Phytochemistry and biological activities of algerian Centaurea and related genera

Phytochemistry and biological activities of algerian Centaurea and related genera

Chapter 12 Phytochemistry and biological activities of algerian Centaurea and related genera Radia Ayad and Salah Akkal* Valorization of Natural Reso...

3MB Sizes 0 Downloads 70 Views

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.

408 Studies in Natural Products Chemistry

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].

Algerian Centaurea and related genera Chapter

12 409

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).

410 Studies in Natural Products Chemistry

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].

Algerian Centaurea and related genera Chapter

12 411

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

412 Studies in Natural Products Chemistry

References [1] A.I. Charles Dorni, A. Amalraj, S. Gopi, K. Varma, S.N. Anjana, J. Appl. Res. Med. Aromat. Plants 7 (2017) 1–26. [2] K. Bremer, Compositae. Cladistics and Classification, Timber Press, Portland, Oregon, 1994. [3] W.B. Zomlefer, Guide to Flowering Plant Families, University of North Carolina Press, Chapel Hill, NC, 1994. [4] H. Meusel, E.J. J€ager, Vergleichende Chorologie der zentraleurop€aischen Flora 3, G. Fischer, Jena-Stuttgart, New York, 1992. [5] G. Wagenitz, Proc. Roy. Soc. Edinb. 89B (1986) 11–21. [6] F.H. Hellwig, Plant Syst. Evol. 246 (2004) 137–162. [7] A. Susanna, N. Garcia-Jacas, in: K. Kubitzki (Ed.), The Families and Genera of Vascular Plants, vol. VIII, Springer, Berlin, 2007, pp. 123–146. [8] M. Dittrich, V.H. Heywood, J.B. Harborne, B.L. Turner (Eds.), The Biology and Chemistry of the Compositae, vol. 2, Academic Press, London, 1977. [9] E. Routsi, T. Georgiadis, Bot. Helv. 109 (1999) 139–151. [10] G. Wagenitz, in: Bulgar (Ed.), Academy of Sciences. Problems of the Balkan Flora and Vegetation, Bulgarian Academy of Sciences Publishing House, Sofia, 1975, pp. 223–228. [11] G. Wagenitz, F.H. Hellwig. In: Hind, D.J.N., Beentje, H.J, Proceedings of First International Compositae Conference, Kew (1996) 491–510. [12] W. Greuter, in: D. Bramwell (Ed.), Plants and Islands, Academic Press, London, 1979. [13] S. Pisanu, G. Mameli, E. Farris, G. Binelli, R. Filigheddu, Folia Geobot. 46 (2011) 69–86. [14] P. Quezel, S. Santa, Nouvelle Flore de l’Algerie et des Regions Desertiques et Meridionale, Tome II, CNRS, Paris, France, 1963. [15] F. Benayache, S. Benayache, K. Medjroubi, G. Massiot, P. Aclinou, B. Drodz, G. Nowak, Phytochemistry 31 (1992) 4359–4360. [16] S. Akkal, F. Benayache, M. Jay, Biochem. Syst. Ecol. 25 (1997) 361–362. [17] K. Medjroubi, N. Bouderdara, F. Benayache, S. Akkal, E. Seguin, F. Tillequin, Chem. Nat. Compd. 39 (2003) 506–507. [18] S. Louaar, A. Achouri, M. Lefahal, H. Laouer, K. Medjroubi, H. Duddeck, S. Akkal, Nat. Prod. Commun. 6 (2011) 1603–1604. [19] R. Ayad, Z.E.A. Ababsa, F.Z. Belfadel, S. Akkal, F. Leon, I. Brouard, K. Medjroubi, Int. J. Med. Plants 2 (2012) 151–154. [20] R. Seghiri, O. Boumaza, R. Mekkiou, S. Benayache, P. Mosset, J. Quintana, F. Leon, F. Estevez, J. Bermejo, F. Benayache, Phytochem. Lett. 2 (2009) 114–118. [21] E. Kolli, F. Leon, F. Benayache, S. Estevez, J. Quintana, F. Estevez, J. Bermejo, S. Benayache, J. Braz. Chem. Soc. 23 (2012) 977–983. [22] S. Djeddi, A. Karioti, M. Sokovic, C. Koukoulitsa, H. Skaltsa, Bioorg. Med. Chem. 16 (2008) 3725–3731. [23] D. Azzouzi, K. Bioud, I. Demirtas, F. Gul, D. Sarri, S. Benayache, F. Benayache, R. Mekkiou, Comb. Chem. High Throughput Screen. 19 (2016) 841–846. [24] H. Zater, J. Huet, V. Fontaine, S.C. Stevigny, P. Duez, F. Benayache, Asian Pac J Trop Med 9 (2016) 554–561. [25] K. Medjroubi, F. Benayache, J. Bermejo, Fitoterapia 76 (2005) 744–746. [26] P. Ozenda, Flore et vegetation du Sahara, third ed., CNRS, Paris, France, 1991. [27] J.A. Battandier, Flore de l’Algerie (Dicotyledones), Alger, Algerie, 1889. [28] M.H. Alu’datt, T. Rababah, M.N. Alhamad, M.A. Al-Mahasneh, A. Almajwal, S. Gammoh, K. Ereifej, A. Johargy, I. Alli, Food Chem. 218 (2017) 99–106.

Algerian Centaurea and related genera Chapter

12 413

[29] X. Cong-Cong, W. Bing, P. Yi-Qiong, T. Jian-Sheng, Z. Tong, Chin. J. Nat. Med. 15 (2017) 0721–0731. [30] D. Azzouzi, R. Mekkiou, I. Demirtas, F. G€ul, R. Seghiri, O. Boumaza, S. Benayache, F. Benayache, Int. J. Pharmacogn. Phytochem. Res. 8 (2016) 1526–1528. [31] R. Seghiri, M. Mekkiou, O. Boumaza, S. Benayache, J. Bermijo, F. Benayache, Chem. Nat. Compd. 42 (2006) 610–611. [32] O.M. Andersen, K.R. Markham, Flavonoids. Chemistry, Biochemistry and Applications, CRC Press, 2006. [33] A. Khalfallah, D. Berrehal, A. Kabouche, R. Touzani, K. Kabouche, Chem. Nat. Compd. 48 (2012) 482–483. [34] S. Mouffok, H. Haba, C. Lavaud, C. Long, M. Benkhaled, Rec. Nat. Prod. 3 (2012) 292–295. [35] R. Kitouni, F. Benayache, S. Benayache, Chem. Nat. Compd. 51 (2015) 762–763. [36] S. Akkal, F. Benayache, K. Medjroubi, F. Tillequin, E. Seguin, Biochem. Syst. Ecol. 31 (2003) 641–643. [37] A. Bentamene, S. Benayache, J. Creche, J. Bermejo, F. Benayache, Chem. Nat. Compd. 43 (2007) 749–750. [38] L. Hammoud, R. Seghiri, S. Benayache, P. Mosset, A. Lobstein, M. Chaabi, F. Leo´n, I. Brouard, J. Bermejo, F. Benayache, Nat. Prod. Res. 26 (2012) 203–208. [39] A. Nacer, A. Bernard, J. Boustie, R. Touzani, Z. Kabouche, Chem. Nat. Compd. 42 (2006) 230–231. [40] S. Belkacem, H. Belbache, C. Boubekri, P. Mosset, O. Rached-Mosbah, E. Marchioni, S. Benayache, F. Benayache, Res. J. Pharm. Biol. Chem. Sci. 5 (2014) 1275–1279. [41] C. Bensouici, A. Kabouche, K. Kabouche, R. Touzani, C. Bruneau, Chem. Nat. Compd. 48 (2012) 510–511. [42] G. Atmani, S. Benayache, F. Benayache, H. Dendougui, M. Jay, J. Soc. Alger. Chim. 8 (1998) 29–36. [43] A. Kabouche, Z. Kabouche, R. Touzani, C. Bruneau, Chem. Nat. Compd. 46 (2011) 966–967. [44] R. Ayad, F.Z. Belfadel, K. Medjroubi, F. Leon, I. Brouard, J. Bermejo, Emir. J. Food Agric. 25 (Suppl. Issue) (2013) 69. [45] K. Medjroubi, S. Mezhoud, F. Benayache, E. Seguin, F. Tillequin, Chem. Nat. Compd. 41 (2005) 226–227. [46] S. Akkal, F. Benayache, A. Bentamene, K. Medjroubi, E. Seguin, F. Tillequin, Chem. Nat. Compd. 39 (2003) 219–220. [47] K. Medjroubi, F. Benayache, S. Benayache, S. Akkal, M. Kaabeche, F. Tillequin, E. Seguin, Phytochemistry 49 (1998) 2425–2427. [48] M. Eleni Grafakou, S. Djeddi, H. Tarek, H. Skaltsa, Biochem. Syst. Ecol. 76 (2018) 15–22. [49] A. Bentamene, R. Boucheham, M. Baz, S. Benayache, I. Creche, F. Benayache, Chem. Nat. Compd. 46 (2010) 452–453. [50] S. Bicha, A. Amrani, O. Benaissa, F. Leo´n, D. Zama, I. Brouard, S. Benayache, A. Bentamene, F. Benayache, Pharm. Lett. 5 (2013) 24–30. [51] S. Akkal, F. Benayache, S. Benayache, K. Medjroubi, M. Jay, F. Tillequin, E. Seguin, Fitoterapia 70 (1999) 368–370. [52] N. Mezache, D. Bendjeddou, D. Satta, R. Mekkiou, S. Benayache, F. Benayache, Chem. Nat. Compd. 46 (2010) 801–802. [53] S. Akkal, F. Benayache, K. Medjroubi, F. Tillequin, Chem. Nat. Compd. 43 (2007) 319–320. [54] M.J. Abad Martı´nez, L.M. Bedoya Del Olmo, L.A. Ticona, P.B. Benito, In: Bioactive Natural Products (Part Q) vol. 37 (2012), Studies in Natural Products Chemistry, 43–65.

414 Studies in Natural Products Chemistry [55] S.M. Adekenov, Proc. Natl. Acad. Sci. Belarus 3 (2016) 39–40. [56] M. Bruno, S. Bancheva, S. Rosselli, A. Maggio, Phytochemistry 95 (2013) 19–93. [57] A. Bentame`ne, S. Benayache, J. Cre`che, G. Petit, J. Bermejo-Barrera, F. Leon, F. Benayache, Biochem. Syst. Ecol. 33 (2005) 1061–1065. [58] A.G. Gonzalez, J. Bermejo, G.M. Massanet, Rev. Latinoam. Quim. 8 (1977) 176–180. [59] G. Nowak, B. Drozdz, W. Kroszczynski, M. Holub, Acta Soc. Bot. Pol. 55 (1986) 17–22. [60] A. Nacer, J. Merza, Z. Kabouche, S. Rhouati, J. Boustie, Biochem. Syst. Ecol. 43 (2012) 163–165. [61] H. Lakhal, T. Boudiar, A. Kabouche, Z. Kabouche, R. Touzani, Nat. Prod. Commun. 5 (2010) 849–850. [62] S. Djeddi, A. Karioti, M. Sokovic, D. Stojkovic, R. Seridi, H. Skaltsa, J. Nat. Prod. 70 (2007) 1796–1799. [63] S. Bicha, P. Chalard, L. Hammoud, F. Leo´n, I. Brouard, V.P. Garcia, A. Lobstein, A. Bentamene, S. Benayache, J. Bermejo, F. Benayache, Rec. Nat. Prod. 7 (2013) 114–118. [64] G. Massiot, A.M. Morfaux, O. Le Men, J. Bouquant, A. Madaci, A. Mahmoud, M. Chopova, P. Aclinou, Phytochemistry 25 (1986) 258–261. [65] M. L´opez-Rodrı´guez, V.P. Garcı´a, H. Zater, S. Benayache, F. Benayache, Acta Cryst. E65 (2009) O1867–O1868. [66] K. Medjroubi, F. Benayache, S. Benayache, S. Akkal, S. Khalfallah, P. Aclinou, Phytochemistry 45 (1997) 1449–1451. [67] J. Conzalez-Platas, C. Ruiz- Perez, A.G. Gonzalez, J. Bermejo, K. Medjroubi, Acta Crystallogr. Sect. C: Cryst. Struct. Commun. 55 (1999) 1837–1839. [68] K. Medjroubi, F. Benayache, F. Leo´n, J. Bermejo, Rev. Colomb. Quim. 32 (2003) 17–22. [69] G. Nowak, J. Chromatogr. 505 (1990) 417–423. [70] R. Xu, G.C. Fazio, S.P. Matsuda, Phytochemistry 65 (2004) 261–291. [71] L.P. Sandjo, V. Kuete, Medicinal Plant Research in Africa, Elsevier Inc, Dschang, Cameroon, 2013 Available from: https://doi.org/10.1016/B978-0-12-405927-6.00004-7. [72] G. Zengin, A. Aktumsek, G.O. Guler, Y.S. Cakmak, Y. Kan, Nat. Prod. Res. 26 (2012) 1–10. [73] Y.B. Kose, A. Altintas, B. Demirci, S. Celik, K.H.C. Baser, Asian J. Chem. 21 (2009) 1719–1724. [74] B. Demirci, Y.B. Kose, K.C. Başer, E. Yucel, J. Essent. Oil Res. 20 (2008) 335–338. [75] T. Dob, D. Dahmane, B. Gauriat-Desrdy, V. Daligault, J. Essent. Oil Res. 21 (2009) 216–219. [76] T. Dob, D. Dahmane, B. Gauriat-Desrdy, V. Daligault, J. Essent. Oil Res. 21 (2009) 417–422. [77] S. Djeddi, M. Sokovic, H. Skaltsa, J. Essent. Oil Bear. Plants 14 (2011) 658–666. [78] D. Azzouzi, R. Mekkiou, P. Chalard, J.-C. Chalchat, O. Boumaza, R. Seghiri, F. Benayache, S. Benayache, Int. J. Pharmacogn. Phytochem. Res. 8 (2016) 1545–1548. [79] H. Belbache, Y. Mechehoud, J.-C. Chalchat, G. Figueredo, P. Chalard, S. Benayache, F. Benayache, Int. J. Pharmacogn. Phytochem. Res. 9 (2017) 79–82. [80] P. Aclinou, A. Boukerb, J. Bouquant, G. Massiot, L. Le Men-Olivier, Plant Med. Phytother. 16 (1982) 303–309. [81] A. Khammar, S. Djeddi, Eur. J. Sci. Res. 84 (2012) 398–416. [82] S. Louaar, A. Zellagui, N. Gherraf, K. Medjroubi, S. Derbre, E. Seguin, H. Laouer, S. Akkal, J. Biol. Act. Prod. Nat. 4 (2014) 249–253. [83] S. Djeddi, C. Argyropoulou, R. Chatter, J. Appl. Sci. Res. 8 (2012) 2876–2880.