they have also been used to treat diseases of the stomach [6], [7].
Several known species from the Eugenia genus have been reported for their medicinal uses and chemical constituents, as well as antimicrobial and cytotoxic activities, including Eugenia axillaris (SW.) Willd., Eugenia beaurepaireana (Kiaersk.) D.Legrand, Eugenia brasiliensis Lam., Eugenia dysenterica DC., Eugenia punicifolia (Kunth) DC., Eugenia pyriformis Cambess., Eugenia rigida DC., Eugenia sulcata Spring ex Mart, Eugenia umbelliflora O.Berg, and Eugenia uniflora L., among others. Thus, the aim of the present study was to develop a systematic review to analyze whether plants in the Eugenia genus have antimicrobial and cytotoxic properties in vitro, as well as the chemical composition of the various species. This review demonstrates the importance of the Eugenia genus in providing secondary metabolites of pharmacological interest and establishes that further research of many species would be beneficial.
Search Strategy
This systematic review was carried out using bibliographic research in 2016, and includes articles published from 1973 to 2015. We used specialized databases (Web of Science, Scielo, Lilacs, Pubmed, Science Direct, Scopus, and an article selected from Google Scholar) and included Eugenia and antimicrobial activity, Eugenia and toxicity, and Eugenia and chemical composition as key words for the literature searches. The articles included in this manuscript were original articles. Further, articles containing isolated compounds identified via spectroscopic techniques and articles reporting antimicrobial and cytotoxic activity were included. Species of the genus Eugenia were selected according to the classification of Kew Royal Botanic Garden and The Plant List, excluding species not belonging to the genus. Duplicate items or items that were not within the review area of interest were excluded. The three major compounds identified in the species studied were selected for the chemical composition of the essential oil. The Endnote program was used to store the selected articles. Initially, two researchers selected articles by titles, and article abstracts were evaluated. Finally, the complete articles were read in whole, and references that met the inclusion criteria were included in the review. Disagreements were resolved through consensus among researchers, and in the case of nonagreement, a third reviewer was consulted.
Initially, 1057 articles were selected. We excluded 227 duplicate articles, 53 of which were excluded with the help of an Endnote tool and 174 of which were manually excluded. Of the original 1057 articles, 673 did not fit the inclusion criteria and were excluded after reading the titles and abstracts, while 64 were excluded after reading the complete article. As such, this review includes 93 articles that reported the isolation of phytoconstituents, as well as the antimicrobial and cytotoxic properties of species from the genus Eugenia.
The Eugenia Genus
The Eugenia genus is considered the fourth most important genus of the family Myrtaceae for the production of essential oils after the Eucalyptus, Melaleuca, and Psidium genera. Essential oils from Eugenia species comprise approximately 300 compounds that have been previously identified, with cyclic sesquiterpenes predominating and monoterpenes found in smaller quantities. A few species produce aliphatic and aromatic compounds. These various types of terpenoid compounds are used in the pharmaceutical, cosmetic, and agrochemical industries [6], [8]. In addition to essential oils, flavonoids, triterpenoids, and tannins have also been identified in Eugenia species. Among the flavonoids, there is a predominance of polyhydroxy flavanols, and most of the isolated pentacyclic triterpenes have a lupan or oleanane skeleton [4].
The most studied Eugenia species are E. uniflora L. and E. brasiliensis Lam., which produce exotic fruits such as “pitanga” (E. uniflora L.) [9] and “grumixama” or “Brazilian cherry” (E. brasiliensis Lam.) [10]. These fruits are consumed fresh or in the form of juices and jellies and have high nutritional value, as well as being rich in calcium, phosphorous, provitamin A, vitamin C, carotenoids, and phenolic compounds (anthocyanins) [11]. In addition, these compounds have therapeutic properties that are widely used in folk medicine, such as diuretic, antirheumatic, antipyretic, antidiarrheal, and antidiabetic properties [12], [13]. The essential oils are used in the Brazilian cosmetic industry, attributable to their astringent properties and pleasant smell [14].
Traditional uses
In traditional medicine, most of the plants of the genus Eugenia have been used to treat a wide variety of ailments such as infectious diseases, intestinal infections, and gastrointestinal disorders, as well as in the treatment of wounds or as repellents or insecticides against domestic and agricultural pests [15], [16]. The traditional uses of Eugenia species are described in [Table 1].
Table 1 Data on the traditional use of Eugenia species in the studies selected through this systematic review.
|
Species
|
Extracts and/or part of the plant
|
Traditional uses
|
References
|
|
E. axillaris (SW.) Willd.
|
Decoction of the leafy branch tips
|
Aphrodisiac, antidiarrheic, and for bathing women after childbirth
|
[17], [18]
|
|
E. beaurepaireana (Kiaersk.) D.Legrand
|
No date
|
Anti-inflammatory, antidiarrheic, diuretic, antirheumatic, anti-febrile, antidiabetic, and antirheumatism
|
[7]
|
|
E. brasiliensis Lam.
|
Leaves, fruits, and bark infusions
|
Stomach diseases, antirheumatic, anti-inflammatory, antidiarrheic, and diuretic
|
[4], [7], [19]
|
|
E. dysenterica DC.
|
Leaves
|
Anti-inflammatory, antimicrobial, antihypertensive, antidiarrheic, purgative
|
[7], [8], [16], [18]
|
|
E. punicifolia (Kunth) DC.
|
No date
|
Hypoglycemic activity
|
[8]
|
|
E. pyriformis Cambess.
|
Leaves
|
Treatment for gout
|
[20]
|
|
E. rigida DC.
|
No date
|
Leukemia
|
[5]
|
|
E. sulcata Spring ex Mart
|
No date
|
Fever treatment and antidiarrheic
|
[21]
|
|
E. umbelliflora O.Berg
|
Aerial parts
|
Infections, inflammation, and diabetes
|
[22]
|
|
E. uniflora L.
|
Leaf and fruit infusions, hydroalcoholic leaves extract
|
Exciting, febrifuges, antidysenteric, antidiarrheic, antihypertensive, antirheumatic, anti-inflammatory, hyperlipidemia, hypotriglyceridemic, hypoglycemic, bronchitis, coughs, fevers, anxiety, diuretic, stomach diseases, digestive disorders, verminosis, gout, vasorelaxant, antioxidant, and with antimicrobial property
|
[7], [8], [11], [14], [15], [16], [23], [24], [25], [26], [27], [28], [29], [30], [31]
|
Phytochemical constituents of Eugenia genus
An investigation of the chemical constituents of Eugenia species resulted in the isolation and identification of sesquiterpenes, monoterpenes, aliphatic compounds, triterpenes, flavonoids, tannins, and cyanidins.
Essential oils
To obtain the essential oils, fresh samples of Eugenia species are collected and then identified, and an exsiccated sample is deposited in an herbarium. Most reports focus on the composition of essential oils from the plant leaves, however, in some studies, the stem, fruit, and flowers were analyzed. The most commonly used extraction processes were hydrodistillation and supercritical fluid extraction. The compounds were characterized using mass spectrometry, retention indexes, and retention times. We compared the results of each study to the current literature and spectra from databases.
The essential oils from 56 species of Eugenia were analyzed, and approximately 500 compounds were identified. Sesquiterpenes (hydrocarbons and oxygen derivatives) were found and classified as the main class of volatile constituents, together with monoterpenes in smaller amounts. Some species produce small amounts of aromatic and aliphatic compounds, with concentrations below 1%. However, 90.0% of the compounds identified in Eugenia stigmatosa DC. were aliphatic compounds. Further, the aliphatic compounds from Eugenia burkatiana D.Legrand (7.9%), Eugenia catharinensis D.Legrand (10.5%), and Eugenia joensonii Kausel (14.6%) differed from the other species analyzed. The amount of each component is given as a percentage of the total oil and, in general, 80 – 90% of the oil was identified. The essential oils from Eugenia species are characterized by chemical diversity ([Table 2]), and their molecules are shown in [Figs. 1]–[6].
Table 2 Chemical composition of essential oils from Eugenia species in the studies selected through this systematic review.
|
No
|
Species
|
Part of plant
|
Major components
|
References
|
|
Arabic numeral in bold corresponds to the chemical structures shown in [Figs. 1]–[6]
|
|
1
|
E. arenosa Mattos
|
Leaves
|
Farnesyl acetate (70.4%) 59, Aromadrendene (11.7%) 20, Globulol (7.1%) 42
|
[31]
|
|
2
|
E. argentea Bedd.
|
Leaves
|
β-Caryophyllene (18.0%) 17, δ-Cadinene (7.8%) 32, Germacrene D (7.1%) 24
|
[15]
|
|
3
|
E. austin-smithii Standl.
|
Leaves
|
Trans-2-hexenal (33.6%) 9, α-Terpineol (7.8%) 10, Germacrene D (7.1%) 24
|
[32]
|
|
4
|
E. axillaris (SW.) Willd.
|
Leaves
|
Guaiol (35.4%) 44, α-Pinene (15.5%) 1, Germacrene D (12.1%) 24
|
[17], [33]
|
|
5
|
E. bacopari D.Legrand
|
Leaves
|
δ-Cadinene (15.8%) 32, Aromandrendene (12.2%) 20, Viridiflorene (7.9%) 27
|
[34]
|
|
6
|
E. beaurepaireana (Kiaersk.) D.Legrand
|
Leaves
|
Bicyclogermacrene (14.3%) 29, Germacrene D (8.6%) 24, β-Caryophyllene (8.0%) 17
|
[35], [36]
|
|
7
|
E. biflora (L.) DC.
|
Leaves
|
β-Pinene (27.85%) 2, α-Pinene (27.34%) 1, β-Caryophyllene (15.36%) 17
|
[37]
|
|
8
|
E. brasiliensis Lam.
|
Leaves
|
Cubenol (33.1%) 52, Trans-α-Bergamotene (19.0%) 18, Sphatulenol (18.17%) 40
|
[10], [19]
|
|
9
|
E. burkartiana (D.Legrand) D.Legrand
|
Leaves
|
Bicyclogermacrene (14.2%) 29, Germacrene D (8.8%) 24, β-Caryophyllene (7.8%) 17
|
[34]
|
|
10
|
E. calycina Cambess.
|
Leaves
|
Bicyclogermacrene (19.3%) (29), Spathulenol (21.36%) 40, β-Caryophyllene (8.57%) 17
|
[7]
|
|
11
|
E. candolleana DC.
|
Leaves
|
δ-Elemene (13.87%) 14, Muurola-4,10(14)-dien-1β-ol (8.68%) 49, 1-Epi-cubenol (7.59%) 48
|
[38]
|
|
12
|
E. cartagensis O.Berg.
|
Leaves
|
Trans-2-hexenal (31.2%) 9 (E) β-Ocimene (16.2%) 7, Germacrene D (12.3%) 24
|
[39]
|
|
13
|
E. catharinensis D.Legrand
|
Leaves
|
Ethyl palmitate (10.5%) 63, Trans-α-Bergamotene (6.5%) 18, α-Humulene (5.9%) 22
|
[34]
|
|
14
|
E. chlorophyla O.Berg.
|
Stem
|
Caryophyllene oxide (17.2%) 41, Globulol (16.5%) 42, t-Muurolol (16.8%) 51
|
[40]
|
|
Leaves
|
Globulol (22.5%) 42, α -Cadinol (9.4%) 35, 1,10-di-epi-Cubenol (9.8%) 46
|
|
Flowers
|
β-Caryophyllene (12.8%) 17, α-Cadinol (10.1%) 35, Caryophyllene oxide (8.9%) 41
|
|
15
|
E. copacabanensis Kiaersk.
|
Leaves
|
β-Pinene (50.4%) 2, α-Pinene (20.2%) 1, 1,10-di-epi-Cubenol (14.24%) 46
|
[8], [38]
|
|
16
|
E. cuprea (O.Berg) Nied.
|
Leaves
|
Spathulenol (12.1%) 40, β-Caryophyllene (9.2%) 17, Caryophyllene oxide (8.7%) 41
|
[31]
|
|
17
|
E. dimorpha O.Berg.
|
Leaves
|
α-Pinene (22.4%) 1, α-Humulene (12.9%) 22, 1,8-Cineole (9.9%) 6
|
[34]
|
|
18
|
E. dysenterica DC.
|
Leaves
|
γ-Cadinene (27.0%) 31, β-Caryophyllene (14.8%) 17, δ-Cadinene (13.0%) 32
|
[41]
|
|
19
|
E. flavescens DC.
|
Leaves
|
α-Curcumene (14.95%) 23, α-Selinene (11.72%) 28, δ-Cadinene (5.71%) 32
|
[37]
|
|
20
|
E. foetida Pers.
|
Leaves
|
Caryophyllene oxide (14.8%) 41, Caryophyllene alcohol (9.1%) 39, α-Cadinol (6.0%) 35
|
[42]
|
|
21
|
E. haberi Barrie
|
Leaves
|
α-Pinene (29.0%) 1, α-Terpineol (19.4%) 10, trans-2-Hexenal (11.2%) 9
|
[32]
|
|
22
|
E. hiemalis Cambess.
|
Leaves
|
Bicyclogermacrene (37.7%) 29, β-Caryophyllene (7.4%) 17, Germacrene D (7.0%) 24
|
[43]
|
|
23
|
E. involucrata DC.
|
Leaves
|
β-Caryophyllene (10.1%) 17, Spathulenol (7.8%) 40, β-Bisabolene (7.2%) 30
|
[44]
|
|
24
|
E. joensonii Kausel
|
Leaves
|
5-epi-Paradisiol (8.4%) 45, δ-Selinene (7.9%) 26, β-Selinene (7.2%) 25
|
[34]
|
|
25
|
E. klappenbachiana Mattos & D.Legrand
|
Leaves
|
Globulol (8.7%) 42, Viridiflorene (6.9%) 27, Spathulenol (5.9%) 40
|
[45]
|
|
26
|
E. langsdorfii O.Berg
|
Leaves
|
Epi-Longipinanol (13.6%) 37, γ-Eudesmol (12.3%) 58, Limonene (11.8%) 5
|
[46]
|
|
Fruits
|
10-epi-Eudesmol (35.7%) 47, 1,10-di-epi-Cubenol (15.6%) 46, Caryophyllene oxide (7.5%) 41
|
|
27
|
E. melanadenia Krub & Urb.
|
Leaves
|
1,8-Cineole (45.3%) 6, α-Terpineol (10.6%) 10, p-Cymene (8.2%) 4
|
[47]
|
|
28
|
E. monteverdensis Barrie
|
Leaves
|
α-Pinene (92.0%) 1, Linalool (30.4%) 8, trans-2-Hexenal (22.5%) 9
|
[32], [48]
|
|
Fruits
|
α-Pinene (55.1) 1, Linalool (22.7%) 8, Limonene (7.7%) 5
|
|
29
|
E. moraviana O.Berg.
|
Leaves
|
β-Caryophylene (14.5%) 17, β-Elemene (11.8%) 16, α-Copaene (7.9%) 15
|
[45]
|
|
30
|
E. multicostata D.Legrand
|
Leaves
|
α-Pinene (16.1%) 1, Spathulenol (10.7%) 40, Globulol (8.7%) 42
|
[31]
|
|
31
|
E. neonitida Sobral
|
Leaves
|
Bicyclogermacrene (24.3%) 29, Germacrene D (18.7%) 24, β-Caryophyllene (12.5%) 17
|
[49]
|
|
32
|
E. octopleura Krug & Urb.
|
Leaves
|
α-Pinene (43.0%) 1, Limonene (23.6%) 5, (E)- β-Ocimene (5.1%) 7
|
[50]
|
|
33
|
E. patrisii Vahl
|
Leaves
|
β-Bisabolene (16.52%) 30, (E)-Muurola-3,5-diene (13.28%) 21, β-Caryophyllene (11.07%) 17
|
[37]
|
|
34
|
E. piauhiensis O.Berg
|
Leaves
|
γ-Elemene (17.48%) 19, β-Caryophyllene (16.46%) 17, Bicyclogermacrene (8.11%) 29
|
[51]
|
|
35
|
E. pitanga (O.Berg) Nied.
|
Leaves
|
Germacrene D (29.3%) 24, Bicyclogermacrene (22.4%) 29, (E)-β-Ocimene (10.5%) 7
|
[31]
|
|
36
|
E. platysema O.Berg
|
Leaves
|
β-Selinene (17.9%) 25, Aromandrene (12.6%) 20, 7-epi-α-Selinene (10.4%) 33
|
[52]
|
|
37
|
E. pluriflora DC.
|
Leaves
|
(E)-nerolidol (24.6%) 36, α-Pinene (24.0%) 1, 1,8-Cineole (12.7%) 6
|
[52]
|
|
38
|
E. protenta McVaugh
|
Leaves
|
Selin-11-en-4α-ol (18.3%) 54, β-Elemene (16.9%) 16, Germacrene D (15.6%) 24
|
[53]
|
|
39
|
E. punicifolia (Kunth) DC.
|
Leaves
|
Linalool (61.2%) 8, β-Caryophyllene (22.7%) 17, α-Cadinol (10.6%) 35
|
[54], [55]
|
|
40
|
E. pyriformis Cambess.
|
Leaves
|
β-Pinene (25.7%) 2, Limonene (22.0%) 5, 1,8-Cineole (14.7%) 6
|
[56]
|
|
41
|
E. ramboi D.Legrand
|
Leaves
|
β-Elemene (10.6%) 16, Bicyclogermacrene (9.7%) 29, β-Caryophyllene (8.2%) 17
|
[52]
|
|
42
|
E. repanda O.Berg
|
Leaves
|
β-Caryophyllene (16.3%) 17, α-Humulene (10.2%) 22, Bicyclogermacrene (9.4%) 29
|
[45]
|
|
43
|
E. rhombea (O.Berg) Krug & Urb.
|
Leaves
|
Cubenol (12.6%) 52, α-Cadinol (12.5%) 35, α-Pinene (12.1%) 1
|
[57]
|
|
44
|
E. riedeliana O.Berg
|
Leaves
|
Valerianol (28.1%) 53, 10-epi-Eudesmol (12.6%) 47, β-Caryophyllene (10.9%) 17
|
[58]
|
|
45
|
E. rocana Britton & P.Wilson
|
Leaves
|
Caryophyllene oxide (57.7%) 41, 14-hydroxy-9-epi-β-Caryophyllene (10.3%) 55, Verbenone (10.2%) 11
|
[59]
|
|
46
|
Eugenia sp.
|
Leaves
|
β-Caryophyllene (49.0%) 17, 1,8-Cineole (26.0%) 6, Zingiberene (24.7%) 34
|
[10], [32]
|
|
47
|
E. speciosa Cambess.
|
Leaves
|
α-Pinene (47.3%) 1, Limonene (23.0%) 5, Bicyclogermacrene (11.1%) 29
|
[31]
|
|
48
|
E. stigmatosa DC.
|
Leaves
|
Physeteric acid (90.5%) 62, δ-Tetradecalactone (2.2%) 60, γ-Tetradecalactone (1.3%) 61
|
[43]
|
|
49
|
E. stitipata McVaught
|
Leaves
|
Germacrene D (38.3%) 24, β-Caryophyllene (22.7%) 17, Caryophyllene oxide (15.4%) 41
|
[60], [61]
|
|
50
|
E. sulcata Spring ex Mart
|
Leaves
|
α-Pinene (34.2%) 1, β-Caryophyllene (24.6%) 17, 1,8-Cineole (19.0%) 6
|
[21], [31], [55]
|
|
51
|
E. supraaxilaris Spreng.
|
Leaves
|
Limonene (21.8%) 5, β-Pinene (17.4%) 2, α-Humulene (8.7%) 22
|
[1]
|
|
Fruits
|
Eugenol (35.5%) 12, Methyl eugenol (32.8%) 13, Myrcene (12.8%) 3
|
|
52
|
E. umbeliflora O.Berg
|
Leaves
|
α-Pinene (24.7%) 1, Viridiflorol (17.7%) 43, β-Pinene (13.2%) 2
|
[52], [62]
|
|
53
|
E. uniflora L.
|
Leaves
|
Curzerene (47.3%) 38, Selina1,3,7(11) trien-8-one (43%) 50, Selina-1,3,7(11)-trien-8-one epoxide (29.0%) 57
|
[13], [63]
|
|
Fruits
|
Selina1,3,7(11) trien-8-one (48.2%) 50, Curzerene (42.6%) 38, Germacrone (17.3%) 56
|
[27], [64]
|
|
54
|
E. uruguayensis Cambess.
|
Leaves
|
α-Pinene (23.5%) 1, β-Pinene (11.8%) 2, β-Caryophyllene (9.5%) 17
|
[52]
|
|
55
|
E. xiririicana Mattos
|
Leaves
|
Spathulenol (15.4%) 40, β-Pinene (14.1%) 2, Globulol (8.6%) 42
|
[31]
|
|
56
|
E. zuchowskiae Barrie
|
Leaves
|
α-Pinene (28.3%) 1, β-Caryophyllene (13.2%) 17, α-Humulene (13.1%) 22
|
[18], [32]
|
Fig. 1 Chemical structures of monoterpenes α-pinene (1), β-pinene (2), myrcene (3), cymene (4), limonene (5), 1,8-cineole (6), (E)-β-ocimene (7), linalool (8), trans-2-hexenal (9), α-terpineol (10), verbenone (11), eugenol (12), and Methyl eugenol (13) isolated from Eugenia species.
Fig. 2 Structures of sesquiterpene hydrocarbons δ-elemene (14), α-copaene (15), β-elemene (16), β-caryophyllene (17), trans-α-bergamotene (18), γ-elemene (19), aromandrene (20), (E)-muurola-3,5-diene (21), α-humulene (22), α-curcumene (23), germacrene d (24), β-selinene (25), δ-selinene (26), viridiflorene (27), and α-selinene (28) isolated from Eugenia species.
Fig. 3 Structures of sesquiterpene hydrocarbons bicyclogermacrene (29), β-bisabolene (30), γ-cadinene (31), β-cadinene (32), 7-epi-α-selinene (33), and zingiberene (34) isolated from Eugenia species.
Fig. 4 Structures of oxigenated sesquiterpene α-cadinol (35), (E)-nerolidol (36), epi-longipinanol (37), Curzerene (38), Caryophyllene alcohol (39), Spathulenol (40), Caryophyllene oxide (41), Globulol (42), Viridiflorol (43), Guaiol (44), 5-epi-paradisiol (45), 1,10-di-epi-cubenol (46), 10-epi-Eudesmol (47), and 1-epi-cubenol (48) isolated from Eugenia species.
Fig. 5 Structures of oxigenated sesquiterpene muurola-4,10(14)-dien-1β-ol (49), selina1,3,7(11) trien-8-one (50), t-muurolol (51), cubenol (52), valerianol (53), selin-11-en-4α-ol (54), 14-hydroxy-9-epi-β-caryophyllene (55), germacrone (56), selina-1,3,7(11)-trien-8-one epoxide (57), γ-eudesmol (58), farnesyl acetate (59), tetradecalactone (60), and γ-tetradecalactone (61) isolated from Eugenia species.
Fig. 6 Structures of aliphatic compounds physeteric acid (62) and ethyl palmitate (63) isolated from Eugenia species.
Triterpenes
The reported triterpenes were isolated from the stem and leaves of five species of Eugenia and are described in [Table 3], and their structures are shown in [Fig. 7]. The triterpenic acids present in many botanical families have also been isolated from species in the Eugenia genus, including betulinic acid, which has several biological properties, including cytotoxic and anticancer potential [65]. Other compounds, such as α, β-amirins, have been identified in Eugenia species. The structural characteristics of the compounds were determined via 1H and 13C nuclear magnetic resonance spectroscopy and are compared to experimental data described in the literature.
Table 3 Isolated compounds from Eugenia species in the studies selected through this systematic review.
|
Species
|
Part of plant
|
Components
|
References
|
|
Arabic numeral in bold corresponds to the chemical structures shown in [Figs. 7]–[10]
|
|
E. beaurepaireana (Kiaersk.) D.Legrand
|
Leaves
|
α-Amirin 64
β-Amirin 65
|
[36]
|
|
E. brasiliensis Lam.
|
Leaves
|
α-Amirin 64
β-Amirin 65
Betulin or 3β,28-dihydroxy-lup-20(29)-ene 66
Quercetin or 3,5,7,3′,4′-Pentahydroxyflavone 70 Catechin or (+)-(2R,3S)-5,7,3′,4′-Tetrahydroxyflavan-3-ol 68
Gallocatechin or (+)-(2R,3S)- 5,7,3′,4′,5′-Pentahydroxyflavan-3 ol 69
|
[4]
|
|
E. dysenterica DC.
|
Leaves
|
Procyanidin-B1 71
Catechin 68
Dimeric procyanidin gallate 72
|
[66]
|
|
E. florida DC.
|
Leaves
|
Betulinic acid 64
|
[65]
|
|
E. rigida DC.
|
Leaves
|
(Z)- 3,4,3′,5′ -Tetramethoxystilbene 73
|
[5]
|
|
(E)- 3,4,3′,5′ -Tetramethoxystilbene 74
|
|
(Z)- 3,5,4′ -Trimethoxystilbene 75
|
|
(E)- 3,5,4′ -Trimethoxystilbene 76
|
|
E. umbelliflora O.Berg.
|
Leaves
|
Taxaferol
Mixture of α- and β-Amirin 64 and 65
Mixture of Betulin and Betulinic acid 66 and 67
Betulinic acid 67
|
[22]
|
|
Fruits
|
Trimethoxy ellagic acid 77
Eugenial A similar to Euglobal A 78
Eugenial B similar to Euglobal B 79
Delphinidin 3-O-β-glucopyranoside 80
Cyanidin 3-O-β-glucopyranoside 81
Petunidin 3-glucoside 82
Pelargonidin 3-glucoside 83
Peonidin 3-glucoside 84
Malvidin 3- glucoside 85
|
[22], [67], [68]
|
Fig. 7 Structures of triterpenes isolates α-amirin (64), β-amirin (65), betulin (66), and betulinic acid (67) isolated from Eugenia species.
Polyphenols and cyanidins
Several species of Eugenia are used in traditional medicine as antibacterial and anti-inflammatory agents, attributable to high concentrations of polyphenolic compounds, hydrolysable tannins, and flavonoids. Natural phytoalexins (also called stilbenes) having several important biological activities, including anticancer properties, were isolated from E. rigida. The first stilbene reactant isolated from the genus Eugenia was (Z)-3,4,3′,5′-tetramethoxystilbene [5]. Further, euglobals were found in E. umbelliflora. Euglobals are substances that occur exclusively in the Eucalyptus genus of the family Myrtaceae and have known biological activities, including chemoprotective, antileishmanial, and antimalarial properties [67]. These compounds are described in [Table 3], and their chemical structures are shown in [Figs. 8]–[10].
Fig. 8 Structures of polyphenolic compounds isolates catechin (68), gallocatechin (69), quercetin (70), procyanidin-B1 (71), and dimeric procyanidin gallate (72) isolated from Eugenia species.
Fig. 9 Structures of polyphenolic compounds isolates (Z)-3,4,3′,5′-tetramethoxystilbene (73), (E)-3,4,3′,5′-tetramethoxystilbene (74), (Z)-3,5,4′-trimethoxystilbene (75), (E)-3,5,4′-trimethoxystilbene (76), trimethoxy ellagic acid (77), eugenial A (78), and eugenial B (79) isolated from Eugenia species.
Fig. 10 Structures of cyanidins isolates delphinidin 3-O-β-glucopyranoside (80), cyanidin 3-O-β-glucopyranoside (81), petunidin 3-glucoside (82), pelargonidin 3-glucoside (83), peonidin 3-glucoside (84), and malvidin 3-glucoside (85) isolated from Eugenia species.
Biological activities
Antimicrobial activity
Some Eugenia species were investigated for their antibacterial and antifungal activities. Studies of the antimicrobial activity of Eugenia species are reported in [Table 4].
Table 4 Antimicrobial activity of Eugenia species selected through this systematic review.
|
Eugenia species
|
Extraction/isolation procedure
|
Antimicrobial activity assay/control
|
Microrganisms and results
|
References
|
|
E. axillaris (SW.) Willd.
|
Essential oil of leaves/
hydrodistillation
|
Microdiluition method/gentamicin sulfate and amphotericin B
|
Bacillus cereus ATCC 14579 = 625 µg/mL
Staphylococcus aureus ATCC 29213 = 625 µg/mL
Pseudomonas aeruginosa ATCC 27853 = 625 µg/mL
Escherichia coli ATCC 25922 = 625 µg/mL
Candida albicans ATCC 10231 = 625 µg/mL
Aspergillus niger ATCC 16401 = 625 µg/mL
|
[17]
|
|
E. bacopari D.Legrand
|
Essential oil of leaves/
hydrodistillation
|
Agar diffusion method/
no date
|
Staphylococcus aureus ATCC 6538 p = 7 – 11 mm
|
[69]
|
|
E. beaurepaireana (Kiaersk.) D.Legrand
|
Essential oil of leaves/
hydrodistillation
|
Microdiluition method/gentamycin
|
Staphylococcus aureus ATCC 25923 = 1110 µg/mL
Escherichia coli ATCC 25922 = 556.6 µg/mL
Pseudomonas aeruginosa ATCC 27853 = 278.3 µg/mL
|
[62]
|
|
E. brasiliensis Lam.
|
Essential oil of leaves/
hydrodistillation
|
Microdiluition method/
no date
|
Staphylococcus saprophyticus = 500 – 1000 µg/mL
Staphylococcus aureus = 1000 µg/mL
Escherichia coli = 1000 µg/mL
Pseudomonas aeruginosa = 500 – 1000 µg/mL
|
[19]
|
|
Essential oil of leaves/
hydrodistillation
|
Microdiluition method/gentamycin
|
Staphylococcus aureus ATCC 25923 = 156.2 µg/mL
Escherichia coli ATCC 25922 = 624.9 µg/mL
Pseudomonas aeruginosa ATCC 27853 = 624.9 µg/mL
|
[62]
|
|
ethanol extract/
maceration Fractions: hexane, dichloromethane, and ethyl acetate
|
Microdiluition method/gentamycin
|
Staphylococcus aureus ATCC 25923 = 1560 – 6250 µg/mL
Escherichia coli ATCC 25922 = 390 – 6250 µg/mL
Pseudomonas aeruginosa ATCC 27853 = 780 – 6250 µg/mL
|
[4]
|
|
E. calycina Cambess.
|
Ethanol extract of bark and leaves/maceration Fractions were prepared from the ethanolic extracts (hexane, dichloromethane, and ethyl-acetate)
|
Microdiluition method/vancomycin, gentamycin, and itraconazole
|
Bacillus cereus ATCC 14579 = 250 – 2000 µg/mL
Bacillus subtilis ATCC 6633 = 1000 – 2000 µg/mL
Micrococcus roseus ATCC 1740 = 1000 – 2000 µg/mL
Micrococcus luteus ATCC 9341 = 1000 – 2000 µg/mL
Staphylococcus epidermidis ATCC 12229 = 1000 – 2000 µg/mL
Staphylococcus aureus ATCC 6538 = 500 – 2000 µg/mL
Staphylococcus aureus ATCC 25923 = 1000 – 2000 µg/mL
Enterobacter aerogenes ATCC 13048 = 1000 – 2000 µg/mL
Escherichia coli ATCC 11229 = 1000 – 2000 µg/mL
Pseudomonas aeruginosa ATCC 9027 = 2000 µg/mL
Pseudomonas aeruginosa (clinical isolate) = 2000 µg/mL
Salmonella spp. ATCC 19430 = 1000 – 2000 µg/mL
Serratia marcenscens ATCC 14756 = 1000 – 2000 µg/mL
Candida parapsilosis ATCC 22019 = 250 – 2000 µg/mL
Enterobacter cloacae (clinical isolate) = 1000 – 2000 µg/mL
Candida parapsilosis (clinical isolate) = 250 – 2000 µg/mL
Candida albicans (clinical isolate) = 500 – 2000 µg/mL
Cryptococcus sp. D (clinical isolate) = 15.62 – 2000 µg/mL
Cryptococcus gatti (clinical isolate) = 31.2 – 2000 µg/mL
Cryptococcus neoformans (clinical isolate) = 31.2 – 2000 µg/mL
|
[6]
|
|
E. chlorophyla O.Berg
|
Essential oil of leaves, steam, and flowers/
hydrodistillation
|
Microdiluition method/
bacitracina and ketoconazole
|
Streptococcus mutans ATCC 15175 = 50 – 500 µg/mL
Streptococcus sobrinus (clinical isolate) = 50 – 500 µg/mL
Staphylococcus aureus ATCC 6538 = 500 µg/mL
Kocuria ryzophila ATCC 9341 = 100 – 500 µg/mL
Staphylococcus aureus ATCC 6538 = 500 µg/mL Candida albicans ATCC 1023 = 500 µg/mL
|
[40]
|
|
E. dysenterica DC.
|
Essential oil of leaves/
hydrodistillation
|
Microdiluition method/
fluconazole, amphotericin B and itraconazole
|
Criptococcus neoformans = < 250 µg/mL
Criptococcus gatii (clinical isolate) = < 250 µg/mL
|
[70]
|
|
E. mansoni O.Berg
|
Ethanolic, acetonic, and chroroform extract of leaves/maceration
|
Agar diffusion method Microdiluition method/nystatin and gentamicin
|
Pseudomonas aeruginosa ATCC 27853 = resistant Staphylococcus aureus ATCC 6538 p = sensitive (+)
Listeria inocua (clinical isolate) = sensitive (+)
Aspergillus niger ATCC 2601 = sensitive (+)
Mycobacterium tuberculosis H37RvATCC 27294 = sensitive (+)/200 µg/mL
|
[71]
|
|
E. monteverdensis Barrie
|
Essential oil of leaves/
hydrodistillation
|
Microdiluition method/gentamycin
|
Bacillus cereus ATCC 14579 = 1250 µg/mL
Staphylococcus aureus ATCC 29213 = 1250 µg/mL
Escherichia coli ATCC 25922 = 1250 µg/mL
|
[48]
|
|
E. pyriformis Cambess.
|
Ethanolic extracts of leaves, flowers, roots, stems, and fruits/
maceration
|
Microdiluition method Agar diffusion method/chlorhexidine and rifamycin
|
Candida albicans ATCC 10231 = 12.5 – 50 µg/mL
Saccharomyces cerevisiae ATCC 2601 = 25 – 50 µg/mL
Bacillus subtilis ATCC 6633 = 25 – 50 µg/mL
Bacillus cereus ATCC 11778 = 12.5 – 50 µg/mL
Micrococcus luteus ATCC 9341 = 25 – 50 µg/mL
Enterococcus faecalis ATCC 51299 = 50 µg/mL
Staphylococcus aureus ATCC 6538 = 12.5 – 25 µg/mL
Escherichia coli ATCC 25922 = 12.5 µg/mL
Pseudomonas aeruginosa ATCC 27853 = 50 µg/mL
Proteus mirabilis ATCC 25922 = 50 µg/mL
Salmonella typhimurium ATCC 14028 = 2 – 50 µg/mL
Enterobacter cloacae (clinical isolate) = 12.5 – 50 µg/mL
Serratia marcescens (clinical isolate) = 25 – 50 µg/mL
|
[30]
|
|
Ethanolic extract fractions: hexane, chloroform, and ethyl acetate, hydroalcoholic. Acetonic extract/Soxhlet
|
Microdiluition method/vancomycin and fluconazole
|
Enterococcus faecalis ATCC 29212 = 62.5 – 1000 µg/mL
Stapylococcus aureus ATCC 25923 = 62.5 – 250 µg/mL
Escherichia coli ATCC 25922 = 250 – 1000 µg/mL
Klebsiella pneumoniae ATCC 700603 = 250 – 1000 µg/mL
Pseudomonas aeruginosa ATCC 27853 = 250 – 1000 µg/mL
Candida albicans ATCC 40175 = 7.81 – 62.5 µg/mL
Candida krusei ATCC 40147 = 7.81 – 31.25 µg/mL
Candida parapsilosis ATCC 40038 = 7.81 – 62.5 µg/mL
|
[20]
|
|
E. pluriflora DC.
|
Essential oil leaves of leaves/hydrodistillation
|
Agar diffusion method/
no date.
|
Staphylococcus epidermidis ATCC 12228 = 7 – 11 mm
Staphylococcus aureus ATCC 6538 p = 7 – 11 mm
Candida albicans ATCC 10231 = 7 – 11 mm
Micrococcus luteus ATCC 9341 = 11 – 16 mm
Saccharomyces cerevisae ATCC 160 = 11 – 16 mm
|
[69]
|
|
E. repanda O.Berg
|
Ethanolic extract/
maceration
|
Agar diffusion method Microdiluition method/nystatin and gentamicin
|
Psudomonas aeruginosa ATCC 27853 = resistant
Staphylococcus aureus ATCC 6538p = resistant
Listeria inocua (clinical isolate) = sensitive (+)
Aspergillus niger ATCC 2601 = sensitive (+)
Mycobacterium tuberculosis H37Rv ATCC 27294 = sensitive (+)/200 µg/mL
|
[71]
|
|
E. stipitata McVaugh
|
Essential oil of leaves/
hydrodistillation
|
Agar diffusion method/
tetracycline
|
Listeria monocytogenes ATCC 7973 = 12 mm Staphylococcus aureus ATCC 25923 = 14 mm Pseudomonas aeruginosa ATCC 27853 = 11 mm
|
[60]
|
|
E. umbelliflora O.Berg
|
Essential oil of leaves/
hydrodistillation
|
Microdiluition method/gentamycin
|
Staphylococcus aureus ATCC 25923 = 119.2 µg/mL
Escherichia coli ATCC 25922 = 477 µg/mL
Pseudomonas aeruginosa ATCC 27853 = 477 µg/mL
|
[62]
|
|
Methanol extracts of leaves and fruits/
maceration Fractions: dchloromethane and ethyl acetate
|
Microdiluition method/
ketoconazole
|
Aspergillus flavus ATCC 9170 = > 1000 µg/mL
Aspergillus fumigatus ATCC 26934 = > 1000 µg/mL
Aspergillus niger ATCC 9092 = > 1000 µg/mL
Rhizopus sp (clinical isolate) = > 1000 µg/mL
Microsporum canis (clinical isolate) = 300 > 1000 µg/mL
Microsporum gypseum (clinical isolate) = 300 – > 1000 µg/mL
Trichophyton mentagrophytes ATCC 9972 = 600 – > 1000 µg/mL
Trichophyton rubrum (clinical isolate) = 400 – > 1000 µg/mL
Epidermophyton floccosum (clinical isolate) = 300 – > 1000 µg/mL
Cryptococcus neoformans ATCC 32264 = > 1000 µg/mL
Candida albicans ATCC 1023 = > 1000 µg/mL
Candida tropicalis ATCC 7349 = > 1000 µg/mL
|
[72]
|
|
Methanol extracts of leaves and fruits/
maceration Fractions: dchloromethane and ethyl acetate
|
Microdiluition method/vancomycin
|
Bacillus cereus ATCC 14579 = 7 – 300 µg/mL
Enterobacter cloacae ATCC 35030 = 900 µg/mL
Escherichia coli ATCC 11775 = 900 µg/mL
Pseudomonas aeruginosa ATCC 27853 = 900 µg/mL
Salmonella typhimurium ATCC 14028 = 900 µg/mL
Staphylococcus aureus ATCC 6538P = 6 – 100 µg/mL
Staphylococcus saprophyticus ATCC 35552 = 10 – 200 µg/mL
Streptococcus agalactiae ATCC 13813 = 2 – 400 µg/mL
|
[73]
|
|
E. uniflora L.
|
n-Hexane fraction of leaves/maceration
|
Disc diffusion/trimethoprim, sulfamethoxazole, and para-chlorocresol
|
Escherichia coli = 5.000 µg/mL
Aspergillus flavus = 5.000 µg/mL
|
[24]
|
|
Essential oil leaves of leaves/hydrodistillation
|
Disc diffusion/ketoconazole
|
Epidermophyton floccosum = 12 – 18 mm
Trichophyton mentagrophytes = 16 – 18 mm
Trichophyton rubrum = 15 – 20 mm
|
[74]
|
|
Essential oil of leaves/
hydrodistillation
|
Agar diffusion method Microdiluition method/
sulphadiazine and cephalotine
|
Candida albicans (clinical isolate) = 208.3 µg/mL Candida parapsilosis (clinical isolate) = 208.3 µg/mL
Candida guilhermondii (clinical isolate) = 109.4 µg/mL
Candida globosa (clinical isolate) = 187.5 µg/mL
Candida lipolytica (clinical isolate) = 93.7 µg/mL
Candida laurentii (clinical isolate) = 208.3 µg/mL
Trichosporon asahii (clinical isolate) = 312.5 µg/mL
|
[75]
|
|
Essential oil leaves/
hydrodistillation
|
Disc diffusion Microdiluition method/
fluconazole and chloramfenicol
|
Candida dubliniensis ATCC 7978 = 230 µg/mL
Candida tropicalis ATCC 13803 = 900 µg/mL
Candida albicans ATCC 18804 = 1.800 µg/mL
Candida glabrata ATCC 90030 = 930 µg/mL
Candida parapsilosis (clinical isolate) = 3.750 µg/mL
Candida grubii KN99 (serotype A) = 450 µg/mL Candida gattii R265 (serotype B) = 220 µg/mL
Cryptococcus neoformans JEC21 (serotype D) = 110 µg/mL
Saccharomyces cerevisiae BY4742 = 220 µg/mL
|
[76]
|
|
Ethanol extract/
maceration
|
Microdiluition method/amphotericin B and itraconazole
|
Candida krusei = 250 µg/mL
Aspergillus fumigatus = > 500 µg/mL
|
[77]
|
|
Essential oil leaves/
hydrodistillation
|
Microdiluition method/
no date
|
MIC90 Clinical Isolates: Staphylococcus aureus methicillin-resistant (MRSA), Staphylococcus aureus methicillin-sensitive (MSSA), Escherichia coli, Pseudomonas aeruginosa, Salmonella typhimurium, Salmonella enteritidis = 50.800 – 92.400 µg/mL
|
[78]
|
|
Essential oil leaves/
hydrodistillation
|
Macrodiluition method/
no date
|
Paracoccidioides brasiliensis = 62.5 – 250 µg/mL
|
[27]
|
|
Ethanolic extracts of leaves/maceration
|
Microdiluition method/pennicilin G and eritromicin
|
Micrococcus roseus ATCC 1740 = 2.187 µg/mL
Micrococcus luteus ATCC 9341 = 273 µg/mL
Bacillus cereus ATCC 14576 = 1.094 µg/mL
Bacillus stearothermophylus ATCC 1262 = 2.187 µg/mL
Bacillus subtilis ATCC 6633 = 2.187 µg/mL
Enterobacter aerogenes ATCC 13048 = 17.500 µg/mL
Escherichia coli ATCC 8739 = 17.500 µg/mL
Staphylococcus aureus ATCC 6538 = 2.187 µg/mL
Staphylococcus aureus ATCC 25923 = 2.187 µg/mL
Staphylococcus epidermidis ATCC 12228 = 273 µg/mL
Pseudomonas aeruginosa ATCC 27853 = 8.750 µg/mL
Serratia marcescens ATCC 14756 = 35.000 µg/mL
Enterobacter cloacae (clinical isolate) = 17.500 µg/mL
Candida albicans (clinical isolate) = 547 µg/mL
|
[28]
|
|
Ethanolic extracts of leaves/maceration Fractions: hexane, chloroform, and ethyl acetate
|
Agar diffusion method Microdiluition method/
no date
|
n = 80, Pseudomonas aeruginosa (clinical isolate) = 1.090 – 17.500 µg/mL
|
[79]
|
|
Ethanolic extracts of leaves/maceration
|
Agar diffusion method Microdiluition method/
ceftriaxone
|
Staphylococcus aureus ATCC 25923 = 250 µg/mL
Staphylococcus epidermidis ATCC 14990 = 52 µg/mL
Pseudomonas aeruginosa ATCC 27853 = 14 mm
Escherichia coli ATCC 14942 = 11 mm
|
[80]
|
|
Ethanolic extracts of leaves/maceration
|
Microdiluition method/amphotericin B, mebendazole, nystatin and metronidazole
|
Candida albicans = > 1.024 µg/mL
Candida krusei = > 1.024 µg/mL
Candida tropicalis = 1.024 µg/mL
|
[81]
|
|
Methanolic extracts of leaves/maceration
|
Microdiluition method/
no date
|
Pseudomonas aeruginosa = 10 µg/mL
Shigella sonnei = 156 µg/mL
Bacillus cereus = 39 µg/mL
|
[25]
|
|
Methanolic extracts of leaves/maceration
|
Agar diffusion method/chloramphenicol and nystatin
|
Staphylococcus aureus ATCC 6538P = sensitive (+)
Bacillus subtilis ATCC 6633 = sensitive (+)
Micrococcus luteus ATCC9341 = sensitive (+++)
Staphylococcus epidermidis ATCC12228 = resistant
Escherichia coli ATCC 25922 = resistant
Candida albicans ATCC 10231 = resistant
|
[82]
|
|
Hydroalcoholic extracts of leaves/maceration process with ethanol-water (90 – 10%)
|
Microdiluition method Bioautography method/tetracycline, vancomycin, penicillin and nistatin
|
Escherichia coli ATCC 25922 = 500 µg/mL Pseudomonas aeruginosa ATCC 15442 = > 1000 µg/mL Bacillus subtilis ATCC 6623 = > 1000 µg/mL
Staphylococcus aureus ATCC 25923 = 250 µg/mL
Candida albicans (clinical isolate) = > 1000 µg/mL
Candida krusei (clinical isolate) = 31.2 µg/mL
Candida parapsilosis (clinical isolate) = 125 µg/mL
Candida tropicalis (clinical isolate) = 31.2 µg/mL
|
[83]
|
|
Hydroalcoholic extracts/percolation
|
Microdiluition method/ampycilin and nistatyn
|
Staphylococcus aureus ATCC 6538 = 80 µg/mL
Salmonella choleraesuis ATCC 10708 = 100 µg/mL
Pseudomonas aeruginosa ATCC 15442 = 400 µg/mL
Candida albicans ATCC 10231 = 500 µg/mL
Aspergillus niger ATCC 16404 = 900 µg/mL
|
[29]
|
|
E. uruguayensis Cambess.
|
Extracts/maceration with EtOH/H2O 70 : 30, acetone and CHCl3
|
Microdiluition method/
no date
|
Staphylococcus aureus ATCC 6538 p MSSA = 31.3 µg/mL
Staphylococcus aureus ATCC 700699 MRSA = 31.3 µg/mL
Staphylococcus aureus ATCC 43300 MRSA = 31.3 µg/mL
Staphylococcus aureus USA 100 MRSA = 31.3 µg/mL
|
[84]
|
|
Essential oil of leaves/
hydrodistillation
|
Agar diffusion method/
no date
|
Staphylococcus epidermidis ATCC 12228 = 11 – 16 mm
Escherichia coli ATCC 25922 = 11 – 16 mm
Saccharomyces cerevisae ATCC 160 = 10 – 16 mm
|
[69]
|
Preparations of essential oils, leaf extracts, stems, and seeds of Eugenia species have been widely researched for their activities against gram-positive and gram-negative bacteria, as well as some species of yeast-like fungi, and compared to the activity of standard drugs. There are few studies on the antimicrobial activity of the isolated compounds.
Different antimicrobial activity assays with different antibiotic and antifungal controls were used, including agar diffusion, disc diffusion, bioautography, macrodilution, and microdilution.
Eugenia species were tested against ATCC and clinical isolates of gram-positive and gram-negative bacteria, as well as yeast-like fungi.
When the results were analyzed, the minimum inhibitory concentration (MIC) values were classified as having good inhibitory potential (less than 100 µg/mL), moderate inhibitory potential (between 100 and 500 µg/mL), weak inhibitory potential (between 500 and 1000 µg/mL), or the absence of inhibitory potential (above 1000 µg/mL) [20].
According to this established profile, the Eugenia calycina, E. pyriformis, E. umbelliflora, E. uniflora, and Eugenia uruguayensis species demonstrated good inhibitory potential against gram-positive and gram-negative bacteria, as well as yeast-like fungi. Samples of ethanolic, methanolic, and ketonic extracts and essential oil evaluated against strains of several microorganisms showed MIC values ranging from 7 to 100 µg/mL. The antimicrobial activity observed has been attributed to the presence of different bioactive compounds that have an impact on the growth and metabolism of microorganisms. Medicinal plants are known to produce antimicrobial substances belonging to many chemical classes, such as alkaloids, lignins, phenolic compounds, and terpenoids [20].
Moderate antimicrobial potential was observed against strains of gram-positive and gram-negative bacteria, as well as yeast-like fungi, with MIC values ranging from 156.2 to 500 µg/mL in several Eugenia species.
Antimicrobial activity in the presence of standard antibiotics
The compounds present in plants are capable of retarding or inhibiting the growth of bacteria, yeasts, and yeast-like fungi when used alone. However, there is also the possibility of using them in combination with conventional antimicrobials to improve their effectiveness [20]. The MIC of an E. uniflora ethanolic extract was reduced in the presence of the antibiotics amikacin, gentamicin, kanamycin, neomycin, and tobramycin at concentrations of 16 and 32 µg/mL when tested against clinical isolates of Staphylococcus aureus, demonstrating a synergistic effect [23]. However, the same samples evaluated against clinical isolates of Escherichia coli at a concentration of 128 µg/mL showed no synergistic effects [85]. An ethanolic extract from E. uniflora leaves evaluated against Candida tropicalis (ATCC 13803) alone and in combination with the antifungal metronidazole reduced the MIC of metronidazole from 128 to 32 µg/mL, a fourfold reduction [81].
The checkerboard method was used to evaluate synergistic interactions between E. pyriformis and vancomycin or fluconazole. A combination of the hydroalcoholic fraction from the E. pyriformis leaves and vancomycin exhibited synergism against Enterococcus faecalis, with a fractionated inhibitory concentration index (FICI) of 0.37. FICI values are interpreted as synergistic (FICI < 0.5), additive (0.5 < FICI > 4), or antagonistic (FICI > 4) [20]. In addition, combinations of fluconazole with an E. pyriformis crude leaf extract and acetone extract showed activity against Candida krusei and Candida parapsilosis, with FICI values between 0.24 and 0.50. Further, a synergistic interaction was observed when an ethyl acetate fraction of E. pyriformis leaves was combined with vancomycin or fluconazole to treat Candida albicans, C. krusei, and C. parapsilosis resulted in FICI values between 0.24 and 0.37 [20].
Cytotoxicity
The cytotoxic activity of Eugenia species is reported in [Table 5]. In these studies, several extraction methods were used to obtain extracts, fractions, and essential oils from leaves, fruits, and seeds of some Eugenia species. Effective results against growth in different tumor cell lineages and Artemia salina were observed. Specimens of A. salina Leach (brine shrimp), a marine microcrustacean, were used as target organisms to detect bioactive compounds in plant extracts, and toxicity tests against these animals have shown a good correlation with antitumor activity [86]. Medium lethal concentrations (LC50) were used to estimate the toxicity of A. salina, providing a general toxicity analysis, and several studies correlated this method with antiviral, antiparasitic, and antitumor activity [87], [88], [89]. The essential oil of Eugenia zuchowskiae Barrie was cytotoxic, with 100% death when used to treat cell lines at 100 µg/mL [18]. E. zuchowskiae Barrie extracts comprise α-pinene, β-caryophyllene, and α-humulene compounds. α-Pinene has exhibited cytotoxic activity in Hep G2 human hepatocellular carcinoma cells, and α-humulene has been shown to be active in several tumor cell lines [90].
Table 5 Cytotoxic activity of Eugenia species in the studies selected through this systematic review.
|
Species
|
Extraction
|
Cytotoxicity assays
|
Cell lineages
|
Cytotoxic activity
|
Reference
|
|
E. axilaris (SW.) Willd
|
Essential oils of leaves/hydrodistillation
dichloromethane extraction
|
In vitro cytotoxicity assay MTS
|
PC-3 (human prostatic adenocarcinoma)
MDA-MB-231 (human mammary adenocarcinoma)
MCF7 (human mammary adenocarcinoma)
Hs 578T (human ductal carcinoma)
Hep G2 (human hepatocellular carcinoma)
|
PC-3 = 67.47%
MDA-MB-231 = 42.66%
MCF7 = 30.21%
Hs 578 T = 95.79%
Hep G2 = 92.21%
Cytotoxicity expressed as percentage kill at 250 µg/mL for Hs 578T and Hep G2; and at 100 µg/mL for PC-3, MDA-MB-231 and MCF7
|
[17]
|
|
E. calycina Cambess.
|
Essential oils of leaves/hydrodistillation
Fractions obtained of Dichloromethane: F1, F2, F3, and F4
|
In vitro cytotoxicity assay MTT cervical cancer cell lines
|
Cervical cancer cell lines (HeLa ECACC 93021013)
|
EO CC50 = 137.4 ± 9.6 µg/mL
F1 CC50 = 120.0 ± 9.4 µg/mL
F2 CC50 = 117.6 ± 9.6 µg/mL
F3 CC50 = 151.1 ± 8.3 µg/mL
F4 CC50 = 139.2 ± 5.1 µg/mL
|
[7]
|
|
E. cartagensis O.Berg
|
Essential oils of leaves/hydrodistillation
|
In vitro cytotoxicity assay MTT
|
Colorectal carcinoma cells (HCT-15 and SW 620)
Malignant melanoma cells (MCF7, M-14 and SK-Mel-28)
Malignant melanoma cells (Malme-3M and UACC-257)
Mammary adenocarcinoma cells (MDA-MB-231)
Mammary ductal carcinoma cells (MDA-MB-435)
Ovarian adenocarcinoma cells (OVCAR-5 cells)
|
Cytotoxic against HCT-15 and SW 620 cells at a concentration of 100 µg/mL, with 100 and 84.1% cell death, respectively.
These oils were less active against MCF7 (73.5%), M-14 (45.3%), and SK-Mel-28 (41.3%) cells and were inactive against MDA-MB-468 cells, Malme-3M and UACC-257 cells, MDA-MB-231 cells, MDA-MB-435 cells, and OVCAR-5 cells.
|
[39]
|
|
E. dysenterica DC.
|
Ethanolic extract of leaves/maceration
|
In vitro cytotoxicity in Rhesus neonato monkey cells
|
Rhesus neonato monkey cells (MA-104)
|
Disruption of the cell layer observed at a concentration of 5000 µg/mL
|
[16]
|
|
E. monteverdensis Barrie
|
Essential oils of leaves and fruits/hydrodistillation
|
In vitro cytotoxicity assay MTT
|
Human MDA-MB-231 breast adenocarcinoma cells Human Hs 578T breast ductal carcinoma cells
|
MDA-MB-231 or Hs 578 T human tumor cells (0% killing at 100 µg/mL)
|
[48]
|
|
E. uniflora L.
|
Ethanolic extract of leaves/maceration
|
Brine shrimp lethality bioassay
|
Artemia salina Leach eggs
varying concentrations 1 to 1000 µg/mL
|
LC50 values above 250 µg/mL, with a 95% confidence interval (194.2 – 433.7)
|
[88]
|
|
Methanolic extract of leaves/maceration
|
Brine shrimp lethality bioassay
|
Artemia salina Leach eggs
varying concentrations 10 to 1000 µg/mL
|
LC50 values above 250 µg/mL
|
[25]
|
|
Ethanolic extract of leaves/maceration
|
In vitro cytotoxicity assay
|
J774 macrophages
|
8% cytotoxic activity in J774 macrophages at a concentration of 100 µg/mL
|
[91]
|
|
Ethanolic extract of fruits/maceration
|
MTT assay
Tritiated thymidine incorporation assay
GRX
MitoTracker Green
MitoTracker
Flow cytometry assays Cell
|
HSC line was obtained from livers of C3H/HeN mice that were infected by transcutaneous penetration of cercariae from the Schistosoma mansoni BH strain (GRX)
|
Viability cell was significantly decreased on cells treated with 50 µg/mL of extract for 72 h and on cells treated with 100 µg/mL for 48 and 72 h.
Proliferation cell: The reduction of cell proliferation was dose dependent at the cell counting assay and the cells treated with 100 µg/mL of extract visually, not increased in three days of treatment.
Mitochondrial content was significantly reduced in GRX cells treated with 50 and 100 µg/mL of an extract at all times studied. The cells treated with 50 and 100 µg/mL of extract for 24 h showed a 13% increase in the number of GRX cells in the G0G1 phase and a reduction in the S phase.
We did not observe an increase in
apoptosis in cells treated for 24 and 48 h. However, the percentage of necrotic cells increased significantly in cells treated with 50 and 100 µg/mL for 48 h.
|
[26]
|
|
Methanolic extracts of leaves and seeds
Fraction: ethyl acetate, n-butanol and aqueous fraction
|
In vitro cytotoxicity assay splenocytes from BALB/c mice
|
Splenocytes from BALB/c mice Each sample was evaluated in six concentrations (1, 5, 10, 25, 50, and 100 g/mL) in triplicate
|
Ethyl acetate fraction of leaves = 50 and 100 µg/mL
Ethyl acetate fraction of seeds = 25, 50, and 100 µg/mL
Butanol fraction of seeds = 100 µg/mL
Control saponin
|
[92]
|
|
Essential oils of leaves/hydrodistillation
|
In vitro cytotoxicity assay MTT
|
Vero cell line
|
IC50 = 117.4 ± 11.9 µg/mL
|
[77]
|
|
Essential oils of leaves/hydrodistillation
|
In vitro cytotoxicity assays (3T3 cells) neutral red
|
Balb/c 3T3 fibroblast
|
IC50 = > 1 mg/mL (no potential cytotoxic at concentrations > 1 mg/mL)
|
[93]
|
|
E. supraaxillaris Spreng.
|
Essential oils of leaves and fruits/hydrodistillation
|
In vitro cytotoxicity assay tumor cell lines
|
Tumor cell lines (cervices, colon, larynx, liver, and breast)
|
Cervices IC50 = 0.62 µL leaves and 1.30 µL fruits
Colon IC50 = 0.43 µL leaves and 0.43 µL fruits
Larynx IC50 = 0.54 µL leaves and 0.87 µL fruits
Liver IC50 = 0.40 µL leaves and 0.38 µL fruits
Breast IC50 = 0.40 µL leaves and 1.40 µL fruits
|
[1]
|
|
E. zuchowskiae Barrie
|
Essential oils of leaves/hydrodistillation
|
In vitro cytotoxicity assay MTT
|
MCF-7, MDA-MB-468, and
UACC-257 human tumor
|
MCF-7 = 100% kill MDA-MB-468 = 100% kill
UACC-257 = 100% kill
Expressed as % kill at 100 µg/mL concentration
|
[18]
|
Conclusions, Discussion, and Future Perspectives
Species of Eugenia have been investigated in recent decades, revealing a great diversity in chemical composition. Hydrocarbons and oxygenated derivatives have been identified in the essential oils of Eugenia species, while in extracts of the aerial parts, the compounds triterpenes, flavonoids, tannins, and cyanidins have been identified. In view of the chemical diversity described, Eugenia species are likely a promising source of bioactive compounds. Of the Eugenia species known, only 350 have been investigated for their chemical composition and biological activity, demonstrating a shortage of studies for this genus. E. uniflora was the most studied species, attributable to its popular use. It is important to consider that Eugenia species are used in folk medicine, and several therapeutic properties have been reported, including antibacterial and antifungal activity against various microorganisms. Several studies evaluating the antimicrobial activity of extracts and derivatives used in combination with commercial antimicrobials revealed synergistic effects against microorganisms, potentializing the efficacy of these agents. However, some studies evaluating the bioactivities did not present a positive control or use a comparator to infer value to the results obtained, such as MIC or IC50 values. Finally, we observed that cytotoxicity studies performed with Eugenia species presented wide methodological variations, making it difficult to compare the observed biological effects.
Studies exploring the association between the various phytochemicals and their biological activities may lead to the discovery of new bioactive compounds with therapeutic potential in Eugenia species that are native to Brazilian flora. Natural sources should be further explored and may result in the discovery of chemically diverse and biologically active compounds, including promising drugs in the search for new antimicrobial agents. Detection of these agents is important, as the increase in pathogen resistance to commercially available antimicrobials is a global health problem. Thus, this review suggests that species in the Eugenia genus have promising biological activities, supporting the need for future research on the development of drugs from the extracts and chemical constituents.
