Chapter 12
Phytochemistry and biological activities of algerian Centaurea and related genera Radia Ayad and Salah Akkal* Valorization of Natural Resources, Bioactive Molecules and Biological Analysis Unit, Department of Chemistry, University Fre`res Mentouri Constantine1, Constantine, Algeria * Corresponding author: e-mail:
[email protected]
Chapter Outline Introduction Chemical constituents Phenolic compounds Phenolic acids Flavonoids Terpenoids Germacranolides Elemanolides Eudesmanolides Guaianolides Triterpenoids Other compounds
357 358 359 359 359 381 383 399 399 399 400 400
Essential oils Biological activities Antioxidant and antiradical activities Antibacterial and antifungal effects Cytotoxic properties Antiplasmodial activity Analgesic activity Concluding remarks Abbreviations References
400 408 408 409 410 411 411 411 411 412
Introduction Asteraceae also called Compositae, the aster, daisy or composite family of the plant order Asterales, is one of the biggest and important plant families which embraces more than 1620 genera and 23,600 species of herbs, shrubs and trees. It has a cosmopolitan distribution throughout the world. South America is home of about 20% of the existing genera and it is accepted to be phylogenetically the geographic origin of this family [1–3]. Based on analyses of 9 chloroplast regions, the family Asteraceae is divided into 12 subfamilies and 35 tribes. One of the largest tribes is Cardueae Cass. with four subtribes (Carlininae, Echonipinae, Carduinae, and Centaureinae) that consist of more than 2500 species. Studies in Natural Products Chemistry, Vol. 63. https://doi.org/10.1016/B978-0-12-817901-7.00012-5 Copyright © 2019 Elsevier B.V. All rights reserved.
357
358 Studies in Natural Products Chemistry
The Mediterranean basin can be considered as the center of species diversity for the sub-tribe Centaureinae [4,5], containing about 31 genera with roughly 800 species, varying from tall shrubs to small annuals, with the majority being polycarpic perennial herbs or monocarpic biennials [6]. According to Susanna and Garcia-Jacas [7], the genera of Centaureinae is organized into several informal groups, confirmed by recent molecular studies as natural: 1. Basal genera; 2. Volutaria group; 3. Rhaponticum group; 4. Serratula group; 5. Carthamus group; 6. Crocodylium group; 7. Centaurea group. The genus Centaurea is one of the largest genera of the sub-tribe Centaureinae including approximately 250 species [7] (400 in an earlier classification [8]). East Anatolia and Transcaucasus are the primary centers of origin of the genus Centaurea while the Mediterranean area and the Balcan Peninsula are secondary centers [9–11]. The Mediterranean region is considered as a refugium for many of these species [12], and several endemic taxa of Centaurea are very narrowly distributed in the region [13]. In Algerian flora, 45 species are present with 7 species localized in the Sahara [14]. Algerian taxa of Centaurea and related genera (Cheirolophus, Rhaponticoides, and Volutaria) have been the object of many phytochemical investigations highlighting their richness in bioactive secondary metabolites mainly flavonoids and sesquiterpene lactones [15–19]. As reported by many pharmacological studies, various crude extracts and isolated compounds from Algerian Centaurea species have shown important biological activities, such as cytotoxic, antimicrobial, antioxidant and antiplasmodial [20–25]. The aim of this paper is to compile and recap the existing data on phytochemical and pharmacological research of Algerian Centaurea and related genera (Cheirolophus, Rhaponticoides, and Volutaria) to date by focusing on their chemical analysis, structural features, biological and pharmacological properties to provide information for further research on these genera. The listed species in this paper were identified mainly on the basis of Quezel and Santa [14], as well as Ozenda [26], and Battandier [27]. The names of the plant species have been updated from the Euro + Med PlantBase (www.emplantbase.org).
Chemical constituents According to several previous phytochemical studies on Algerian plant species, overall 23 species from the genus Centaurea and 3 from related genera (Cheirolophus, Rhaponticoides, and Volutaria) were investigated for the period from 1977 to 2018. These studies have led to the isolation and identification of more than 155 secondary metabolites, including 14 phenolic acids, 65 flavonoids, 59 sesquiterpene lactones, 6 triterpenoids, 14 other compounds and essential oils (Fig. 12.1).
Algerian Centaurea and related genera Chapter
Other constituents 9% Phenolic acids 9%
12 359
Triterpenoids 4% Flavonoids 41%
Sesquiterpene lactones 38% FIG. 12.1 Chemical constituents from Algerian Centaurea and related genera 1977–2018.
Phenolic compounds Phenolic compounds, the most abundant secondary metabolites in plants, are found ubiquitously in Algerian plant species. Phenolic compounds possess a common chemical structure comprising an aromatic ring with one or more hydroxyl substituents that can be divided into several classes, and the main groups of phenolic compounds include flavonoids, phenolic acids, tannins, stilbenes, and lignans [28,29]. Phenolic compounds are extensively present in Algerian Centaurea and related genera (Cheirolophus, Rhaponticoides, and Volutaria). Among all the phenolic compounds described in this paper, flavonoids are the most abundant with 65 different structures. Phenolic acids and simple phenols also exist in some species.
Phenolic acids Phenolic acids belong to a major class of phenolic compounds in plants and are present in free and bound forms. Phenolic acids can be divided into two subgroups: hydroxybenzoic acid (C6–C1 structure) and hydroxycinnamic acid (C6–C3 structure) [29]. Two Algerian Centaurea species, namely, C. choulettiana and C. fragilis have been studied for their phenolic profile: seven hydroxybenzoic acids (1–7) and seven hydroxycinnamic acids (8–14) have been identified. Indeed paridol (3), protocatechuic acid (4) and 5-hydroxyferulic acid (12) were isolated from C. diluta subsp. algeriensis, C. melitensis and Rhaponticoides africana (¼ C. africana), respectively. The chemical structures of phenolic acids are summarized in Table 12.1.
Flavonoids Flavonoids represent the largest group of phenolic compounds from plants. More than 8000 kinds of flavonoids have been reported until 2006 [32], and
TABLE 12.1 Phenolic acids isolated from Algerian Centaurea and related genus Rhaponticoides. No
Phenolic acids
1
HO
Name
Taxa
Reference
Salicylic acid
C. choulettiana
[23]
4-Hydroxybenzoic acid
C. choulettiana
[23]
C. fragilis
[30]
Paridol
C. diluta subsp. algeriensis
[24]
Protocatechuic acid
C. choulettiana
[23]
C. fragilis
[30]
C. melitensis
[19]
C. choulettiana
[23]
C. fragilis
[30]
HO
O
2
O OH HO
3
O OH MeO
4
OH HO OH O
5
Gentisic acid
HO HO
O OH
6
Vanillic acid
OH
C. choulettiana
[23]
C. fragilis
[30]
Syringic acid
C. fragilis
[30]
Cinnamic acid
C. fragilis
[30]
P-coumaric acid
C. choulettiana
[23]
Caffeic acid
C. choulettiana
[23]
Ferulic acid
C. choulettiana
[23]
O
OMe
OH
7
OMe HO OH O OMe
8
HO
O
9
HO
OH
O
10
HO
OH
O
OH
11
HO
O
OH
OMe
Continued
TABLE 12.1 Phenolic acids isolated from Algerian Centaurea and related genus Rhaponticoides.—Cont’d No
Phenolic acids
12
HO
OH
Name
Taxa
Reference
5-Hydroxyferulic acid
Rhaponticoides africana (sub C. africana)
[31]
Sinapic acid
C. fragilis
[30]
Chlorogenic acid
C. choulettiana
[23]
C. fragilis
[30]
OH
O
OMe
13
HO
OMe
OH
O
OMe
14
HO COOH
HO
O HO
O
OH OH
Algerian Centaurea and related genera Chapter
12 363
3′ 4′
2' 8 7
A
B
1 O
5′
2 6'
C
3
6 4
5 O FIG. 12.2 The base skeleton of flavonoids.
the number continues growing. The flavonoid consists of 15 carbon atoms arranged in three rings (C6–C3–C6) labeled as A, B, and C, respectively. A and B are two aromatic rings, and C is a three-carbon bridge, usually in the form of a heterocyclic ring. Based on saturation degree and C-ring substituents, flavonoids are divided into several subgroups, including flavonols, flavones, flavanones, isoflavones, flavanonols, chalcones, dihydrochalcones, aurones, flavans, proanthocyanidins and anthocyanins [29] (Fig. 12.2). The occurrence of flavonoids has been reported in the majority of Algerian Centaurea and related genera. In fact 65 flavonoids from different classes have been detected, including 33 flavonoid aglycones (15–47) and 32 flavonoid glycosides (48–79). Their structures are summarized in Tables 12.2 and 12.3. The flavonoid profile of Algerian Centaurea species encompasses flavones (15–35), flavonols (36–46), a single flavanone (47), flavone O-glycosides (48–58), flavonol glycosides (59–71), two flavanone glycosides (72, 73) and flavone C-glycosides (74–79) (Fig. 12.3). Most flavonoids have polyhydroxy substitutions, a wide variety of O-methylation patterns and diverse glycosylations (glucopyranosyl, galactosyl, neohesperidosyl, gentiobiosyl, sophorosyl and rutinosyl groups). The presence of 5,7 dihydroxy groups attached to ring A, is a common feature in 33 flavonoids. The 40 hydroxy group is present in most structures, while the rest show the presence of a 40 methoxy substituent rather than the hydroxyl group. Moreover, 23 flavonoids show a 6-methoxy substituent. Also the methoxy substituted group at C-7, C-8, C-30 and C-50 are reported. Another interesting observation is the occurrence of tetramethoxylated flavonoids in Algerian Centaurea and related genus Rhaponticoides. On the other hand, the glycosylation at C-7 is the widespeared position in the majority of heterosides (flavonoid glycosides). Flavones represent the most numerous subgroup, containing 21 compounds, among which, two (15, 19) are devoid of substituents in the ring B, two (16, 22) show the presence of 20 hydroxy group and one (20) contains a 5 methoxy group; five rare cases detected in Algerian Centaurea species (C. omphalotricha and C. parviflora).
TABLE 12.2 Flavonoid aglycones from Algerian Centaurea and related genus Rhaponticoides. No
Flavonoid aglycones
Name
Taxa
Reference
Chrysin
C. omphalodes
[33]
C. omphalotricha
[34]
5,7,20 -Trihydroxyflavone
C. omphalotricha
[34]
Apigenin
C. calcitrapa
[35]
C. furfuracea
[36]
C. maroccana
[37]
C. sicula (sub C. nicaensis)
[38]
C. omphalotricha
[21]
C. tougourensis
[39]
Flavones 15 O
HO
OH
O
16
HO O
HO
O
OH
17
OH O
HO
OH
O
18
OH
Luteolin
C. omphalotricha
[21]
Oroxylin A
C. omphalotricha
[34]
Thevtiaflavone
C. parviflora
[40]
Genkwanin
C. parviflora
[40]
Tenaxin II
C. omphalotricha
[34]
OH O
HO
OH
O
19 O
HO
MeO O
OH
20
OH O
HO
OMe
O
21
OH O
MeO
OH
O
22
HO O
HO
MeO OH
O
Continued
TABLE 12.2 Flavonoid aglycones from Algerian Centaurea and related genus Rhaponticoides.—Cont’d No
Flavonoid aglycones
23
OH HO
Name
Taxa
Reference
Hispidulin
C. acaulis
[38]
Rhaponticoides africana (sub C. africana)
[31]
C. furfuracea
[36]
C. melitensis
[19]
C. maroccana
[37]
C. pubescens (sub C. incana)
[16]
Rhaponticoides africana (sub C. africana)
[20]
C. omphalodes
[33]
C. furfuracea
[36]
C. omphalodes
[33]
C. omphalotricha
[21]
C. sulphurea
[40]
O
MeO OH
O
24
Chrysoeriol
OMe OH HO
O
OH
O
25
OH
Cirsimaritin
O
MeO
MeO OH
O
26
OMe HO
O
MeO OH
O
Pectolarigenin
27
OMe MeO
Salvigenin
C. omphalodes
[33]
Nepetin
Rhaponticoides africana (sub C. africana)
[31]
C. foucauldiana
[41]
C. pubescens (sub C. incana)
[16]
C. melitensis
[19]
C. microcarpa
[18]
C. sicula (sub C. nicaensis)
[42]
C. sulphurea
[43]
C. tougourensis
[39]
C. diluta subsp. algeriensis
[24]
C. foucauldiana
[41]
C. melitensis
[44]
C. sicula (sub C. nicaensis)
[38]
C. sulphurea
[43]
C. tougourensis
[39]
C. parviflora
[40]
C. pullata
[45]
O
MeO OH
O
28
OH OH O
HO
MeO OH
O
29
Jaceosidin
OMe OH HO
O
MeO OH
O
Continued
TABLE 12.2 Flavonoid aglycones from Algerian Centaurea and related genus Rhaponticoides.—Cont’d No
Flavonoid aglycones
30
Name
Taxa
Reference
C. pubescens (sub C. incana)
[16]
Eupatrin;
C. calcitrapa
[35]
Cirsilineol
C. foucauldiana
[41]
C. napifolia
[46]
C. sicula (sub C. nicaensis)
[38]
C. parviflora
[40]
C. pullata
[45]
C. sulphurea
[43]
C. calcitrapa
[35]
C. granata
[47]
C. papposa
[48]
C. parviflora
[40]
OMe OH MeO
7,30 ,50 -Trimethyltricetin
O OMe
OH
O
31
OMe OH MeO
O
MeO OH
O
32
Eupatorin
OH OMe MeO
O
MeO OH
O
33
Eupatilin
OMe
C. calcitrapa
[35]
C. diluta subsp. algeriensis
[24]
C. parviflora
[40]
C. sulphurea
[43]
C. tougourensis
[39]
7,3 ,4 ,5 -Tetramethyltricetin
C. pubescens (sub C. incana)
[16]
6-Methoxyluteolin7,30 , 40 -trimethylether
C. foucauldiana
[41]
C. granata
[47]
C. napifolia
[46]
C. sicula (sub C. nicaensis)
[42]
C. parviflora
[40]
C. sulphurea
[43]
C. tougourensis
[39]
OMe O
HO
MeO OH
O
34
0
OMe
0
0
OMe MeO
O OMe
OH
O
35
OMe OMe MeO
O
MeO OH
O
Continued
TABLE 12.2 Flavonoid aglycones from Algerian Centaurea and related genus Rhaponticoides.—Cont’d No
Flavonoid aglycones
Name
Taxa
Reference
Kaempferol
C. tougourensis
[39]
Quercetin
C. omphalotricha
[21]
C. napifolia
[46]
Flavonols 36
OH HO
O
OH OH
O
37
OH OH HO
O
OH OH
O
38
HO
OH
Morin
C. fragilis
[28]
OH
Isokaempferide
C. furfuracea
[36]
O
HO
OH OH
O
39 O
HO
OMe OH
O
40
OH
6-Methoxykaempferol
C. pubescens (sub C. incana)
[16]
C. microcarpa
[18]
C. sicula (sub C. nicaensis)
[42]
C. sicula (sub C. nicaensis)
[42]
C. pubescens (sub C. incana)
[16]
Corniculatusin
Rhaponticoides africana (sub C. africana)
[20]
40 -Methylgossypetin
Rhaponticoides africana (sub C. africana)
[20]
O
HO
OH
MeO OH
O
41
Patuletin
OH OH O
HO
OH
MeO OH
O
42
OH OH OMe HO
O
OH OH
O
43
OH OMe OH O
HO
OH OH
O
Continued
TABLE 12.2 Flavonoid aglycones from Algerian Centaurea and related genus Rhaponticoides.—Cont’d No
Flavonoid aglycones
44
OMe
Name
Taxa
Reference
Jaceidin
Rhaponticoides africana (sub C. africana)
[20]
Centaureidin
Rhaponticoides africana (sub C. africana)
[20]
30 -Hydroxyflindulatin
Rhaponticoides africana (sub C. africana)
[20]
Naringenin
C. fragilis
[30]
OH HO
O
OMe
MeO OH
O
45
OH OMe O
HO
OMe
MeO OH
O
46
OH OMe OMe O
MeO
OMe OH
O
Flavanones 47
OH O
HO
OH
O
TABLE 12.3 Flavonoid glycosides in Algerian Centaurea and related genera Rhaponticoides and Volutaria. No
Flavonoid glycosides
Name
Taxa
Reference
Baicalin
C. fragilis
[30]
Apigetrin;
C. fragilis
[30]
Cosmosiin;
C. furfuracea
[36]
C. sphaerocephala
[49]
C. furfuracea
[36]
C. sicula (sub C. nicaensis)
[38]
C. sicula (sub C. nicaensis)
[38]
Flavone glycosides 48 O
GlucurO
HO O
OH
49
OH O
GluO
Apigenin 7-O-β-glucoside OH
O
50
OH MeGlucurO
O
OH
51
O
OGlucurMe HO
Apigenin 7-(600 -methylglucuronide)
Apigenin 40 -(600 -methylglucuronide)
O
OH
O
Continued
TABLE 12.3 Flavonoid glycosides in Algerian Centaurea and related genera Rhaponticoides and Volutaria.—Cont’d No
Flavonoid glycosides
52
Name OH
MeGalacturO
Taxa
Reference
Apigenin 7-(6 -methylgalaturonide)
C. pubescens (sub C. incana)
[16]
Scutellarin
C. fragilis
[30]
Hispidulin 7-O-β-D-glucopyranoside
C. acaulis
[50]
C. furfuracea
[36]
C. microcarpa
[18]
C. pubescens (sub C. incana)
[16]
Chrysoeriol 7-O-β-glucoside
C. sphaerocephala
[49]
Hispidulin 7-O-methylglucuronide
C. furfuracea
[51]
00
O
OH
O
53
OH GlucurO
O
HO OH
O
54
OH GluO
O
MeO OH
O
55
OMe OH GluO
O
OH
O
56
OH MeGlucurO
O
MeO OH
O
57
OMe
Tricin 7-O-glucoside
C. pubescens (sub C. incana)
[16]
Diosmin
C. fragilis
[30]
Kaempferol 7-O-β-D-glucoside
C. microcarpa
[18]
Isoquercitrin;
C. fragilis
[30]
Quercetin3-O-β glucoside
Volutaria lippii (sub C. lippii)
[52]
OH GluO
O OMe
OH
O
58
OH OMe RutO
O
OH
O
Flavonol glycosides 59
OH GluO
O
OH OH
O
60
OH OH HO
O
OGlu OH
O
Continued
TABLE 12.3 Flavonoid glycosides in Algerian Centaurea and related genera Rhaponticoides and Volutaria.—Cont’d No
Flavonoid glycosides
61
OH GlucurO
Name
Taxa
Reference
Bracteoside
C. furfuracea
[53]
Isokaempferide 7-O-methylglucuronide
C. furfuracea
[53]
Patulitrin;
C. acaulis
[50]
Patuletin 7-O-glucoside
C. furfuracea
[36]
C. microcarpa
[43]
C. sicula (sub C. nicaensis)
[18]
C. pubescens (subC. incana)
[16]
C. pubescens (sub C. incana)
[16]
O
OMe OH
O
62
OH MeGlucurO
O
OMe O
OH
63
OH OH GluO
O
OH
MeO OH
O
64
30 -Methylmyricetin 7-O-glucoside
OMe OH GluO
O OH OH OH
O
65
OMe
3,50 -Dimethylmyricetin 7-O-glucoside
C. pubescens (sub C. incana)
[16]
7-O-Glucosylspinacetin
C. sicula (sub C. nicaensis)
[42]
5,7,40 -Trihydroxy-3,6-dimethoxyflavone 7-O-β-glucoside
C. microcarpa
[18]
Centaurein
Rhaponticoides africana (sub C. africana)
[20]
OH GluO
O OH OMe OH
O
66
OMe OH GluO
O
OH
MeO OH
O
67
OH GluO
O
OMe
MeO OH
O
68
OH OMe GluO
O
OMe
MeO OH
O
Continued
TABLE 12.3 Flavonoid glycosides in Algerian Centaurea and related genera Rhaponticoides and Volutaria.—Cont’d No
Flavonoid glycosides
69
OH OMe SinGluO
O
Name
Taxa
Reference
Algerianin;
Rhaponticoides africana (sub C. africana)
[20]
Nicotiflorin;
Volutaria lippii (sub C. lippii)
[52]
Kaempferol 3-O-β-D-rutinoside
C. parviflora
[40]
Rutin
C. fragilis
[30]
C. pubescens (sub C. incana)
[16]
00
7-(6 -Sinapyl-O-β glucopyranosyl) Centaureidin
OMe
MeO OH
O
70
OH O
HO
ORut OH
O
71
OH OH HO
O
ORut OH
O
Flavanone glycosides 72
OMe RutO
Hesperidin
C. fragilis
[30]
Neohesperidin
C. fragilis
[30]
Chrysin-8-C-glucoside
C. omphalodes
[33]
Isovitexin
Volutaria lippii (sub C. lippii)
[52]
O OH
OH
O
73
OMe NeohO
O OH
OH
O
C-Glycosylflavonoids 74
Glu O
HO
O
OH
75
OH HO
O
Glu OH
O
Continued
TABLE 12.3 Flavonoid glycosides in Algerian Centaurea and related genera Rhaponticoides and Volutaria.—Cont’d No
Flavonoid glycosides
76
OH Glu HO
Name
Taxa
Reference
Vicenin 2
C. pubescens (sub C. incana)
[16]
C. sicula (sub C. nicaensis)
[50]
Isovitexin 200 -O-glucoside
C. pubescens (sub C. incana)
[16]
Isoorientin 7-O-glucoside
C. sicula (sub C. nicaensis)
[42]
Isoorientin 600 -O-glucoside
C. sicula (sub C. nicaensis)
[42]
O
Glu O
OH
77
OH HO
O
GlcGlc OH
O
78
OH
GluO
O
Glu O
OH
79
OH OH Glu HO
O
GluGlu OH
O
Algerian Centaurea and related genera Chapter
Flavanones Flavanone glycosides Flavone C-glycosides
1 2 6
Flavonols
11
Flavone O-glycosides
11
Flavonol glycosides Flavones
12 381
13 21
Number of compounds FIG. 12.3 Classification of reported flavonoids from Algerian Centaurea and related genera.
Second, 13 flavonol glycosides were found in the Algerian Centaurea and related genera Rhaponticoides and Volutaria, most of them were substituted with a glycosyl group at C-7 (except Algerianin (69), which has an acylated glucopyranosyl at C-7). However, heterosides (60, 70, and 71) were substituted in the position 3. In fact, heterosides (70) and (71) were attached with a rutinosyl group. Concerning flavonols, overall 11 different chemical structures were identified. Among them five polyhydroxy and polymethoxy flavonols (42–46) were isolated from the flowering and aerial parts of Rhaponticoides africana (¼ C. africana). A total of 17 flavone glycosides, including 11 flavone O-glycosides and 6C-glycosides, were isolated to date. Glucopyranosyl group and their derivatives are the most abundant sugar moieties. The glucuronopyranoside methyl ester was reported at the position 40 and 7 in compounds (51) and (56), respectively. Moreover, both galactopyranoside methyl ester and rutinosyl groups were described only in heterosides (52) and (58), respectively. 6C-glycosylflavones were detected in some Algerian Centaurea and related genus Volutaria which are linked with mainly glucopyranosyl sugars, at the position 6 and/or 8 position. Among these, (74) is devoid of substituents in the ring B. At last, the subgroup flavanones was represented with three structures: one aglycone (47) and two glycosides (72, 73), all these compounds were detected in C. fragilis. Sugar moieties indicated in abbreviated form in Tables 12.2 and 12.3 are reported in Fig. 12.4.
Terpenoids Sesquiterpene lactones Sesquiterpene lactones compose a large group of biologically active plant constituents emerging as one of the largest groups of plant products.
382 Studies in Natural Products Chemistry
FIG. 12.4 Sugar groups and their derivatives.
Sesquiterpene lactones are a diverse group of terpenoids (15-carbon compounds) with a characteristic isoprenoid ring system, a lactone ring containing a conjugated exomethylene group (α-methylene-γ-lactone). By 2015, more than 6000 sesquiterpene lactones belonging to various structural types had been discovered and described by various sources. They are almost exclusively derived from Asteraceae. With a few exceptions, the active sesquiterpene lactones contain an exocyclic α, β-unsaturated lactone moiety. From over of 40 structural types of sesquiterpene lactones known to date the most widespread are germacrane, guaiane, eudesmane, and pseudoguaiane, while elemanolides, xanthanolides, eremophilanolides, drimanolides, and bakkenolides are met less frequently [54,55] (Fig. 12.5). Based on bibliographic research, a total of 59 different sesquiterpene lactones were isolated and identified from Algerian Centaurea and related genera. The most abundant sesquiterpene lactones reported so far were: germacranolides (12 compounds), elemanolides (12 compounds), eudesmanolides (8 compounds) and guainolides (27 compounds) (Fig. 12.6). Tables 12.4–12.7 contain all the sesquiterpene lactones with their semi systematic and/or trivial names and the species which the compounds have been isolated.
Algerian Centaurea and related genera Chapter
9
1
14
10
2 3
10
13
7
3
11
6
8
2
7
5
9
1
8 14
4
12 383
4 15
13
5
11
6
12
15
Germacrane
12
Elemane
14
14 9
1
10
8
2
10 5
3 4
7 6
15
9
2 13
1
3 4
11
8
5 7
13
6
12
11
15
12
Eudesmane
Guaiane
FIG. 12.5 widespread sesquiterpene skeletons [56].
Eudesmanolides
8
Elemanolides
12
Germacranolides
12
Guaianolides
27 Number of compounds
FIG. 12.6 Classification of reported sesquiterpene lactones from Algerian Centaurea and related genera.
Germacranolides The Algerian Centaurea and related genera (Rhaponticoides, Volutaria) comprise about 12 germacranolides (80–91). With the exception of two heliangolides: 90 and 91 present in C. foucauldiana, C. sulphurea and C. tougourensis, all the germacranolides have a trans-C-1(C-10)/trans-C-4 configuration. Besides, they are all almost C-6/C-12 olides with the typical exocyclic C-11/C-13 double bond (80–84, 90, 91) or with a C-11/C-13 dihydro moiety (85–89). Except for the germacranolides (80, 86), the oxygenated function at C-8 is almost always α-oriented.
TABLE 12.4 Germacranolides from Algerian Centaurea and related genera Rhaponticoides and Volutaria. No
Germacranolides
80
Name
Taxa
Reference
Costunolide
C. acaulis
[57]
40 -Desoxyarctiopicrin;
C. melitensis
[19]
C. melitensis
[19]
C. melitensis
[19]
O O
81 O
15-Hydroxy-8α-isobutyryloxy-costunolide O
O HO
O
82
Onopordopicrin O
OH O
O HO
O
Arctiopicrin;
83 O
OH O
O HO
O
0
Salonitenolide-8-(4 -hydroxyisobutyrate)
84
Cnicin
Rhaponticoides africana (sub C. africana)
[58,59]
C. calictrapa
[35]
C. foucauldiana
[41]
Volutaria lippii (sub C. lippii)
[52]
C. papposa
[48]
C. parviflora
[40]
C. sulphurea
[60]
C. tougourensis
[61]
C. sicula (sub C. nicaensis)
[17]
C. pullata
[22]
8-Oxo-15-hydroxygermacra-1(10), E, 4Z-dien-11βH-12,6α-olide
C. pullata
[22]
11β,13-Dihydro-19-deoxycnicin
C. pullata
[15,59]
O OH O
OH
O HO
O
85
11β,13-Dihydrosalonitenolide
OH
O HO
O
86
O
O HO
O
87 O OH O O HO O
Continued
TABLE 12.4 Germacranolides from Algerian Centaurea and related genera Rhaponticoides and Volutaria.—Cont’d No
Germacranolides
88
Name
Taxa
Reference
11β,13-Dihydrocnicin
C. sicula (sub C. nicaensis)
[17]
C. pullata
[15,62]
8α-O-(40 -acetoxy-50 -hydroxyangeloyl)-11β, 13-dihydrosalonitenolide
C. pullata
[62]
15-Acetoxy-8α-O-(3 hydroxy-4acetoxy-2methylene-butanoyloxy)-7αH, 6βH-germacra-4E, 1(10),11(13)-trien-12,6-olide
C. foucauldiana
[41]
C. sulphurea
[60]
C. tougourensis
[61]
C. sulphurea
[60]
C. tougourensis
[61]
O OH O
OH
O HO O
89
OH O O
OAc
O HO
O
90 O OH O
OH
O AcO
O
Sulphurein
91 O OH O CHO
O O
OH
TABLE 12.5 Elemanolides from Algerian Centaurea species. No
Elemanolides
92
93
OH
Name
Taxa
Reference
11,13-Dehydromelitensin
C. maroccana
[62]
15-Acetyldehydromelitensin
C. omphalotricha
[21]
8α-(40 -Hydroxy-methacryloyl)-dehydromelitensin
C. omphalotricha
[21]
C. melitensis
[19]
C. foucauldiana
[41]
C. maroccana
[63]
C. papposa
[48]
C. parviflora
[40]
C. tougourensis
[61]
O AcO
O
94 O
OH O
O HO
O
Isocnicin;
95 O OH O O HO
O
OH
5Hα, 6Hβ, 7Hα-15-hydroxy-8α-(10 ,20 dihydroxyethyl-acryloxy)-elema-1(2),3(4),11(13)-trien 6,12olide
Continued
TABLE 12.5 Elemanolides from Algerian Centaurea species.—Cont’d No
Elemanolides
96 O
Name
Taxa
Reference
11,13-Dehydromelitensin β-hydroxyisobutyrate
C. melitensis
[19]
8α-(20 -Hydroxymethyl-20 -butenoyloxy)-dehydromelitensin
C. maroccana
[63]
8α-O-(3,4-dihydroxy-2-methylenebutanoyloxy)-15oxo-5,7RH, 6αH-eleman-1,3,11(13)-trien-6,12-olide
C. papposa
[48]
Melitensin
C. sicula (sub C. nicaensis)
[17,38]
C. pullata
[22]
OH O
O HO
O
97
OH O O O HO
O
98 O OH O CHO
OH
O O
99
OH
O HO O
100
15-Acetylmelitensin
C. omphalotricha
[21]
8α-O-(40 -hydroxy-20 -methylenebutanoyloxy)-melitensin
C. pullata
[22]
C. sicula (sub C. nicaensis)
[17]
OH
5α,6β,7α,8β,11β(H)-15-Hydroxy-8-(10 ,20 dihydroxyethyl)acrloelema-1,3-dien-6,12-olide
C. papposa
[48]
OH
Methyl 8α-O-(30 ,40 -dihydroxy-20 -methylene-butanoyloxy)-6α, 15-dihydroxyelema-1, 3,11(13)-trien-12-oate
OH
O AcO
O
101 O OH O O HO
O
102 O O
OH
O HO O
103 O O OH COOMe OH HO
TABLE 12.6 Eudesmanolides from Algerian Centaurea species. No
Eudesmanolides
104
Name
Taxa
Reference
β-Cyclocostunolide
C. acaulis
[57]
Santamarin
C. acaulis
[57]
Malacitanolide
C. papposa
[48]
8α-Hydroxy-11β,13-dihydro-onopordaldehyde
C. granata
[47]
C. pullata
[22]
H O O
105
OH
H O O
106
OH O OH O H CHO
OH
O O
107
OH
H CHO
O O
108
OH
8α-Hydroxy-11β,13-4-epi-sonchucarpolide
C. pullata
[22]
8α-O-(40 -hydroxy-20 -methylene-butanoyloxy)-11β, 13-dihydrosonchucarpolide
C. pullata
[62]
8α-O-(40 -hydroxy-20 -methylene-butanoyloxy)-11β, 13-dihydro-4-epi-sonchucarpolide
C. pullata
[62]
8α-O-(20 -hydroxymethyl-20 -butenoyloxy)-sonchucarpolide
C. maroccana
[63]
OH
H CHO
O O
109
OH O OH O H CHO
O O
110
OH O OH O H CHO
O O
111
OH O
OH O
H CHO
O O
TABLE 12.7 Guaianolides from Algerian Centaurea and related genus Rhaponticoides. No
Guaianolides
112
HO Cl
H
Name
Taxa
Reference
14-Chloro-10-β-hydroxy-10(14)dihydrozaluzanin D
C. acaulis
[57]
Zaluzanin D
C. acaulis
[57]
Desacylcynaropicrin
C. omphalotricha
[21]
Kandavanolide
C. acaulis
[57]
AcO H O O
113
H AcO H O O
114
H OH
HO H O O
115
H OH
AcO H O O
116
H
Aguerin B
C. musimomum
[25]
Cynaropicrin;
Rhaponticoides africana (sub C. africana)
[58,59]
C. omphalotricha
[21]
C. musimomum
[25]
40 -Acetyl cynaropicrin
C. omphalotricha
[21]
3-Acetyl cynaropicrin
C. omphalotricha
[21]
O
HO
O
H O O
117
H O
HO
OH
Sauprin
O
H O O
118
H O
HO H
OAc O
O O
119
H O
AcO H
OH O
O O
Continued
TABLE 12.7 Guaianolides from Algerian Centaurea and related genus Rhaponticoides.—Cont’d No
Guaianolides
Name
Taxa
Reference
4 -Acetyl cebellin F
C. omphalotricha
[21]
Linichlorin B
C. omphalotricha
[21]
C. musimomum
[25]
19-Deoxyrepin;
C. musimomum
[25]
17,18-Desoxyrepin;
C. pubescens (sub C. incana)
[64]
8-Deacyloxy-8α-(methylacryloxy)-subteolide
Janerin
C. musimomum
[25]
C. pubescens (sub C. incana)
[64]
0
120
H O
HO
OAc H
O O O
121
Cl
H
OH O
HO H
O O O
122
H O
HO O
H
O
O O
123
H O
HO O
H
OH O
O
O
124
Repin
C. musimomum
[25]
Subluteoline
C. pubescens (sub C. incana)
[64]
Cl
Acroptilin; Chlorohyssopifolin C
C. pubescens (sub C. incana)
[64]
OH
C. pubescens (sub C. incana)
[64]
H O O
HO O
H
O O O
125
H O O
HO O
H
O O O
126
H O
HO O
H
O O O
127
Pterocaulin;
H
HO HO
Repdiolide triol
O
HO H
O O O
Continued
TABLE 12.7 Guaianolides from Algerian Centaurea and related genus Rhaponticoides.—Cont’d No
Guaianolides
128
H
Taxa
Reference
Elegin;
C. musimomum
[25]
Epi-solstiziolide
C. pubescens (sub C. incana)
[64]
Cebellin C;
C. musimomum
[25]
C. musimomum
[25]
Linochlorin A;
O
HO
Name
19-Deoxychlorojanerin
HO H Cl
O O O
129
H O O
HO HO
O
H
Cl
O O
130
H OH
O
HO
Chlorojanerin
HO O
H
Cl
O O
131
Cl
H
OH O
HO
Chlorohyssopifolin A; Hyrcanin
HO H Cl
Centaurepensin;
O O O
132
Cl
H
OH O
HO
Chlorohyssopifolin A 17-epi;
C. musimomum
[25]
Cynaratriol
C. musimomum
[65]
8-Hydroxy-11,13-dihydrozaluzanin C
C. omphalotricha
[21]
3-Oxo-4α-hydroxy-15-hydroxy 1αH, 5αH, 6βH,
C. musimomum
[66]
17-Epi-centaurepensin
HO O
H
Cl
O O
133
H OH
HO H
OH
O
OH O
134
H OH
HO H O O
135
H
7αH,11βH-guai-10(14)-ene-6,12-olide
O HO H HO
O O
Continued
TABLE 12.7 Guaianolides from Algerian Centaurea and related genus Rhaponticoides.—Cont’d No
Guaianolides
136
H
Name
Taxa
Reference
3-Oxo-4α-acetoxy-15-hydroxy 1αH, 5αH, 6βH,
C. musimomum
[66]
4β,15-Dihydro-3-dehydrosolstitialin A
C. musimomum
[67,68]
4β,15-Dihydro-3-dehydro-13-acetylsolstitialin A
C. musimomum
[25,69]
7αH,11βH-guai-10(14)-ene-6,12-olide
O AcO H
HO
O O
137
H O OH H O OH O
138
H O OAc H O OH O
Algerian Centaurea and related genera Chapter
12 399
Indeed, most of isolated germacranolides have a free hydroxyl at C-15, with the exception of (90, 91) which attached to an acetoxy and an aldehyde groups, respectively. In fact, only costunolide (80) has a C-15 methyl and is devoid of the ester side chain at C-8.
Elemanolides To date, 12 elemanolides were isolated and identified from the Algerian genus Centaurea. They possess almost all an α-oriented hydroxyl or ester at C-8 and a free hydroxyl at C-15 (except 93, 100 which have an acetoxy group, and 98 which has an aldehyde group). With the exception of the elemane 103, the presence of the moiety C-6/C-12 γ lactone with the typical exocyclic C-11/ C-13 double bond (92–98) or with a C-11/C-13 dihydro moiety (99–102) is a common feature for all these elemanolides.
Eudesmanolides Eudesmanolides are present in five Algerian Centaurea species: C. acaulis, C. granata, C. maroccana, C. papposa and C. pullata. Phytochemical investigation of these plants resulted in the identification of eight eudesmanolides characterized by a trans fused decalin moiety. The presence of an aldehyde at C-4 that can be α or β oriented is a common structural feature in the majority of isolated eudesmanolides (104–111). All eudesmanes described in this paper have the moiety C-6/C-12 γ lactone with the typical exocyclic C-11/C-13 double bond (104–106) or with a C-11/C-13 dihydro moiety (107–111). In addition, they have a free β-oriented hydroxyl group at C-1, except 104, 107 which are devoid of functionality.
Guaianolides Guaianolides are considered the most widespread sesquiterpene lactones in the Algerian Centaurea and related genus Rhaponticoides. Indeed, 27 different structures have been described (112–138). Except for the guaianolide 112, all of them have a trans-6,12 γ lactone; a 1,5-cis junction and a C-10/C-14 double bond. The free hydroxyl group (ester derivative) at C-3 is almost always β oriented (112–134), while the oxygenated function at C-8 is almost always α-orientated (except for 112, 113, 135–138 which are devoid of substituent at C-8). The exocyclic C-11/C-13 double bond is most frequently met in 21 guaianolides (112 2 132). The majority of guaianolides listed in Table 12.7 have a molecular variety on the basis of the different esters chains linked at C-8 and the C-4/C-15 functionality: double bound (112–121, 134), epoxide (122–126), chlorohydrine (128–132), diol and derivatives (127, 135, 136), or methyl (133, 137, 138).
400 Studies in Natural Products Chemistry
Triterpenoids Triterpenoids are a large group of natural products derived from C30 precursors. The triterpenoids group displays well over 100 distinct skeletons [70]. This class of natural products includes triterpenes, steroids, limonoids, quassinoids, and triterpenoidal and steroidal saponins [71]. Most of triterpenic skeletons are tetracycles and pentacycles. However, acyclic, mono-, di-, tri- and hexacyclic triterpenoids have also been isolated and identified from natural sources [70,71]. Triterpenoids including sterols (139, 140) and triterpenes (141–144) are minor compounds in Algerian Centaurea and related genus Rhaponticoides; these compounds were isolated from C. omphalotricha and Rhaponticoides africana (Table 12.8).
Other compounds Simple phenols (145–147), phenylpropanoids (148–150), a lignan (151), a coumarin (152) and other minor metabolites (153–158) have been detected in some Algerian Centaurea and related genus Rhaponticoides. Of these, Maroccanin 158, a new γ lactone, was recently isolated from the endemic species C. maroccana (Table 12.9).
Essential oils The content of essential oils of Centaurea species are characterized by the presence of sesquiterpenes skeleton (caryophyllene, eudesmol and germacrene); hydracarbons (tricosane, pentacosane and heptacosane); fatty acids (hexadecanoic acid, tetradecanoic acid, and dodecanoic acid) and monoterpenes (aspinene, terpinene and carvacrol) [72–74]. Some Algerian Centaurea and related genus Cheirolophus were documented for their volatile compounds. The essential oil composition of C. calcitrapa, C. choulettiana, C. pullata and Cheirolophus sempervirens (¼ Centaurea sempervirens) was obtained by steam distillation and was analyzed by GC and GC-MS. The results showed that these species are dominated by the presence of oxygenated sesquiterpene. Caryophyllene oxide was present in all plant species listed in Table 12.10, and it appeared to be the major component in C. calcitrapa, C. choulettiana and C. pullata. This gathered information is in accordance with the results obtained in reported studies on essential oils from other Centaurea species. The main constituents and yields of essential oils of investigated species are described in Table 12.10. Based on the present review, Algerian Centaurea and related genera produce a variety of compounds, among which flavonoids and sesquiterpene lactones are the most predominant (Table 12.11).
TABLE 12.8 Triterpenoids from the Algerian Centaurea and related genus Rhaponticoides. No
Triterpenoids
Name
Taxa
Reference
β-Sitosterol
Rhaponticoides africana (sub C. africana)
[20]
C. omphalotricha
[34]
Daucosterol;
Rhaponticoides africana (sub C. africana)
[20]
β-Sitosterol 3-O-glucoside
C. omphalotricha
[34]
Lupeol
C. omphalotricha
[34]
Sterols 139 H H H
H
HO
140 H H H
H GluO
Triterpenes 141 H H H HO
Continued
TABLE 12.8 Triterpenoids from the Algerian Centaurea and related genus Rhaponticoides.—Cont’d No
Triterpenoids
142
Name
Taxa
Reference
Taraxasterol
C. omphalotricha
[34]
α-Amirin
Rhaponticoides africana (sub C. africana)
[20]
β-Amirin
Rhaponticoides africana (sub C. africana)
[20]
H H H HO
143
H H HO
144
H H HO
TABLE 12.9 Other compounds from Algerian Centaurea and related genus Rhaponticoides. No
Compound
145
OMe
Name
Taxa
Reference
Vanillin
C. diluta subsp. algeriensis
[24]
Ethyl 3,4-dihydroxybenzoate
Rhaponticoides africana (sub C. africana)
[32]
Isovanillic acid ethyl ester
Rhaponticoides africana (sub C. africana)
[32]
Methyl 3-(4-hydroxyphenyl) propanoate
Rhaponticoides africana (sub C. africana)
[32]
3-(30 -Methoxy-40 ,50 dihydroxyphenyl) propan-1-ol
C. maroccana
[37]
O OH
146
OH O OH O
147
OH O OMe O
148
O
OH
MeO
149
OH
HO
OH
OMe
Continued
TABLE 12.9 Other compounds from Algerian Centaurea and related genus Rhaponticoides.—Cont’d No
Compound
150
HO
HO
Name
Taxa
Reference
Syringin
C. parviflora
[40]
()-Arctigenin
C. diluta subsp. algeriensis
[24]
Scopoletin
C. maroccana
[63]
Prunasin
C. sicula (sub C. nicaensis)
[38]
OH OMe O OH O
HO
OMe
151
O
O HO OMe OMe OMe
152
MeO
HO
153
O
O
H
C
OH O HO HO
O OH
N
154
OH HO O
Cornicinine
C. parviflora
[40]
Dehydrovomifoliol
C. omphalotricha
[21]
3-Hydroxy-5α,6α-epoxy-β-ionone
C. omphalotricha
[21]
Ethyl-O-α L-arabinofuranoside
C. parviflora
[40]
Maroccanin
C. maroccana
[63]
OH
O
O
OH Et O
155
O
OH O
156
O
H
O
HO
157
O O OH
OH
OH
158
O
H H
H
H O O O
406 Studies in Natural Products Chemistry
TABLE 12.10 Main constituents and yields of essential oils of Algerian Centaurea and related genus Cheirolophus. Taxa
Yield
Main constituents
Ref.
C. calcitrapa
0.01%
β-Caryophyllene (5.3%)
[75]
6,10,14-Trimethylpentadecan-2-one (4.7%) (Z)-β-Farnesene (4.2%). C. pullata
0.03%
Caryophyllene oxide (27.0%)
[76]
Phytol isomer (16.5%) 6,10,14-Trimethyl 2-pentadecanone (14.9%) 0.03%
Caryophyllene oxide (38.5%)
[77]
Aldehydes (16.3%) Heneicosane (8.6%) C. choulettiana
0.02%
β-Eudesmol (6.8%)
[78]
1,5-Epoxysalvial-4(14)-ene (6.6%) Caryophyllene oxide (4.28%) Cheirolophus sempervirens (sub Centaurea sempervirens)
0.2%
Diisopentylphthalate (33.0%)
[79]
6,10,14-Trimethylpentadecan-2-one (12.4%) Epi-torilenol (5.1%)
TABLE 12.11 The occurrence of flavonoids and sesquiterpene lactones in Algerian Centaurea and related genera (Cheirolophus, Rhaponticoides, and Volutaria). Taxa
Flavonoids
Sesquiterpene lactones
C. acaulis
23, 54, 63
80, 104, 105, 112, 113, 115
C. calcitrapa
17, 31, 32, 33
84
C. choulettiana
NR
NR
C. diluta subsp. algeriensis
29, 33
C. fragilis
38, 47, 48, 49, 53, 58, 60, 71, 72, 73
C. foucauldiana
28, 29, 31, 35
84, 90, 95
Algerian Centaurea and related genera Chapter
12 407
TABLE 12.11 The occurrence of flavonoids and sesquiterpene lactones in Algerian Centaurea and related genera (Cheirolophus, Rhaponticoides, and Volutaria).—Cont’d Taxa
Flavonoids
Sesquiterpene lactones
C. furfuracea
17, 23, 25, 39, 49, 50, 54, 56, 61, 62
C. granata
32, 35
107
C. maroccana
17, 23
92, 95, 97, 111
C. melitensis
23, 28, 29
81, 82, 83, 94, 96
C. microcarpa
28, 40, 54, 59, 63, 67 116, 117, 121, 122, 123, 124, 128, 130, 131, 132, 133, 135, 136, 137, 138
C. musimomum
C. napifolia
31, 35, 37
C. omphalodes
15, 24, 25, 27, 74
C. omphalotricha
15, 16, 17, 18, 19, 22, 25, 37
93, 94, 100, 114, 117, 118, 119, 120, 121, 134
C. papposa
32
84, 95, 98, 103, 106
C. parviflora
20, 21, 29, 31, 32, 33, 35, 70
84, 95
C. pubescens
23, 28, 30, 34, 40, 41, 52, 54, 57, 63, 64, 65, 76, 77
122, 123, 125, 126, 127, 129
C. pullata
29, 31
85, 86, 87, 88, 89, 99, 101, 107, 108, 109, 110
C. sicula
17, 29, 31, 35, 40, 41, 50, 51, 63, 66, 76, 78, 79
85, 88, 99, 102
C. sphaerocephala
49, 55
C. sulphurea
26, 28, 29, 31, 33, 35
84, 90, 91
C. tougourensis
17, 28, 29, 33, 35, 36
84, 90, 91, 95
Cheirolophus sempervirens
NR
NR
Rhaponticoides africana
23, 24, 28, 42, 43, 44, 45, 46, 68, 69
84, 117
Volutaria lippii
60, 70, 75
84
NR: not reported.
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Throughout our literature research we observed that flavonoids and/or sesquiterpene lactones are present in all species, except for C. choulettiana and Cheirolophus sempervirens. It is remarkable that C. musimomum produce mainly sesquiterpene lactones. On the contrary, C. diluta subsp. algeriensis, C. furfuracea and C. microcarpa are recorded to contain principally flavonoids. Both C. pubescens and C. nicaensis with 14 flavonoids are the richest Algerian species in flavonoids, published so far. Similarly C. musimomum ranks the first on the production of sesquiterpene lactones belonging to the class of guaianolides. In this period (1977–2018), authors published 56 works resulting in the detection of 16 new natural products comprising four flavonoids: 43, 51, 56 and 69; eleven sesquiterpene lactones: 87, 88, 91, 93, 100, 101, 107, 118, 120, 135, 136 and one γ lactone: 158.
Biological activities Since Aclinou reported that the roots of C. pubescens are used in the area of Aure`s for the treatment of liver diseases [80], Algerian Centaurea species have been object of many pharmacological studies [81]. Pharmacological investigations on the extracts and pure compounds from Algerian Centaurea and related genera (Cheirolophus, Rhaponticoides, and Volutaria) cover a relatively wide range of biological activities; they have been reported to possess antioxidant, antimicrobial and analgesic activities, as well as cytotoxic and antiplasmodial effects. These various properties are discussed below.
Antioxidant and antiradical activities 6-Methoxykaempferol 40 and 5,7,40 -trihydroxy-3,6-dimethoxyflavone7-Oβ-glucoside 67 were isolated from the aerial parts of C. microcarpa. An antiradical assay using the DPPH method indicated that compound 40 displayed a strong DPPH radical scavenging activity (76%) higher than standard vitamin C (64%). The glycoside 67 was reported to possess an inhibition rate of 21% at 101 M [82]. Patuletin 7-O-β-glucopyranoside 63 was isolated from the n-butanol extract of C. acaulis. The antioxidant capacity of this glycoside was performed using DPPH radical-scavenging, lipid peroxidation using vitellose and hydroxyl radical scavenging methods. The scavenging effect of patuletin-7-Oβ-glucopyranoside (97.92%) was better than the standard vitamin C (95.00%) on the DPPH at 15 μg/mL. In the term of IC50, heteroside 63 has an IC50 value of 4.83 μg/mL, compared to ascorbic acid IC50 ¼ 5 μg/mL. In addition, the percentage inhibition of lipid peroxidation at 100 μg/mL of patuletin-7-O-β-glucopyranoside 63 was found to be 51.93% less than that found for vitamin C (86.95%). On the other hand, the IC50 value of compound 63 and ascorbic acid was 25.16 and 10.53 μg/mL, respectively, using hydroxyl radical scavenging method [50].
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The methanol extract of C. melitensis displaced a strong and potent scavenging capacity against free radical DPPH, with a concentration-dependent manner. Indeed, the maximum inhibition ratio was 89.02% at concentration of 0.70 mg/L [19]. Recently, extracts of both leaves and flowers of C. choulettiana were tested for their antioxidant effects using total phenolic and flavonoid contents, DPPH radical scavenging and lipid peroxidation inhibition assays. The results revealed a higher level of phenolic and flavonoid content in ethyl acetate extract of leaves (325.81 0.038 mgGAE and 263.73 0.004 mgQE/g of extract), respectively. In addition, this extract exhibited high antioxidant effects on the DPPH radical scavenging activity with (96.54%) and on lipid peroxydation inhibition (64.17%) [23].
Antibacterial and antifungal effects Sesquiterpene lactones 85, 87, 88, 89, 99, 101, 107, 108, 109, 110 isolated from C. pullata were tested for their antibacterial and antifungal activities, against six bacteria; Gram-negative bacteria: Escherichia coli (ATCC 35210), Pseudomonas tolaasii (isolated from Agaricus bisporus), Salmonella enteritidis (ATCC 13076), and the following Gram-positive bacteria: Bacillus subtilis (ATCC 10907), Micrococcus flavus (ATCC 10240), and Staphylococcus epidermidis (ATCC 12228). Eight fungal species were also used: Alternaria alternata (DSM 2006), Aspergillus flavus (ATCC 9643), Aspergillus niger (ATCC 6275), Aspergillus ochraceus (ATCC 12066), Fusarium tricinctum (CBS 514478), Penicillium funiculosum (ATCC 36839), Penicillium ochrochloron (ATCC 9112) and Trichoderma viride (IAM 5061). They all had an antibacterial activity and fungicidal potential in varying degrees, greater than that of the used positive control (streptomycin and miconazole). Interestingly, compounds 101, 107 and 108 exert remarkable inhibitory activity against all tested strains [22,62]. Whereas, the pharmacokinetic profile of all compounds using computational methods had predicted that these compounds cannot be transported across the intestinal epithelium, because of their low affinity to the plasma protein: they cannot cross to the blood-brain barrier and are medium-low aqueous soluble [22]. On the other hand, essential oils from the same species showed a moderate activity against the majority of tested microorganisms [77]. In contrast, the chloroform extract and most isolated secondary metabolites from C. diluta subsp. algeriensis didn’t show any antimicrobial effect on the following strains (Gram-positive bacteria: Staphylococcus aureus (ATCC 6538), S. aureus (C98506), S. aureus (C100459) and S. aureus (ATCC 33591); Gram-negative bacteria: Escherichia coli (ATCC 25922) and a plant pathogen: Pseudomonas syringae (DC 3000); plant pathogen fungi: Fusarium oxysporum, F. oxysporum sporulent, Cladosporium cucumerinum, Botrytis cinerea, Colletotrichum lagenarium and Pythium aphanidermatum; and a plant pathogen yeast: Rhodotorula aurantiaca).
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Except that Jaceosidin 29 showed a moderate antimicrobial activity against all strains, and had an important potency (MICs 16–32 mg/mL) against most of S. aureus isolates. On the other hand the chloroform extract was able to potentiate the effect of beta-lactam antibiotics on methicillin-resistant Staphylococcus aureus (MRSA), reducing the minimal inhibitory concentrations (MICs) by a factor of 2–32-fold [24].
Cytotoxic properties Besides the biological investigations mentioned above, the cytotoxic activity of the chloroform extract of C. musimomum and C. furfuracea was carried out against cells derived from human carcinoma of the nasopharynx (KB), the results revealed significant growth inhibitory effects of 89% at 10 μg/mL in the case of C. musimomum and 90% at 10 mg/mL and 26% at 1 mg/mL for C. furfuracea [25,53]. On the other hand, the cytotoxic effects of the chloroform extract of C. diluta subsp. algeriensis were carried out against three human cancer cell lines, i.e., the A549 non-small-cell lung carcinoma (NSCLC), the MCF7 breast adenocarcinoma and the U373 glioblastoma. While isolated compounds were evaluated for cytotoxic activities on six cancer cell lines (A549, MCF7, U373, Hs683 human glioma, PC3 human prostate and B16-F10 murine melanoma). The crude extract reduced cell viability with IC50s of 27, 25 and 21 mg/mL on A549, MCF7 and U373, respectively. Whereas, moderate cytotoxic activities were found for ()-arctigenin 151 (IC50s: 28 and 33 mM on Hs683 and B16F10, respectively), eupatilin 33 (IC50s: 33 and 47 mM on B16-F10 and PC3, respectively) and jaceosidin 29 (IC50s: 32 and 40 mM on PC3 and B16-F10, respectively) [24]. Algerianin 69, an acylated flavonoid glucoside from Rhaponticoides africana, was examined for its cytotoxicity against human myeloid leukemia HL-60 and human melanoma SK-MEL-1 cells, using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide assay. Algerianin 69 showed potent cytotoxic properties (IC50 of 26.1 mM) for HL-60 cells, but it was inactive against human SK-MEL-1 cells on cell proliferation [20]. In addition, an investigation on sesquiterpene lactones 93, 94, 100, 114, 117, 118, 119, 120, 121, 134 isolated from C. omphalotricha for their viability of the human tumor cell lines HL-60 and U937 was assessed. This study resulted that all compounds were found to inhibit the growth and cell viability of HL-60 and U937 cells in culture as determined by the 3-[4,5-dimethylthiazol-2-yl] 2,5diphenyl tetrazolium bromide (MTT) dye-reduction method. Whereas, the elemanolide 100 is not an effective antiproliferative agent showing an IC50 value higher than 100 mmol L1 in leukemia cells. 40 -Acetyl cynaropicrin 118 and 3-acetyl cynaropicrin 119 were found to be relatively strong cytotoxic compounds against human leukemia cells with IC50 values of 2.0 0.9 and 5.1 0.4 μmol L1, respectively [21].
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Antiplasmodial activity Concerning the antiplasmodial activity, the chloroform extract of C. musimomum and C. furfuracea exhibited a considerable antiparasitic activity against Plasmodium falciparum with IC50 3.16 mg/mL and IC50 7.94 mg/mL, respectively [25,53].
Analgesic activity The eudesmanolides 110 named, 8α-O-(40 -hydroxy-20 -methylen-butanoyloxy)-11β,13-dihydro-sonchucarpolide, isolated from Centaurea pullata, was evaluated for their in vivo analgesic activity using acetic acid-induced abdominal pains, and showed a significant decrease (88%) in pain during 30 min post treatments with a dose of 1 mg/kg. So, this eudesmanolide could be therapeutically useful for mitigating inflammatory pain [83].
Concluding remarks From the data present in this paper, there is a considerable volume of published work that discusses the richness of Algerian Centaurea and related genera on secondary metabolites. This review summarizes reports on chemical constituents from the Centaurea and related genera (Cheirolophus, Rhaponticoides, and Volutaria) of the Asteraceae family growing in Algeria. A total of 158 different compounds have been reported from 26 species, and many of them are biologically active. Centaurea extracts and isolated compounds have been reported to have diverse biological features, such as antioxidant, antimicrobial, antiplasmodial and analgesic activities. Although ca. 45 species of Centaurea are distributed all over in Algeria, only 23 species were investigated. Future studies of those remaining species are desirable. To fully exploit the therapeutic value and utilize the resources of the species of this genus, their pharmacophylogenetics should be investigated further.
Abbreviations DPPH GAE GC GC-MS IC50 QE
2,2-diphenyl-1-picrylhydrazyl gallic acid equivalent gas chromatography gas chromatography-mass spectrometry the half maximal inhibitory concentration quercetin equivalent
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