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Natural Product Research
Formerly Natural Product Letters
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The ethnobotany, phytochemistry, and biological
properties of genus Phagnalon (Asteraceae): a
review
Adele Cicio, Natale Badalamenti & Maurizio Bruno
To cite this article: Adele Cicio, Natale Badalamenti & Maurizio Bruno (2022): The ethnobotany,
phytochemistry, and biological properties of genus Phagnalon (Asteraceae): a review, Natural
Product Research, DOI: 10.1080/14786419.2022.2112039
To link to this article: https://doi.org/10.1080/14786419.2022.2112039
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The ethnobotany, phytochemistry, and biological
properties of genus Phagnalon (Asteraceae): a review
Adele Cicio
a
, Natale Badalamenti
a
and Maurizio Bruno
a,b
a
Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF),
University of Palermo, Palermo, Viale delle Scienze, Italy;
b
Centro Interdipartimentale di Ricerca
“Riutilizzo bio-based degli scarti da matrici agroalimentari”(RIVIVE), Universit
a di Palermo, Palermo,
Viale delle Scienze, Italy
ABSTRACT
The genus Phagnalon Cass., included within the Asteraceae family,
has a wide distribution, expanding from Macaronesia in the West
to the Himalayas in the East, from S. France and N. Italy to
Ethiopia and Arabian Peninsula. Various species of Phagnalon
have been used in the popular medicine of several countries as
medicinal herbs and food. This literature review, the first one of
the Phagnalon genus, includes publications with the word
‘Phagnalon’, and considers the extracts and the single metabolites
identified, characterized, and tested to evaluate their biological
potential. The extracts and the secondary metabolites, have a var-
ied application spectrum at a biological level, with antimicrobial,
antioxidant, antidiabetic, antitumor, etc. properties having been
reported. Unfortunately, in vitro tests have not always been
accompanied by in vivo tests, and this is the major critical aspect
that emerges from the study of the scientific aspects related to
this genus.
ARTICLE HISTORY
Received 4 May 2022
Accepted 28 July 2022
KEYWORDS
Phagnalon ssp.; Asteraceae;
secondary metabolites;
cinnamic acid derivatives;
ethnopharmacology; bio-
logical properties
CONTACT Maurizio Bruno maurizio.bruno@unipa.it
Supplemental data for this article can be accessed online at https://doi.org/10.1080/14786419.2022.2112039.
ß2022 Informa UK Limited, trading as Taylor & Francis Group
NATURAL PRODUCT RESEARCH
https://doi.org/10.1080/14786419.2022.2112039
1. Introduction
The genus Phagnalon Cass., belonging to the tribe Inuleae (Asteraceae), is distributed
from Macaronesia in the West to the Himalayas in the East, from S. France and N. Italy
in the North to Ethiopia in the South, but its greatest diversity is found in the Arabian
Peninsula (Figure 1). All species are perennial and grow in a variety of habitats ranging
from rocky crevices in high mountains to sandy soils in coastal plains (Qaiser and Lack
1985,1986). It is important to underline that, at a phylogenetic level, analysing the
sequences of the trnL intron and trnL-trnF spacer and ribosomal nrDNA together with
the ycf3-trnS and trnT-trnL spacers of cpDNA, the relationship between the genus
Aliella and the genus Phagnalon has been clarified. The monophyly of Aliella and
Phagnalon is not statistically supported and Aliella is paraphyletic in most analyses.
The resulting phylogeny suggests an African origin for Aliella and Phagnalon and iden-
tifies three main clades in Phagnalon, the Irano-Turanian clade, the Mediterranean-
Macaronesian clade and the Yemenite-Ethiopian clade. Incongruence between the
chloroplast and nuclear molecular data and the lack of resolution in some clades may
indicate that hybridization could have played an important role in the evolution and
diversification of Phagnalon and Aliella (Montes-Moreno et al. 2010). Actually, The
Plant List (2022) shows 149 plant name records, of which only 31 have the rang of
accepted species or sub-species whereas, according to another database (Plants of the
Word Online 2022) more than forty have the rang of accepted taxa. Tables S1 and S2
list all the accepted taxa including the main synonymous. The first investigation on
species of genus Phagnalon appeared in literature in 1975 (Bicchi et al. 1975) and in
the following years many papers on the phytochemical composition, isolation of pure
metabolites and biological properties of extracts and pure compounds have
been published.
Since no previous review on this genus has been published, the aim of this paper
is to provide a comprehensive update of ethnopharmacological, phytochemical and
pharmacological aspects of crude extracts and isolated compounds from Phagnalon
species. The review will also indicate perspectives and directions of future research on
Figure 1. Geographical distribution of the genus Phagnalon Cass. according to Plants of the World
Online: POWO (2022) (https://powo.science.kew.org/).
2 A. CICIO ET AL.
the genus in the course of discovery of novel active natural ingredients and their bio-
logical applications.
2. Review methodology
In this review, a complete survey of the chemical composition and biological proper-
ties of the essential oils, extracts and non-volatile compounds isolated from Phagnalon
genus is provided. Moreover, the traditional uses of Phagnalon taxa are also reported.
The available information on these genera was collected from scientific databases and
cover from 1975 up to 2021. The following electronic databases were used: PubMed,
SciFinder, Science Direct, Scopus, Web of Science, and Google Scholar. The search
terms used for this review included Phagnalon, all the botanical names of the species,
both accepted names or synonyms, essential oils, volatile components, traditional
uses, activity, pharmacology, and toxicity. No limitations were set for languages. Tables
S1 and S2 report the taxa of Phagnalon known so far, their synonyms, the accepted
botanical names, and the geographical distribution.
3. Traditional uses
In the Palestinian area the aerial parts of P. rupestre, locally known as ‘Qadeeh, Qadih,
Sufan, Qray’i’, were used in the past to treat asthma, as anaesthetic for toothache and
internally to treat headache (Ali-Shtayeh et al. 1998). Furthermore, the infusion of the
leaves was utilized against infection, kidney stones (Abu-Rabia 2005). The same spe-
cies, in Jordan (vernacular name ‘Kadha’) is recommended for inflammation, rheuma-
tism, migraine, depression, scalp infection. The dried herb is ignited and is used to
cauterize the site of pain. Usually, skin cauterization is done in specific areas in the
body like the hand; between fingers, or on the back of the leg and sometimes on cer-
tain areas in the head. Usually specialized persons are eligible to do this work
(Friedman et al. 1986; Hudaib et al. 2008; Alzweiri et al. 2011). In Israel, the decoction
of the whole plant is used to treat leprosy (Palevitch et al. 1986)
Phagnalon saxatile (L.) Cass. in Spain, where it is known as ‘t
e de piedra’,itwasused
against mental-nervous diseases (Gonz
alez-Tejero et al. 2008) and as carminative, anal-
gesic, and to low the blood cholesterol levels (Pardo De Santayana et al. 2005), while in
Sicily it has been reported the use of this plant as spice (Lentini and Venza 2007).
Phagnalon sordidum (L.) Reichenb. (Compositae) is a perennial weed widespread in
the entire Mediterranean region. This plant is used alone or mixed with Lippia citrio-
dora and/or Malva sylvestris to cure renal calculosis in the medicinal folk traditions of
the Balearic Islands (Epifano et al. 2002).
4. Compounds identified from Phagnalon species
4.1. Non volatile compounds
Aerial part and root extracts of the Phagnalon species have been shown to contain fla-
vonoids (1–10)(Figure 2), aromatic compounds such as benzofuran derivatives
(11–16)(Figure 3), prenylhydroquinone derivatives (17–22)(Figure 3), other aromatic
NATURAL PRODUCT RESEARCH 3
compounds (23–29)(Figure 3), and cinnamic acid derivatives (30–45)(Figure 4), terpe-
noids, etc. (46–50)(Figure 5).
The occurrence of all these metabolites is reported in Table 1.
In spite of the large occurrence of flavonoids in other genera of the Astearaceae
family (Formisano et al. 2012), the presence of such metabolites is quite limited in
genus Phagnalon. In fact only few derivatives of apigenin, luteolin and quercetin were
identified in P. rupestre (G
ongora et al. 2001,2002a,2002b), P. saxatile (Conforti et al.
2010; Cherchar et al. 2018; Haddouchi et al. 2021) and P. sordidum (Cherchar 2018),
whereas flavanone derivatives of eriodictyol were detected only in P. sordidum col-
lected in Algeria (Cherchar 2018; Cherchar et al. 2019).
Benzofuran tremetone derivatives, identified in P. purpurescens from Canary Islands
(11–13) (Zdero et al. 1991), P. rupestre from Spain (14) and P. sordidum from Algeria
(15,16) (Cherchar 2018; Cherchar et al. 2019) are very important compounds. In fact,
this class of metabolites, largely and exclusively represented also in several other
genus of plants of Asteraceae family, have been shown to possess very interesting bio-
logical properties. A complete review on their occurrence and on their biological activ-
ities has been recently published (Badalamenti et al. 2021).
Principal metabolites of genus Phagnalon are the derivatives of cinnamic acid such
as ferulic acid (30) and caffeic acid (32), mainly present as mono-, di and tri-esters of
Figure 2. Flavonoids from Phagnalon taxa.
4 A. CICIO ET AL.
quinic acid. In fact, with the exception of P. atlanticum (Hausen and Schulz 1977) and
P. siniacum (El-Dahmy et al. 1994), they were identifies in all the other Phagnolon taxa
studied so far (Table 1). Among the other metabolites it is noteworthy the absence of
sesquiterpenes, largely represented in other genus of the Asteraceae family (Bruno
et al. 2013); only two eudesmaniolides (46,47) were isolated from the aerial parts of
P. sordidum collected in Algeria (Cherchar 2018).
4.2. Essential oils
Regarding to the composition of the essential oils obtained from aerial parts of
Phagnalon species of different geographic origin, only four articles have been
Figure 3. Aromatic compounds from Phagnalon taxa.
NATURAL PRODUCT RESEARCH 5
published. Table 2 reports the essential oil compositions of the taxa studied so far.
The essential oils, obtained by hydrodistillation were characterized by quite different
profiles. P. graecum showed to be very rich in sesquiterpenes (64.7%) with germacrene
Figure 4. Cinnamic acid derivatives from Phagnalon taxa.
Figure 5. Other metabolites from Phagnalon taxa.
6 A. CICIO ET AL.
Table 1. Occurrence of non-volatile metabolites in Phagnalon taxa.
Taxa Origin Parts Compounds Ref.
P. atlanticum
(syn. P. bicolor)
Morocco a.p. 2-dimethylallyl-1,4-benzoquinone (22) Hausen and
Schulz 1977
P. graecum (syn. P.
rupestre
subsp. graecum)
Turkey a.p. Ferulic acid (30), o-coumaric acid (31) Erdogan Orhan
et al. 2013
P. lowei Madeira lv. 5-O-caffeoylquinic acid (37), 1,5-di-O-
caffeoylquinic acid (39), 3,5-di-O-
caffeoylquinic acid (41), 4,5-di-O-caffeoyl
quinic acid (43), 3,4,5-tri-O-caffeoyl quinic
acid (45)
Sp
ınola and
Castilho 2017
P. purpurescens Tenerife
Island, Spain
a.p. 11–13,24, methyl caffeoate (33),
dammadienylacetate (48), sitosterol,
stigmasterol, oleanolic acid
Zdero et al. 1991
P. purpurescens Tenerife
Island, Spain
roots 11–13, dammadienylacetate (48) Zdero et al. 1991
P. rupestre Spain a.p. 2-dimethylallyl-1,4-benzoquinone (22) Hausen and
Schulz 1977
P. rupestre Spain a.p. Luteolin-7-O-b-glucopyranoside (4), 1-O-
b-glucopyranosyl-1,4-dihydroxy-2-(30,30-
dimethylallyl)-benzene (17), 1-O-
b-glucopyranosyl-1,4-dihydroxy-2-(30-
hydroxymethyl-30-methylallyl)-benzene
(18), 1-O-(4”-O-caffeoyl)-b-glucopyranosyl-
1,4-dihydroxy-2-(30,30-dimethylallyl)-
benzene (19), 3,5-di-O-dicaffeoylquinic
acid (41), 3,5-di-O-caffeoyl quinic acid
methyl ester (42), 4,5-di-O-caffeoyl quinic
acid (43), 4,5-di-O-caffeoyl quinic acid
methyl ester (44)
G
ongora et al.
2001,2002a
P. rupestre Spain a.p. Luteolin-7-O-b-glucopyranoside (4), apigenin-
7-O-b-D-glucopyranoside (5), luteolin-7-O-
b-glucuronide (6), 12-O-b-glucopyranosyl-
9b,12-dihydroxytremetone (14), 1-O-
b-glucopyranosyl-1,4-dihydroxy-2-(30-
hydroxy-30-methylbutyl) benzene (20),
7,70-bis-(4-hydroxy-3,5-dimethoxyphenyl)-
8,80-dihydroxymethyl-tetrahydrofuran-4-O-
b-glucopyranoside (23), picein (28)
G
ongora
et al. 2002b
P. rupestre Italy a.p. Apigenin (1), luteolin (2), apigenin-7-O-b-D-
glucopyranoside (5)
Dolci and Tira
P. rupestre Sicily, Italy a.p. n-paraffin: C
27
,C
29
,C
31
,C
33
Bicchi et al. 1975
P. saxatile Spain a.p. 2-dimethylallyl-1,4-benzoquinone (22) Hausen and
Schulz 1977
P. saxatile
ssp. saxatile
Algeria a.p. Apigenin (1), luteolin (2), caffeoylquinic acid
isomers, coumaroyl quinic acid, luteolin
di-glucoside, di-O-caffeoylquinic acid
isomers, luteolin glucoside,
quercetin glucoside
Haddouchi
et al 2021
P. saxatile Algeria a.p. Apigenin (1), luteolin (2), 30-methoxyluteolin
(3), luteolin-7-O-b-D-glucopyranoside (4),
apigenin-7-O-b-D-glucopyranoside (5),
luteolin-40-O-b-D-glucopyranoside (7),
hydroquinone glucoside, 1-O-b-D-
glucopyranosyl-1,4-dihydroxy-2-(30,30-
dimethyl-allyl)benzene (17), 1-O-b-D-
glucopyranosyl-1,4-dihydroxy-2-(E)-2-oxo-
3-butenyl)-benzene (21), potassium 4-
hydroxy-3-methoxybenzoic acid methyl
ester-5-sulphate (29), 3,5-di-O-
caffeoylquinicacid methyl ester (42),
dicaffeoylquinic acid derivative
Cherchar et al. 2018
(continued)
NATURAL PRODUCT RESEARCH 7
D (21.3%) as main constituent (Erdogan Orhan et al. 2013). On the other hand both
accessions of P. sordidum, from Algeria (Chikhi et al. 2019) and Corsica were character-
ized by high amount of monoterpenes. Main constituents of both accessions were
b-pinene and (E)-b-caryophyllene. These compounds were also among the main
metabolites of P. saxatile (Senatore et al. 2005) although this oil showed a larger
amount of other constituents with hexadecanoic acid (17.4%) as main product.
5. Biological properties
5.1. Antibacterial and antifungal properties
The ethanolic and aqueous extracts of P. rupestre, collected in Palestinian territory,
were shown to be particularly active against five bacterial species (Staphylococcus aur-
eus,Escherichia coli,Klebsiella pneumoniae,Proteus vulgaris,Pseudomonas aeruginosa)
Table 1. Continued.
Taxa Origin Parts Compounds Ref.
P. saxatile Sicily, Italy a.p. Apigenin (1), luteolin (2), apigenin-7-O-b-D-
glucopyranoside (5), luteolin-40-O-
glucopyranoside (7), 1-O-
b-glucopyranosyl-2-(30,30-dimethylallyl)-
hydroquinone (17), 1-O-b-glucopyranosyl-
2(30-hydroxymethyl-30-methylallyl)
hydroquinone (18), caffeic acid (32),
chlorogenic acid (34), methylchlorogenic
acid (35), 3,5-di-O-caffeoylquinic acid (41),
3,5-di-O-caffeoylquinic acid methyl
ester (42)
Conforti et al. 2010
P. siniacum Egypt a.p. Thymol, dammadienylacetate (48),
squalene, phytol
El-Dahmy et al. 1994
P. sordidum Sardinia, Italy a.p. 2-dimethylallyl-1,4-benzoquinone (22) Hausen and
Schulz 1977
P. sordidum Algeria a.p. Eriodictyol (8), eriodictyol-7-methyl ether (9),
gnaphaliol 3-O-b-D-glucopyranoside (16),
nebrodenside A (17), 3,4-
dihydroxyacetophenone (25), 5-O-b-D-
glucopyranosyl-2-hydroxy-p-cymene (27),
picein (28), caffeic acid (32), 3-O-feruloyl
quinic acid (36), 3-O-caffeoyl quinic acid
(34), 3,4-di-O-caffeoyl quinic acid (40),
ergiside B (49)
Cherchar et al. 2019
P. sordidum Algeria a.p. Chrysoeriol (3), luteolin-7-O-
b-glucopyranoside (4), eriodictyol 7-O-
b-D-glucopyranoside (10), nauplathizine
(15), 1-O-b-glucopyranosyl-2-(30,30-
dim
ethylallyl) hydroquinone
(nebrodenside A) (17), 3,4-
dihydroxybenzaldehyde (26), ameliaroside
(picein) (28), caffeic acid (32), 3-O-caffeoyl
quinic acid (34), methyl 3-O-
caffeoylquinate (35), methyl 5-O-
caffeoylquinate (38), 3,5-di-O-
caffeoylquinique acid (41), armefolin (46),
armexifolin (47)
Cherchar 2018
P. sordidum Umbria, Italy a.p. L-(-)-chiroinositol (50), lupeol, betulin,
betulinic acid, b-sitosterol-b-D-
glucopyranoside
Epifano et al. 2002
8 A. CICIO ET AL.
and one yeast (Candida albicans) (Ali-Shtayeh et al. 1998) whereas the ethanolic and
aqueous extracts of P. sinaicum, collected in Sinai, Egypt, were tested in vitro and
in vivo for its antifungal properties against Phytophthora infestans, the causal agent of
late blight disease of tomato. The overall results suggested that the use of this
Egyptian wild medicinal plant extract was promising, effective and environment-
friendly management measure against Phytophthora blight of tomato and thus, it
could be used in the production of organically grown vegetables (Baka 2014a). Further
investigations on the aqueous extract of P. sinaicum indicated good antifungal proper-
ties against Aspergillus flavus,A. niger,Curvularia lunata,Fusarium moniliforme and
Penicillium chrysogenum (Baka 2014b) and a moderate one against Botrytis fabae,
Fusarium oxysporum and Penicillium italicum (Baka 2015).
The antimicrobial activities of the essential oil of aerial parts of Phagnalon sordidum
(L.) Rchb, collected in Algeria, were evaluated against eleven bacteria. Staphylococcus
aureus,Klebsiella pneumoniae and Salmonella typhimurium were the most susceptible
microorganisms with a minimum inhibitory concentrations (MICs) of 0.01, 0.04,
0.04 mg/mL, respectively (Chikhi et al. 2019). A notable activity on a large panel of
clinically significant microorganisms was also exhibited by P. sordidum essential oil
from plants collected in Corsica. The best results were obtained against Staphylococcus
aureus and Streptococcus dysgalactiae with a MIC value of 0.064 mg/mL, comparable or
better than gentamicin, used as positive control (Brunel et al. 2016).
Table 2. Main components (>3%) and classes of the essential oils of aerial parts of
Phagnalon taxa.
Taxa Origin Components MH OM SH OS O Ref.
P. graecum Turkey Germacrene D (21.3),
hexahydrofarnesyl acetone (9.6),
(E)-b-caryophyllene (9.4),
hexadecanoic acid (6.1),
caryophyllene oxide (6.0),
d-cadinene (3.2)
0.5 0.1 42.7 22.0 20.1 Erdogan Orhan
et al. 2013
P. saxatile Italy Hexadecanoic acid (17.4), b-pinene
(5.4), (E)-b-caryophyllene (4.6),
hexahydrofarnesyl acetone (4.3),
nonacosane (4.2), heptacosane
(4.1), pentacosane (3.7),
limonene (3.5), hentriacontane
(3.3), c-cadinene (3.0)
13.6 2.8 19.5 4.9 51.9 Senatore
et al. 2005
P. sordidum Algeria b-pinene (16.7–27.0), (E)-
b-caryophyllene (9.6–15.8),
limonene (6.6–12.1), germacrene
D (3.1–7.6), decanal (2.4–8.1),
thymol (2.2–11.0), caryophyllene
oxide (1.9–3.6), p-cymene
(1.8–4.3), (Z)-3-hexen-1-ol
(0.1–3.6), sabinene (0.1–3.6)
51.4 10.4 18.0 6.0 11.8 Chikhi
et al. 2019
P. sordidum Corsica,
France
(E)-b-caryophyllene (14.4), b-pinene
(11.0), thymol (9.0),
hexadecanoic acid (5.3),
limonene (4.3), p-cymene (3.5),
decanal (3.5), linalool (3.1)
caryophyllene oxide (3.1),
germacrene D (3.0)
24.3 20.9 22.9 5.4 14.4 Brunel et al.
MH ¼monoterpene hydrocarbons; OM ¼oxygenated monoterpenes; SH ¼sesquiterpene hydrocarbons;
OS ¼oxygenated sesquiterpenes; O ¼others.
NATURAL PRODUCT RESEARCH 9
5.2. Antioxidant properties
The in vitro properties (inhibition of NO production and anticholinesterase) of
Phagnalon saxatile (L.) Cass., collected in Sicily, were described. The methanolic extract
showed antioxidant activity that was measured by DPPH assay and b-carotene bleach-
ing test. The same extract inhibited NO production in the murine monocytic macro-
phage cell line RAW 264.7. Acetylcholinesterase (AChE) and butyrylcholinesterase
(BChE) inhibition was assessed by modifications of Ellman’s method. Purification of the
MeOH extract of P. saxatile allowed the isolation of phenolic compounds. Among
them, the compounds that most effectively inhibited lipopolysaccharide-induced NO
production were caffeic acid (32) and methylchlorogenic acid (35), with IC
50
values of
7lg/mL and 12 lg/mL, respectively. Luteolin (2) and 3,5-dicaffeoylquinic acid (41)
exhibited the most promising activity against AChE with an IC
50
of 25.2 and 54.5 lg/
mL, respectively, while caffeic acid (32) and luteolin (2) showed higher activity against
BChE with an IC
50
of 32.2 and 37.2 lg/mL, respectively (Conforti et al. 2010). Four
extracts, obtained by using different solvents, of the leafy stems of an Algerian acces-
sion of the same species were investigated for their content of phenolic compounds
and their antioxidant activity. The extracts prepared with polar solvents (methanol and
water) contained higher amounts of phenolic compounds and showed better antioxi-
dant activity than the apolar solvents extracts (hexane, dichloromethane). The metha-
nolic extract, richest in total phenolic and total flavonoid, had significant antioxidant
activity as regarded by DPPH scavenging capacity (IC
50
of 5.5 lg/mL),
ABTS þscavenging capacity (IC
50
of 63.8 lg/mL) and inhibition of oxidation of linoleic
acid (IC
50
of 22.7 lg/mL), when compared to synthetic antioxidants. Chlorogenic acids
and several flavonoids were identified and quantified by UPLC-DAD-MSn. The di-O-caf-
feoylquinic acids isomers were the most concentrated phenolics (25.4 mg/g DW) in the
methanolic extract (Haddouchi et al. 2014,2021).
Twelve metabolites were isolated through a biologically oriented approach from
the aerial parts of Phagnalon sordidum L. (Table 1), selected by using three comple-
mentary antioxidant activity assays. Antioxidant activities of ethyl acetate extract, and
purified 3,4-dihydroxyacetophenone (25) and nebrodenside A (17) were demonstrated
by in vitro cell free model assays, and their protective effect against H
2
O
2
-induced oxi-
dative stress in a HepG2 (human hepatocellular carcinoma) cell line was established
(Cherchar et al. 2019).
The n-hexane, chloroform, ethyl acetate, methanol, and water extracts of Phagnalon
graecum Boiss., collected in Turkey, were investigated for their enzyme inhibitory activ-
ity against acetylcholinesterase, butyrylcholinesterase, lipoxygenase, tyrosinase, and
antioxidant activities. Antioxidant activity of the extracts was determined by 2,2-
diphenyl-1-picrylhydrazyl radical scavenging, ferric ion-chelation activity, and ferric
reducing antioxidant power tests. The extracts had insignificant inhibition against the
tested enzymes, whereas they displayed a remarkable antioxidant activity. Due to its
good biological properties, authors remarks that P. graecum could be utilized as
potential antioxidant applicable for food preservation (Erdogan Orhan et al. 2013).
The caffeoyl conjugates of prenylhydroquinone glucoside and of quinic acid, either
in the carboxyl-free or carboxymethyl forms (17–19,41–44), isolated from Phagnalon
rupestre, showed inhibitory activity on lipid peroxidation induced by Fe 2þ/ascorbate
10 A. CICIO ET AL.
and by CCl4/NADPH in rat liver microsomes, with IC
50
values ranging from 3 to 11 mM.
After having demonstrated their effect on the xanthine oxidase-regulated superoxide
production, the active compounds were tested for the direct inhibition of this enzyme.
Methylated dicaffeoylquinic conjugates (42,44) competitively inhibited the enzyme
and the highest potency was obtained for the 4,5-diester (44), with an IC
50
value of
3.6 mM, nearly ten times lower than that of the 3,5-analogue (42). In conclusion,
authors claimed that the presence of the caffeoyl moiety is essential for both the anti-
peroxidative and radical scavenging activities, and the methylation of the quinic carb-
oxyl group enhances the potency on xanthine oxidase inhibitory activity (G
ongora
et al. 2003).
The same metabolites (17–19,41–44) were examined for their effect on tyrosine
nitration, as well as on the oxidation of dihydrorhodamine (DHR) 123 and cytochrome
c2þinduced by peroxynitrite. All the compounds were fairly active in preventing the
oxidation of DHR 123, though inefficient in the cytochrome c test. The highest
potency corresponded to 2-isoprenylhydroquinone-1-glucoside (17), with an IC
50
of
40 mM (Olmos et al. 2005,2007).
Two phenolic antioxidant and anti-inflammatory compounds: isoprenylhydroqui-
none glucoside (17), and 3.5-dicaffeoylquinic acid methyl ester (42), have been studied
for their inhibitory activity against protein carbonylation, a harmful post-translational
modification of peptide chains associated with degenerative diseases. Both com-
pounds have proven to be effective, with 50% inhibitory concentration (IC
50
) values in
the micromolar range, against bovine serum albumin carbonylation caused by hypo-
chlorite, peroxynitrite, and phorbol ester-induced leukocyte oxidative burst (Mar
ın
et al. 2011).
5.3. Antitumor activities
The ethanolic extracts of the aerial pats P. rupestre, collected in Jordan, showed a
moderate antiproliferative activity against Hep-2, MCF-7, and Vero cancer cell lines
(Talib and Mahasneh 2010).
The cytotoxic activity of three isolated compounds from Phagnalon saxatile (L.) Cass
(17,21,29) was evaluated against fibrosarcoma (HT1080), human lung cancer (A549)
and breast cancer (MCF7) cell lines. Compound 17, showed a good cytotoxic activity
against HT1080, A549 and MCF7 (IC
50
33.2, 77.0 and 37.0 lM, respectively), whereas
compounds 21 and 29 showed moderate cytotoxicity on HT1080 cell line only
(Cherchar et al. 2018).
5.4. Other biological properties
A study was carried out in order to assess the in vitro anti-diabetic potential of P. lowei
leaves methanolic extract to inhibit the activity of digestive enzymes (a-amylase, a-,
b-glucosidases and lipase) responsible for hydrolysis/digestion of sugar and lipids. The
extract exhibited significant inhibitory activity against key digestive enzymes linked to
type II diabetes and obesity. A strong inhibition was observed for glucosidases and
mild activity towards amylase and lipase (compared to reference compounds).
NATURAL PRODUCT RESEARCH 11
Consequently, the caffeoylquinic acids (37,39,41,43,45), principal metabolites of the
extract, were demonstrated to be the most relevant hypoglycemic and anti-glycation
agents. From the obtained results Phagnalon lowei showed to be a good candidate for
further development of phyto-pharmaceutical preparations as complementary therapy
for diabetes and obesity control (Sp
ınola and Castilho 2017).
The methanolic extract of Phagnalon rupestre as well as eight isolated compounds,
luteolin-7-O-b-glucopyranoside (4), 1-O-b-glucopyranosyl-1,4-dihydroxy-2-(30,30-dime-
thylallyl)-benzene (17), 1-O-b-glucopyranosyl-1,4-dihydroxy-2-(30-hydroxymethyl-30-
methylallyl)-benzene (18), 1-O-(4”-O-caffeoyl)-b-glucopyranosyl-1,4-dihydroxy-2-(30,30-
dimethylallyl)-benzene (19), 3,5-di-O-caffeoyl quinic acid (41), 3,5-di-O-caffeoyl quinic
acid methyl ester (42), 4,5-di-O-caffeoyl quinic acid (43), 4,5-di-O-caffeoyl quinic acid
methyl ester (44) were tested for dinitrofluorobenzene-induced contact hypersensitiv-
ity inhibitory activity. The flavonoid 4was shown to be the most active, both at 24 h
and 96 h, whereas the three hydroquinones (17–19) were effective after 96 h (G
ongora
et al. 2002a).
In another study in vitro the activity of three prenylhydroquinone glucosides
(17–19) and four caffeoylquinic esters (41–44), obtained from Phagnalon rupestre,on
elastase release, myeloperoxidase activity and superoxide and leukotriene B4 produc-
tion from polymorphonuclear leukocytes was determined. 4,5-Dicaffeoylquinic acid
(43) strongly inhibited elastase release with an IC
50
value of 4.8 mM. Methylated caf-
feoylquinic derivatives (42,44) were the most potent inhibitors of myeloperoxidase
(IC
50
near 60 mM), whereas both methylated and free carboxyl isomers (41–44) inhib-
ited superoxide production with similar potency (IC
50
between 27 and 42 mM). The
monocaffeoyl conjugate of prenylhydroquinone glucoside (19), the most potent inhibi-
tor of leukotriene B4 production (IC
50
¼33 mM), possesses a mixed hydroquinone-caf-
feoyl character that could be considered as a potential anti-inflammatory entity
(G
ongora et al. 2002c).
Later, the same group tested in vivo three phenolic substances: 2-isoprenylhydro-
quinone-1-glucoside (17), 3,5-di-O-caffeoyl quinic acid (41), and 3,5-dicaffeoylquinic
acid methyl ester (42), isolated from the same species, for their efficacy in two mouse
models of dermatitis induced by single and repeated application of 2,4,6-trinitrochloro-
benzene. The effect of these compounds on metalloproteinase-9 (MMP-9) expression
in macrophages stimulated with lipopolysaccharide (LPS) was also investigated. The
results indicated that these three phenolics modulated the immune response in the
skin after exposure to the contact allergen TNCB, at least partly via reduction of ear
swelling and cytokine production, although with different ranges of activity.
Compound 41 was found to be particularly effective in inhibiting most of the inflam-
mation parameters (Giner et al. 2011).
6. Conclusion and future prospective
The genus Phagnalon Cass., belonging to the tribe Inuleae (Asteraceae), is distributed
in the Northern hemisphere and it has been largely used in the popular medicine of
several countries as well as spice due to its interesting biological properties. Up to
April 2022, 50 metabolites have been isolated from the roots and aerial parts of the
12 A. CICIO ET AL.
different species, identified using spectroscopic techniques, and evaluated for bio-
logical potential.
Among these, flavonoids, aromatic compounds, such as benzofuran derivatives and
prenylhydroquinone derivatives, and cinnamic acid derivatives are the most character-
istic. Especially in the last two decades, the extracts obtained from the different parts
of the plants, and the pure isolated compounds, have been tested and evaluated for
their biological activities, such as antitumor, anti-inflammatory, antimicrobial, and anti-
oxidant. However, the few studies on biological properties of Phagnalon species, pre-
sent in literature, do not allow to confirm and validate, the use of species of this
genus in traditional medicine.
Nevertheless, major critical issues remain: most scientific studies have aimed to test
the extracts, or compounds isolated, through in vitro studies; the biological supports
obtainable in vivo, and biochemical investigations relating to the mechanism of action
of the tested samples, are lacking. Only few works report the isolation of essential oils,
which could be used for a chemotaxonomic distinction between dubious species.
This literature review aims to direct current researchers to work on a widely promis-
ing genus at the biological level, since of the 31 accepted species only few have been
investigated.
Disclosure statement
The authors declare no conflict of interest in this article.
Funding
This work was supported by grant from MIUR-ITALY PRIN 2017 (Project N. 2017A95NCJ).
ORCID
Maurizio Bruno http://orcid.org/0000-0003-0583-0487
References
Abu-Rabia A. 2005. Palestinian plant medicines for treating renal disorders: an inventory and
brief history. Altern Compl Ther. 11(6):295–300.
Ali-Shtayeh MS, Yaghmour RMR, Faidi YR, Salem K, Al-Nuri MA. 1998. Antimicrobial activity of 20
plants used in folkloric medicine in the Palestinian area. J Ethnopharmacol. 60(3):265–271.
Alzweiri M, Sarhan AA, Mansi K, Hudaib M, Aburjai T. 2011. Ethnopharmacological survey of
medicinal herbs in Jordan, the Northern Badia region. J Ethnopharmacol. 137(1):27–35.
Badalamenti N, Modica A, Ilardi V, Bruno M. 2021. Chemical constituents and biological proper-
ties of Genus Doronicum (Asteraceae). Chem Biodiv. 18:e2100631.
Baka ZAM. 2014a. Antifungal activity of extracts from five Egyptian wild medicinal plants against
late blight disease of tomato. Arch Phytopathol Plant Protect. 47(16):1988–2002.
Baka ZAM. 2014b. Plant extract control of the fungi associated with different Egyptian wheat
cultivars grains. J Plant Protect Res. 54(3):231–237.
Baka ZAM. 2015. Efficacy of wild medicinal plant extracts against predominant seed-borne fungi
of broad bean cultivars. Acta Phytopathol Entomol Hung. 50(1):45–65.
NATURAL PRODUCT RESEARCH 13
Bicchi C, Nano GM, Tira S. 1975.n–Paraffin components of some Gnaphalieae. Planta Med. 28(4):
389–391.
Brunel M, Vitrac C, Costa J, Mzali F, Vitrac X, Muselli A. 2016. Essential oil composition of
Phagnalon sordidum (L.) from Corsica, chemical variability and antimicrobial activity. Chem
Biodivers. 13(3):299–308.
Bruno M, Bancheva S, Maggio A, Rosselli S. 2013. Sesquiterpenoids in subtribe Centaureinae
(Cass.) Dumort (tribe Cardueae, Asteraceae): distribution,
13
C-NMR spectral data and biological
properties. Phytochemistry. 95:19–93.
Chikhi I, Allali H, Costa J. 2019. Chemical composition and biological activities of essential oils of
Phagnalon sordidum (L.) Rchb. (Asteraceae) from Algeria. Agric Conspec Sci. 84(3):271–281.
Cherchar H. 2018.
Etude phytochimique et
evaluation des activit
es antioxydante, antibact
erienne
et cytotoxique de deux plantes du genre Phagnalon (Asteraceae) [Doctoral Thesis].
Constantine, Algeria: Universite des Freres Mentouri-Constantine, Faculte des Sciences
Exactes, Departement de Chimie.
Cherchar H, Lehbili M, Berrehal D, Morjani H, Alabdul Magid A, Voutquenne-Nazabadioko L,
Kabouche A, Kabouche Z. 2018. A new 2-alkylhydroquinone glucoside from Phagnalon saxa-
tile (L.) Cass. Nat Prod Res. 32(9):1010–1016.
Cherchar H, Faraone I, DʼAmbola M, Sinisgalli C, Dal Piaz F, Oliva P, Kabouche A, Kabouche Z,
Milella L, Vassallo A. 2019. Phytochemistry and antioxidant activity of aerial parts of
Phagnalon sordidum L. Planta Med. 85(11–12):1008–1015.
Conforti F, Rigano D, Formisano C, Bruno M, Loizzo MR, Menichini F, Senatore F. 2010.
Metabolite profile and in vitro activities of Phagnalon saxatile (L.) Cass. relevant to treatment
of Alzheimer’s disease. J Enzyme Inhib Med Chem. 25(1):97–104.
El-Dahmy SI, Abdel Aal M, Abd El-Fatah H, Fid F. 1994. Thymol derivatives from Phagnalon sinai-
cum Bornm and Kneuck. Acta Pharm Hung. 64(4):115–116.
Epifano F, Marcotullio MC, Menghini L. 2002. Constituents of Phagnalon sordidum. Chem Nat
Comp. 38(2):204–205.
Erdogan Orhan I, Senol FS, Demirci B, Ozturk N, Baser KHC, Sener B. 2013. Phytochemical charac-
terization of Phagnalon graecum Boiss. by HPLC and GC-MS with its enzyme inhibitory and
antioxidant activity profiling by spectrophotometric methods. Food Anal Methods. 6(1):1–9.
Formisano C, Rigano D, Senatore F, Bancheva S, Maggio A, Rosselli S, Bruno M. 2012. Flavonoids
in Subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): distribution and
13
C-
NMR spectral data. Chem Biodiv. 9(10):2096–2158.
Friedman J, Yaniv Z, Dafni A, Palewitch D. 1986. A preliminary classification of the healing
potential of medicinal plants, based on a rational analysis of an ethnopharmacological field
survey among Bedouins in the Negev Desert, Israel. J Ethnopharmacol. 16(2–3):275–287.
Giner E, El Alami M, M
a~
nez S, Recio MC, R
ıos JL, Giner RM. 2011. Phenolic substances from
Phagnalon rupestre protect against 2,4,6-trinitrochlorobenzene-induced contact hypersensitiv-
ity. J Nat Prod. 74(5):1079–1084.
G
ongora L, Giner RM, M
a~
nez S, Del Carmen Recio M, R
ıos JL. 2001. New prenylhydroquinone
glycosides from Phagnalon rupestre. J Nat Prod. 64(8):1111–1113.
G
ongora L, Giner RM, M
a~
nez S, Recio MDC, R
ıos JL. 2002a.Phagnalon rupestre as a source of
compounds active on contact hypersensitivity. Planta Med. 68(6):561–564.
G
ongora L, M
a~
nez S, Giner RM, Carmen Recio M, Gray AI, R
ıos JL. 2002b. Phenolic glycosides
from Phagnalon rupestre. Phytochemistry. 59(8):857–860.
G
ongora L, Giner RM, M
a~
nez S, Del Carmen Recio M, Schinella G, R
ıos JL. 2002c. Effects of caf-
feoyl conjugates of isoprenyl-hydroquinone glucoside and quinic acid on leukocyte function.
Life Sci. 71(25):2995–3004.
G
ongora L, M
a~
nez S, Giner RM, Recio MDC, Schinella G, R
ıos JL. 2003. Inhibition of xanthine oxi-
dase by phenolic conjugates of methylated quinic acid. Planta Med. 69(5):396–401.
Gonz
alez-Tejero MR, Casares-Porcel M, S
anchez-Rojas CP, Ramiro-Guti
errez JM, Molero-Mesa J,
Pieroni A, Giusti ME, Censorii E, de Pasquale C, Della A, et al. 2008. Medicinal plants in the
Mediterranean area: synthesis of the results of the project Rubia. J Ethnopharmacol. 116(2):
341–357.
14 A. CICIO ET AL.
Haddouchi F, Chaouche TM, Ksouri R, Medini F, Sekkal FZ, Benmansour A. 2014. Antioxidant
activity profiling by spectrophotometric methods of aqueous methanolic extracts of
Helichrysum stoechas subsp. rupestre and Phagnalon saxatile subsp. saxatile. Chin J Nat Med.
12(6):415–422.
Haddouchi F, Chaouche TM, Ksouri R, Larbat R. 2021. Leafy stems of Phagnalon saxatile subsp.
saxatile from Algeria as a source of chlorogenic acids and flavonoids with antioxidant activity:
characterization and quantification using UPLC-DAD-ESI-MSn. Metabolites. 11(5):280.
Hausen B, Schulz K. 1977. On the sensitizing capacity of naturally occurring quinones. III. A new
contact allergen (2-dimethylallyl-1,4-benzoquinone) from Phagnalon sp. (Compositae). Planta
Med. 32(07):287–296.
Hudaib M, Mohammad M, Bustanji Y, Tayyem R, Yousef M, Abuirjeie M, Aburjai T. 2008.
Ethnopharmacological survey of medicinal plants in Jordan, Mujib Nature Reserve and sur-
rounding area. J Ethnopharmacol. 120(1):63–71.
Lentini F, Venza F. 2007. Wild food plants of popular use in Sicily. J Ethnobiol Ethnomed. 3:15.
Mar
ın M, Giner RM, Recio MC, M
a~
nez S. 2011. Phenylpropanoid and phenylisoprenoid metabo-
lites from Asteraceae species as inhibitors of protein carbonylation. Phytochemistry.
72(14–15):1821–1825.
Montes-Moreno N, S
aez L, Bened
ıC, Susanna A, Garcia-Jacas N. 2010. Generic delineation, phyl-
ogeny and subtribal affinities of Phagnalon and Aliella (Compositae, Gnaphalieae) based on
nuclear and chloroplast sequences. Taxon. 59(6):1654–1670.
Olmos A, M
a~
nez S, Giner RM, Recio MDC, R
ıos JL. 2005. Isoprenylhydroquinone glucoside: a new
non-antioxidant inhibitor of peroxynitrite-mediated tyrosine nitration. Nitric Oxide. 12(1):
54–60.
Olmos A, M
a~
nez S, Giner RM, Recio MC, R
ıos JL. 2007. Protein tyrosine nitration induced by
heme/hydrogen peroxide: inhibitory effect of hydroxycinnamoyl conjugates. Planta Med.
73(1):20–26.
Palevitch D, Yaniv Z, Dafni A, Friedman J. 1986. Medicina plant of Israel in: an ethnobotanical
survey. In: Craker LE, Simon JE, editors. Herbs, spice and medicinal plants. Vol. 1; Binghamton,
NY: Food Product Press, Binghamton, NY. p. 331.
Pardo De Santayana M, Blanco E, Morales R. 2005. Plants known as t
e in Spain: an ethno-phar-
maco-botanical review. J Ethnopharmacol. 98(1–2):1–19.
Plants of the World Online. 2022. Available online (accessed on 20 June 2022). https://powo.sci-
ence.kew.org/.
Qaiser M, Lack HW. 1985. The genus Phagnalon (Asteraceae, Inuleae) in Arabia. Willdenowia.
15(1):3–22.
Qaiser M, Lack HW. 1986. The genus Phagnalon (Asteraceae, Inuleae) in tropical Africa.
Willdenowia. 15(2):437–450.
Senatore F, Formisano C, Grassia A, Rigano D, Bellone G, Bruno M. 2005. Chemical composition
of the essential oil of Phagnalon saxatile (L.) Cass. (Asteraceae) growing wild in Southern Italy.
J Essent Oil-Bear Plants. 8(3):258–263.
Sp
ınola V, Castilho PC. 2017. Evaluation of Asteraceae herbal extracts in the management of dia-
betes and obesity. Contribution of caffeoylquinic acids on the inhibition of digestive enzymes
activity and formation of advanced glycation end-products (in vitro). Phytochemistry. 143:
29–35.
Talib WH, Mahasneh AM. 2010. Antiproliferative activity of plant extracts used against cancer in
traditional medicine. Sci Pharm. 78(1):33–45.
The Plant List. 2022. Available online (accessed on 2 April 2022). http://www.theplantlist.org/.
Zdero C, Bohlmann F, Anderberg AA. 1991. Leysseral derivatives from Anisothrix integra and
Phagnalon purpurescens. Phytochemistry. 30(9):3009–3011.
NATURAL PRODUCT RESEARCH 15
