The Genus Echinops: Phytochemistry and Biological Activities: A Review

Abstract

The genus Echinops belongs to the family of Asteraceae and comprises about 130 species. Many species belonging to the genus Echinops are traditionally used as medicinals mainly in Africa and Asia. The genus is reported to contain diverse secondary metabolites. The aim of this review is to critically evaluate the available research reports on the genus and systematically organize the findings. Information for this study was obtained using various search engines including PubMed and Google Scholar. This review revealed that the genus is used traditionally to treat pain, inflammation, respiratory diseases, diseases caused by different microorganisms, as an aphrodisiac, to fasten expulsion of placenta, and for removal of renal stones. More than 151 secondary metabolites have been reported from the genus in which thiophenic compounds held the biggest share. Various extracts, essential oils, and isolated compounds from members of this genus are shown to exhibit different biological effects mainly anti-microbial, anti-proliferative, and anti-inflammatory. However, there are a number of species in this genus that are claimed to have traditional medicinal uses but their biological effect not yet been evaluated.

Introduction

Echinops L., belongs to the family of Asteraceae, a family which is distributed all over the world except in Antarctica. Asteraceae is a monophyletic taxon distinguished by florets arranged on a receptacle in centripetal heads and bounded by bracts. It comprises 1,600−1,700 genera and 24,000−30,000 species (Funk et al., 2005). The genus Echinops belongs to the tribe Cardueae and is recognized by the presence of uniflowered capitula aggregated into second-order spherical or oval heads. This feature makes it unique within the tribe (Garnatje et al., 2005; Sánchez-Jiménez et al., 2010). It contains 120−130 species distributed across north and tropical Africa, the Mediterranean Basin, and central Asia. Members of this genus are mostly perennial with few annuals (Hedberg et al., 2004; Sánchez-Jiménez et al., 2010).

Many members of this genus are traditionally used to treat different diseases. Some are scientifically investigated for various biological activities and phytoconstituents. Previously, reviews that focus on single species, Echinops spinosus L. and E. echinatus Roxb. have been conducted (Bouzabata et al., 2018; Maurya et al., 2015). To the authors' knowledge, there is no study that reviewed the traditional use, phytochemistry, and biological activities of the whole genus. This review is aimed to critically evaluate available research reports on the genus and systematically organize and present the findings. It is attempted to include all articles published from 1990−2018 while some articles published before 1990 were included considering their significance. This review excluded unpublished findings and publications which were not available online and articles written in languages other than English. Chemical structures of only isolated and characterized compounds were provided while structures of compounds identified from essential oils and other chemical analysis were not. The main sources of the structures of isolated compounds were the research articles and these were confirmed using PubChem. Structures that were not available in the articles were obtained from theses, books, PubChem, and other reliable sources. Different search engines including PubMed and Google Scholar were employed to search literature using searching words such as Echinops, plant, phytochemical, phytochemistry, pharmacological activity, biological effect, and traditional use.

Traditional Uses

Ethnomedicinal claims on the genus Echinops to treat a number of ailments are depicted in Table 1 . The common traditional uses can fall into three general groups. The frequently described application is to treat symptoms like inflammation, pain, and fever (Regassa, 2013; Rathore et al., 2015). The other common traditional use was to treat ailments related to respiratory tract including cough and sore throat (Ghasemi Pirbalouti et al., 2013; Sajjad et al., 2017). Members of the genus have been used as an aphrodisiac (Hamayun et al., 2006), facilitation of expulsion of retained placenta and delivery (Okello and Ssegawa, 2007; Qureshi and Bhatti, 2008), as an abortifacient (Abouri et al., 2012), treatment of uterus tumor (Abderrahim et al., 2013), and leucorrhoea (Wagh and Jain, 2018). Three species (E. bannaticus Rochel ex Schrad, E. cornigerus D.C., and E. polyceras Boiss.) reported to have been employed in the managment of kidney stones (Mustafa et al., 2012; Nawash et al., 2013; Kumar et al., 2018).

Table 1.

Traditional uses of members of the genus Echinops.

Species	Part used	Indication	Country	Ref.
E. amplexicaulis Oliv.	R	HIV/AIDS	Uganda	Lamorde et al., 2010
	R	Ulcerative lymphagitis (LS)	Ethiopia	Fenetahun and Eshetu, 2017
		Stomachache	Ethiopia	Regassa et al., 2017
	R	Trypanosomiasis, liver disease, pasteurellosis	Ethiopia	Kitata et al., 2017
	R	Hydrocele	Uganda	Kamatenesi et al., 2011
	R	Fasten expulsion of placenta, hernia	Uganda	Okello and Ssegawa, 2007
	R	Ulcerative lymphagitis (LS)	Ethiopia	Tekle, 2014
E. bannaticus Rochel ex Schrad	R	Kidney stones	Kosovo	Mustafa et al., 2012
E. bovei (Boiss.) Maire.	AP	Eye complaints, trachoma, sores, inflammation, digestive diseases	Central Sahara	Hammiche and Maiza, 2006
E. cornigerus D.C.	R	Urinary problems mainly caused by kidney stones	India	Kumar et al., 2018
	WP	Insanity	India	Tiwari et al., 2010
	R	Removal of kidney stones	Pakistan	Jabeen et al., 2015
	R	Urinary complaints, fever	India	Dangwal et al., 2011
	WP	Cough, emergence of teeth in infants, fever, urinary trouble, tonic, sepsis, food poisoning	India	Sharma et al., 2012
	R	Urinary disorder, fever	India	Kumar and Pandey, 2015
	VP	Diuretic, aphrodisiac, fever, pain, chronic fever	Pakistan	Hamayun et al., 2006
	R	Fever, emergence of teeth in infants	India	Rathore et al., 2015
E. echinatus Roxb.	R	To treat hernia	India	Shende et al., 2018
	L	Earache	India	Maru et al., 2018
	R	Leucorrhoea	India	Wagh and Jain, 2018
	R, L	Joint pain	Pakistan	Malik et al., 2018
		Aphrodisiac, to facilitate the delivery process, abortifacient, leucorrhea, diabetes, eczema, heatstroke, wounds of cattle for killing maggots, liver disorders, cough, malarial fever, renal colic, lice, polyuria, appetite stimulant		Maurya et al., 2015
E. giganteus A. Rich	R	Anti-hemorrhoidal	Ethiopia	Desta, 1995
	R	Flatulence and bloody stool	Cameroon	Tacham et al., 2015
		Stomache, asthma attacks, as carminative	Cameroon	Menut et al., 1997
E. hispidus Fresen.	R and S	Sunstroke	Ethiopia	Meragiaw et al., 2016
E. hoehnelii Schweinf.	R	Internal parasite, amoebae, common cold	Ethiopia	Tekle, 2014
	R	Malaria, snakebite	Ethiopia	Giday et al., 2010
E. kebericho Mesfin	R	Black leg, respiratory manifestations, liver disease (LS)	Ethiopia	Yigezu et al., 2014
	Bl	Cough, headache	Ethiopia	Mesfin et al., 2014
	R	Scabies	Ethiopia	Amsalu et al., 2018
	R	Toothache, stomachache, common cold, sunstroke, tonsillitis, acute sickness, snake bite	Ethiopia	Regassa, 2013
	S	Fever, headache	Ethiopia	Gari et al., 2015
	R	Malaria, common cold	Ethiopia	Mekuanent et al., 2015
	R	Dislocated bone (LS)	Ethiopia	Teklay et al., 2013
	R	Toothache, vomiting, headache	Ethiopia	Abera, 2014
	R	Trypanosmiasis	Ethiopia	Shilema et al., 2013
	R	Gonorrhea	Ethiopia	Bizuayehu and Garedew, 2018
E. longifolius A. Rich.	RB	Headache, rheumatism, dry cough	Ethiopia	Suleman and Alemu, 2012
	R	Scorpion sting	Sudan	Issa et al., 2018
E. macrochaetus Fresen.	R	Toothache	Ethiopia	Belayneh and Bussa, 2014
	R	Headache	Ethiopia	Moravec et al., 2014
	Sd	Abdominal colic	Ethiopia	Gabriel and Guji, 2014
E. niveus Wall.	R	Diuretic, nerve tonic, cough, indigestion, ophthalmia. Applied to wounds in cattle to destroy maggots	India	Sharma et al., 2004
E. polyceras Boiss.	R	Kidney stones	Jordan	Nawash et al., 2013
E. ritrodes L.	S	Chronic cough	Urmia	Asadbeigi et al., 2014
	WP	Skin diseases, prevention of cough	Iran	Farouji and Khodayari, 2016
E. sphaerocephalus L.	R, S, L	Typhoid	Kenya	Nyang'au et al., 2017
E. spinosissimus Turra.	WP	Splenic diseases, sore throat	Saudi Arabia	El-Ghazali et al., 2010
	WP	Nerve tonic, diuretic, cough suppressant	UAE	Sajjad et al., 2017
	WP	Diuretic, nerve tonic, cough suppressant	Egypt	Mahmoud and Gairola, 2013
E. spinosissimus subsp. fontqueri (Pau) Greuter	R	Rheumatism, colds, uterus pains, uterus tumor	Morocco	Abderrahim et al., 2013
E. spinosissimus subsp. macro-plepis (Boiss.) Greuter	S,R, L	Renal disorders	Lebanon	Baydoun et al., 2015
E. spinosus L.	R	As hypoglycaemic, decoction is drunk.	Morocco	Merzouki et al., 2000
	R	Appetite stimulant, cold, diabetes, renal stones	Morocco	El Abbouyi et al., 2014
	L, S, R	Hepatoprotective, abortifacient	Morocco	Akdime et al., 2015
	R	Diabetes	Morocco	Katiri et al., 2017
	FAP	Colds, kidney stones, diuretic, hypoglycemic	Morocco	Abouri et al., 2012
	Br, R	Abortifacient, labor pain	Morocco	Abouri et al., 2012
	F	Neuralgia, tiredness	Morocco	Abouri et al., 2012
E. spinosus L. subsp Bovei (Boiss). Maire	R-Fr	Labor pains, abortifacient, neuralgia	Algeria	Chermat and Gharzouli, 2015
E. viscidulus Mozaff.	Bl	Cough, cold, sore throat	Iran	Ghasemi Pirbalouti et al., 2013
E. viscosus DC.	C	Boil	Turkey	Bulut et al., 2017

AP, Aerial part; B, Bark; Bl, Bulb; Br, Branch; C, Capitulum; F, Flower; FAP, Flowered aerial part; Fr, Fruit, L, Leaf; LS, Livestock; R, Root; RB, Root bark; S, Stem; Sd, Seed; VP, Vegetative part; WP, Whole plant.

In addition to the traditional medicnal applications described in Table 1 , the plants have nutritional value. In Iran, the bulb of E. viscidulus Mozaff is consumed as a vegetable (Ghasemi Pirbalouti et al., 2013). The roots of E. giganteus A. Rich. and E. spinosus are used as a spice in Morocco and Cameroon, respectively (Pavela et al., 2016; Tbatou et al., 2016). The use of E. giganteus might be attributed to the presence of nutrients including iron, phenols, carotenoids, and vitamins E and C in the plant (Abdou Bouba et al., 2012).

Phytochemicals

As presented in Table 2 and Figure 1 , 151 compounds have been isolated and characterized using different spectroscopic/spectrometric techniques. Members of the genus Echinops contain primarily thiophenes and terpenes. Flavonoids and other phenolic compounds, alkaloids, lipids, and phenylpropanoids were also reported. The root of the plant is the main source of the thiophenes while most of the terpenes and flavonoids were isolated from the aerial part/the whole plant. The genus is also known for essential oil content and all morphological parts of the plants are reported to contain some of the essential oils. Around 53 of the isolated and characterized compounds are reported to have different biological activities. The structural formulae of isolated and characterized compounds are given in Figure 1 .

Table 2.

Secondary metabolites isolated from members of the genus Echinops.

No.	Name of secondary metabolites	Species	Plant part	Pharmacological activity	Ref.
Thiophenes
1.	5-(but-3-en-1-ynyl)-2,2'-bithiophene	E. macrochaetus	R		Abegaz et al., 1991
		E. pappii Chiov.	R		Abegaz et al., 1991; Abegaz, 1991
		E. ritro	Rd	Antifungal	Fokialakis et al., 2006a
		E. ritro	AP
		E. latifolius	R		Wang et al., 2006
		E. grijsii	R		Zhang and Ma, 2010; Chang et al., 2015
		E. grijsii	R	Cytotoxic	Jin et al., 2008
		E. grijsii	R	Insecticidal	Zhao et al., 2017
		E. nanus Bunge	R		Nakano et al., 2012
		E. albicaulis	AP		Kiyekbayeva et al., 2017
		E. albicaulis	WP	Termicidal	Fokialakis et al., 2006b
		E. spinosissimus subsp. spinosissimus	WP	Termicidal	Fokialakis et al., 2006b
2.	α-terthiophene	E. ellenbeckii	R		Abegaz et al., 1991
		E. pappii	R		Abegaz et al., 1991
		E. macrochaetus	R
		E. grijsii	R	Cytotoxic	Jin et al., 2008
		E. grijsii	R		Liu et al., 2002; Zhang and Ma, 2010; Chang et al., 2015
		E. grijsii	R	Insecticidal	Zhao et al., 2017
		E. latifolius	R		Wang et al., 2006
		E. ritro	Rd	Antifungal	Fokialakis et al., 2006a
		E. ritro	AP	Termicidal	Fokialakis et al., 2006b
		E. nanus	R		Nakano et al., 2012
		E. albicaulis	R		Kiyekbayeva et al., 2017
		E. albicaulis	WP	Termicidal	Fokialakis et al., 2006b
		E. albicaulis	WP	Termicidal	Fokialakis et al., 2006b
		E. albicaulis	WP	Termicidal	Fokialakis et al., 2006b
		E. transiliensis	R	Insecticidal	Nakano et al., 2014
3.	5-(penta-1,3-diynyl)-2-(3-chloro-4-hydoxy-but-1-ynyl)-thiophene	E. ellenbeckii	R		Abegaz et al., 1991
		E. giganteus	R
		E. hispidus Fresen.	R
		E. longisetus	R
		E. macrochaetus	R
4.	Cis or trans-2-(pent-3-en-1-ynyl)-5-(4-hydroxybut-1-ynyl)-thiophenes	E. pappii	R		Abegaz, 1991
5.	5-(4-hydroxybut-1-ynyl)-2-(pent-1,3-diynyl)-thiophene	E. pappii	R		Abegaz, 1991
		E. ritro	Rd	Antifungal	Fokialakis et al., 2006a
		E. ritro	AP	Termicidal	Fokialakis et al., 2006b
		E. grijsii	R		Chang et al., 2015
		E. grijsii	R	Cytotoxic	Zhang et al., 2009;
		E. grijsii	R	NQO1-inducing	Zhang and Ma, 2010
		E. giganteus	Rz	Cytotoxic	Kuete et al., 2013
		E. giganteus	Rz	Cytotoxic	Sandjo et al., 2016
6.	5-(penta-1,3-diynyl)-2-(but-3-en-1-ynyl)-thiophene	E. ellenbeckii	R		Hymete et al., 2005b
7.	5-(penta-1,3-diynyl)-2-(4-acetoxy-but-1-ynyl)-thiophene	E. ellenbeckii	R		Hymete et al., 2005b
8.	5-(penta-1,3-diynyl)-2-(3-hydroxy-4-acetoxy-but-1-ynyl)-thiophene	E. ellenbeckii	R		Hymete et al., 2005b
		E. hoehnelii	R		Bitew et al., 2017
		E. transiliensis	R	Insecticidal	Nakano et al., 2014
9.	5-(penta-1,3-diynyl)-2-(3,4-diacetoxy-but-1-ynyl)-thiophene	E. ellenbeckii	R		Hymete et al., 2005a
		E. grijsii	R		Jin et al., 2008
		E. grijsii	R	NQO1-inducing	Zhang and Ma, 2010
		E. transiliensis	R	Insecticidal	Nakano et al., 2014
10.	5-(penta-1,3-diynyl)-2-(3-chloro-4-acetoxy-but-1-ynyl)-thiophene	E. ellenbeckii	R		Hymete et al., 2005b
		E. transiliensis	R	Insecticidal	Nakano et al., 2014
		E. albicaulis	WP	Termicidal	Fokialakis et al., 2006b
		E. hoehnelii	R	Anti-malarial	Bitew et al., 2017
11.	5-(penta-1,3-diynyl)-2-(3,4-epoxy-but-1-ynyl)-thiophene	E. ellenbeckii	R		Hymete et al., 2005b
12.	5-[-(5-acetoxymethyl-2-trienyl)-2-(but-3-ene-1-ynyl)]-thiophene	E. ellenbeckii	R		Hymete et al., 2005b
13.	5-(5,6-dihydroxy-hexa-1,3-diynyl)-2-(prop-1-ynyl)-thiophene (echinoynethiophene A)	E. grijsii	R		Liu et al., 2002; Dong et al., 2008a
		E. grijsii	R	Cytotoxic	Zhang et al., 2009
14.	5-(penta-1,3-diynyl)-2-(3,4-dihydroxybut-1-ynyl)-thiophene	E. grijsii	R		Liu et al., 2002; Dong et al., 2008a; Chang et al., 2015
		E. ritro	WP		Li et al., 2019
		E. grijsii	R	NQO1-inducing	Shi et al., 2010; Zhang and Ma, 2010
		E. grijsii	R	Cytotoxic	Zhang et al., 2009
		E. giganteus	Rz	Cytotoxic	Sandjo et al., 2016
		E. transiliensis	R	Insecticidal	Nakano et al., 2014
		E. hoehnelii	R	Anti-malarial	Bitew et al., 2017
15.	5-(3,4-dihydroxybut-1-ynyl)-2,2′-bithiophene	E. grijsii	R		Liu et al., 2002; Dong et al., 2008a; Zhang et al., 2009; Zhang and Ma, 2010; Chang et al., 2015
		E. ritro	WP		Li et al., 2019
		E. latifolius	R	Cytotoxic	Wang et al., 2007
		E. transiliensis	R	Insecticidal	Nakano et al., 2014
16.	2,2'-bithiophene-5-carboxylic acid	E. grijsii	R		Liu et al., 2002; Chang et al., 2015
		E. ritro	WP		Li et al., 2019
17.	5-(3-buten-1-ynyl)-2,2'-bithiophene	E. grijsii	R		Liu et al., 2002
18.	5-(4-isovaleroyloxybut-1-ynyl)-2,2'-bithiophene	E. grijsii	R		Liu et al., 2002; Chang et al., 2015
		E. grijsii	R		Wang et al., 2006
		E. grijsii	R	Cytotoxic	Jin et al., 2008
		E. grijsii	R	Insecticidal	Zhao et al., 2017
		E. ritro	Rd	Antifungal	Fokialakis et al., 2006a
		E. ritro	AP	Termicidal	Fokialakis et al., 2006b
19.	5-chloro- α-terthiophene	E. grijsii	R		Liu et al., 2002
20.	5-acetyl α-terthiophene	E. grijsii	R		Liu et al., 2002
21.	5,5'-dichloro-α-terthiophene	E. grijsii	R		Liu et al., 2002
22.	Cardopatine	E. grijsii	R		Liu et al., 2002; Chang et al., 2015
		E. latifolius	R		Wang et al., 2006
		E. ritro	Rd	Antifungal	Fokialakis et al., 2006a
		E. ritro	AP	Termicidal	Fokialakis et al., 2006b
23.	Isocardopatine	E. grijsii	R		Liu et al., 2002; Zhang and Ma, 2010; Chang et al., 2015
		E. ritro	Rd	Antifungal	Fokialakis et al., 2006a
		E. grijsii	R	Cytotoxic	Jin et al., 2008
24.	Grijisyne A	E. grijsii	R		Zhang et al., 2008
25.	Grijisone A	E. grijsii	R		Zhang et al., 2008
26.	5-(4-hydroxy-3-methoxy-1-butyny)-2,2'-bithiophene	E. grijsii	R		Chang et al., 2015
27.	5-acetyl-2,2'-bithiophene	E. latifolius	R		Wang et al., 2008
		E. grijsii	R		Chang et al., 2015
		E. ritro	WP		Li et al., 2019
28.	5-formyl-2,2'-bithiophene	E. grijsii	R		Chang et al., 2015
29.	Methyl 2,2'-bithiophene-5-carboxylate	E. grijsii	R		Chang et al., 2015
30.	5-(3-hydroxymethyl-3-isovaleroyloxyprop-1-ynyl)-2,2'-bithiophene	E. latifolius	R		Wang et al., 2006
		E. grijsii	R		Chang et al., 2015
31.	5-(4-hydroxy-1-butynyl)-2,2'-bithiophene	E. latifolius	R		Wang et al., 2008
		E. ritro	Rd	Antifungal	Fokialakis et al., 2006a
		E. latifolius	R	Cytotoxic	Wang et al., 2007
		E. grijsii	R		Zhang et al., 2009; Chang et al., 2015
		E. ritro	WP	Antibacterial, Antifungal	Li et al., 2019
		E. ritro	AP	Termicidal	Fokialakis et al., 2006b
32.	5-(4-acetoxy-1-butynl)-2,2'-bithiophene	E. grijsii	R		Chang et al., 2015
33.	5-(3-hydroxy-4-isovaleroyloxybut-1-ynyl)-2,2'-bithiophene	E. latifolius	R		Wang et al., 2006
34.	5-(3-acetoxy-4-isovaleroyloxybut-1-ynyl)-2,2′-bithiophene	E. latifolius	R		Wang et al., 2006
		E. grijsii	R	Cytotoxic	Jin et al., 2008
35.	Echinopsacetylenes A	E. transiliensis	R		Nakano et al., 2011
36.	Echinopsacetylenes B	E. transiliensis	R		Nakano et al., 2011
37.	Echinothiophenegenol	E. grijsii	R		Zhang et al., 2009
		E. nanus	R		Nakano et al., 2012
38.	5-(4-acetoxy-3-chlorobut-1-ynyl)-2-(pent-1,3-diynyl)-thiophene	E. ritro	Rd	Antifungal	Fokialakis et al., 2006a
39.	5-(3,4-diacetoxybut-1-ynyl)-2,2′-bithiophene	E. ritro	Rd	Antifungal	Fokialakis et al., 2006a
		E. ritro	AP	Termicidal	Fokialakis et al., 2006b
		E. grijsii	R		Zhang and Ma, 2010
		E. grijsii	R	Cytotoxic	Jin et al., 2008
		E. transiliensis	R	Insecticidal	Nakano et al., 2014
40.	5-{4-[4-(5-pent-1,3-diynylthiophene-2-yl)-but-3-yny}-2,2'-bithiophene	E. latifolius	R	Cytotoxic	Wang et al., 2007
41.	5-(4-hydroxybut-1-one)-2,2'-bithiophene	E. latifolius	R	Cytotoxic	Wang et al., 2007
		E. ritro	WP		Li et al., 2019
42.	5-(prop-1-ynyl)- 2-(3,4-diacetoxybut-1-ynyl)-thiophene	E. latifolius	R		Wang et al., 2007
		E. grijsii	R	Cytotoxic	Jin et al., 2008
43.	5-(1,2-dihydroxy-ethyl)-2-(Z)-hept-5-ene-1,3-diynylthiophene	E. latifolius	R	Anti-inflammatory	Jin et al., 2016
44.	5-(1,2-dihydroxyethyl)-2-(E)-hept-5-ene-1,3-diynylthiophene	E. latifolius	R	Anti-inflammatory	Jin et al., 2016
45.	6-Methoxy-arctinol-b	E. latifolius	R	Anti-inflammatory	Jin et al., 2016
46.	Arctinol-b	E. grijsii	R		Zhang et al., 2009
		E. latifolius	R	Anti-inflammatory	Jin et al., 2016
		E. ritro	WP	Antibacterial, Antifungal	Li et al., 2019
47.	Arctinol	E. latifolius	R	Anti-inflammatory	Jin et al., 2016
		E. ritro	WP		Li et al., 2019
		E. ritro	WP		Li et al., 2019
48.	Methyl [5'-(1-propynyf)-2,2'-bithienyl-5-yl] carboxylate	E. latifolius	R	Anti-inflammatory	Jin et al., 2016
49.	5-(penta-1,3-diynyl)-2-(3-methoxy-4-hydroxy-but-1-ynyl)-thiophene	E. hoehnelii	R		Bitew et al., 2017
50.	5-(penta-1,3-diynyl)-2-(3-methoxy-4-acetoxy-but-1-ynyl)-thiophene	E. hoehnelii	R		Bitew et al., 2017
51.	5-(3-hydroxy-4-acetoxybut-1-ynyl)-2,2′-bithiophene	E. transiliensis	R		Nakano et al., 2014
		E. transiliensis	R	Insecticidal	Nakano et al., 2014
52.	5-(penta-1,3-diynyl)-2-(3-acetoxy-4-hydroxy-but-1-ynyl)-thiophene	E. transiliensis	R	Insecticidal	Nakano et al., 2014
53.	5'-(3,4-dihydroxybut-1-yn-1-yl)-[2,2'-bithiophene]-5-carbaldehyde.	E. ritro	WP		Li et al., 2019
54.	5'-(3,4-dihydroxybut-1-yn-1-yl)-[2,2'-bithiophene]-5-carboxylic acid	E. ritro	WP	Antibacterial	Li et al., 2019
55.	4-hydroxy-1-(5'-methyl-[2,2'-bithiophen]-5-yl)butan-1-one	E. ritro	WP	Antibacterial, Antifungal	Li et al., 2019
56.	Junipic acid	E. ritro	WP		Li et al., 2019
57.	Arctinal	E. ritro	WP	Antibacterial	Li et al., 2019
58.	4-(5'-methyl-[2,2'-bithiophen]-5-yl)but-3-yn-1-ol	E. ritro	WP		Li et al., 2019
59.	Arctinol A	E. ritro	WP	Antibacterial	Li et al., 2019
Terpenes
60.	Dehydrocostus lactone	E. amplexicauli	R		Abegaz et al., 1991
		E. kebericho
61.	Costunolide	E. amplexicaulis,			Abegaz et al., 1991,Abegaz, 1991
		E. kebericho,
		E. pappii
62.	Dihydrocostunolide	E. amplexicaulis	R		Abegaz et al., 1991
63.	Echinopines A	E. spinosus	R		Dong et al., 2008b
64.	Echinopines B	E. spinosus	R		Dong et al., 2008b
Terpenes
65.	(3α,4α,6α)-3,13-dihydroxyguaia-7(11),10(14)-dieno-12,6-lactone)	E. ritro	WP		Li et al., 2010
66.	(3α,4α,6α,11ß)-3-hydroxyguai-1(10)-eno-12,6-lactone)	E. ritro	WP		Li et al., 2010
67.	(11α)-11,13-dihydroarglanilic acid methyl ester	E. ritro	WP		Li et al., 2010
68.	Vulgarin	E. ritro	WP		Li et al., 2010
69.	(3R,3aS,6aR,9S,9aR,9bS)-octahydro-3,9-dimethyl-6-methyleneazuleno[4,5-b]furan2,8(3H,9bH)-d ione	E. ritro	WP		Li et al., 2010
70.	(3aS,6aR,8S,9S,9aR,9bR)-decahydro-8-hydroxy-9-methyl-3,6 dimethyleneazuleno[4,5-b]furan-2(9bH)-one	E. ritro	WP		Li et al., 2010
71.	(3aS,6aR,8R,9R,9aR,9bR)-decahydro-8-hydroxy-3,3,9-trimethyl-6-methyleneazuleno[4,5-b]furan-2(9bH)-one	E. ritro	WP		Li et al., 2010
72.	(3R,3aS,6aR,8S,9S,9aR,9bS)-decahydro-8-hydroxy-3,9-dimethyl-6-methyleneazuleno[4,5-b]furan-2(9bH)-one	E. ritro	WP		Li et al., 2010
73.	Santamarin	E. pappii			Abegaz, 1991
		E. ritro	WP		Li et al., 2010
74.	Reynosin	E. pappii	R		Abegaz, 1991
75.	Caryophyllene epoxide	E. giganteus	R		Abegaz et al., 1991
		E. hispidus
76.	Echusoside	E. hussoni Boiss.	AP		Ka, 2001
77.	(3S,3aS,5aR,6R,8R,9bS)-decahydro-6,8-dihydroxy-3,5a-dimethyl-9-methylenenaphtho[1,2-b]furan-2(9bH)-one	E. ritro	WP		Li et al., 2010
78.	(3S,3aS,5aR,6S,9bS)-3,3a,4,5,5a,6-hexahydro-6-hydroxy-3,5a,9-trimethylnaphtho[1,2-b]furan-2,7(9aH,9bH)-dione	E. ritro	WP		Li et al., 2010
79.	2,6,10-trimethyldodeca-2,6,10-triene	E. albicaulis	AP		Kiyekbayeva et al., 2017
80.	Macrochaetosides A	E. macrochaetus	AP	Cytotoxic	Zamzami et al., 2019
81.	Macrochaetosides B	E. macrochaetus	AP	Cytotoxic	Zamzami et al., 2019
82.	Latifolanone A	E. latifolius	R		Jin et al., 2016
83.	Atractylenolide-II	E. latifolius	R	Anti-inflammatory	Jin et al., 2016
84.	ß-amyrin	E. niveus	WP		Singh et al., 1990
85.	Betulinic acid	E. niveus	WP
86.	Lupeol	E. niveus	WP		Singh et al., 1990
		E. giganteus	R		Tene et al., 2004
		E. integrifolius	WP		Senejoux et al., 2013
		E. echinatus	R		Patel, 2016
87.	Taraxasterol	E. niveus	WP		Singh et al., 1990
88.	Taraxasterol acetate	E. niveus	WP		Singh et al., 1990
		E. echinatus	WP	Anti-inflammatory	Singh et al., 1989
89.	ß-sitosterol	E. niveus	WP		Singh et al., 1990
		E. transiliensis	R		Nakano et al., 2012
		E. giganteus	Rz		Kuete et al., 2013
		E. orientalis	Sd	Antioxidant	Erenler et al., 2014
90.	ß-sitosterol glucoside	E. niveus	WP		Singh et al., 1990
		E. giganteus	R		Tene et al., 2004
		E. integrifolius	WP		Senejoux et al., 2013
		E. albicaulis	AP		Kiyekbayeva et al., 2017
91.	Reynosin	E. pappii	R		Abegaz, 1991
92.	Gmeliniin A	E. gmelinii	AP		He et al., 2000
93.	Stigmasterol	E. transiliensis	R		Nakano et al., 2012
		E. macrochaetus	AP		Zamzami et al., 2019
		E. integrifolius	WP		Senejoux et al., 2013
		E. giganteus	Rz		Kuete et al., 2013
94.	Lupeol acetate	E. integrifolius	WP		Senejoux et al., 2013
		E. echinatus	R		Patel, 2016
		E. albicaulis	AP		Kiyekbayeva et al., 2017
95.	Lupeol linoleate	E. albicaulis	AP		Kiyekbayeva et al., 2017
96.	Ajugasterone C	E. grijisii	R		Dong et al., 2008a
97.	Ursolic acid	E. giganteus	Rz	Cytotoxic	Kuete et al., 2013
98.	Echinopsolide A (3ß-acetoxy-15α-bromoolean-13ß,28-olide)	E. giganteus	Rz	Cytotoxic	Sandjo et al., 2016
99.	ß-amyrin acetate	E. giganteus	Rz		Sandjo et al., 2016
100.	3ß-acetoxy-taraxast-12,20(30)-diene-11α-21α-diol	E. galalensis	AP	Hepato-protective	Abdallah et al., 2013
101.	α-amyrin	E. galalensis	Rz	Hepato-protective
102.	Erythrodiol	E. galalensis	Rz	Hepato-protective
Terpenes
103.	Lup-20(29)-ene-1,3-diol	E. galalensis	Rz	Hepato-protective
104.	Cyclostenol	E. macrochaetus	AP	Cytotoxic	Zamzami et al., 2019
Flavonoids and other phenolic compounds
105.	Apigenin	E. niveus	WP		Singh et al., 1990
		E. echinatus			Ram et al., 1995
		E. integrifolius	AP		Senejoux et al., 2013
		E. spinosus	AP		Boumaraf et al., 2016
		E. albicaulis	AP		Kiyekbayeva et al., 2017
106.	Luteolin	E. niveus	WP		Singh et al., 1990
		E. grijisii	R		Dong et al., 2008a
107.	Nivegin	E. niveus	WP		Singh et al., 1990
108.	Nivetin	E. niveus	AP		Singh and Pandey, 1990
109.	Apigenin 7-O-glucoside	E. echinatus	F		Ram et al., 1995
		E. spinosus	AP		Boumaraf et al., 2016
		E. orientalis	Sd	Antioxidant	Erenler et al., 2014
110.	Echitin	E. echinatus	F		Ram et al., 1995
111.	Echinoside	E. echinatus	WP		Singh et al., 2006
112.	7-hydroxyisoflavone	E. echinatus	WP		Singh et al., 2006
113.	Kaempferol	E. echinatus	WP		Singh et al., 2006
114.	Kaempferol-4'-methylether	E. echinatus	WP		Singh et al., 2006
115.	Kaempferol-7-methylether	E. echinatus	WP		Singh et al., 2006
116.	Kaempferol-3-O-α-L-rhamnoside	E. echinatus	WP		Singh et al., 2006
		E. heterophyllus	AP		Mahmood and Khadeem, 2013
117.	Myrecetin-3-O-α-L-rhamnoside	E. echinatus	WP		Singh et al., 2006
118.	Chrysoeriol	E. integrifolius	WP		Senejoux et al., 2013
119.	Hispidulin	E. integrifolius	WP		Senejoux et al., 2013
120.	Jaceidin	E. integrifolius	WP		Senejoux et al., 2013
121.	Centaureidin	E. integrifolius	WP		Senejoux et al., 2013
122.	Axillarin	E. integrifolius	WP		Senejoux et al., 2013
123.	Genkwanin	E. albicaulis	AP		Kiyekbayeva et al., 2017
124.	Apigenin-7-O-(6"-trans-pcoumaroyl- ß -D-glucopyranoside	E. orientalis	L	Antioxidant	Erenler et al., 2014
		E. spinosus	AP		Boumaraf et al., 2016
125.	5,7-dihydroxy-8,4'-dimethoxyflavanone-5-O-α-L-rhamno-pyranosyl-7-O-ß-D-arabinopyranosyl (1→4)-O-ß-D-glucopyranoside	E. echinatus	WP	Anti-inflammatory	Yadava and Singh, 2006
126.	Candidone	E. giganteus	Rz	Cytotoxic	Kuete et al., 2013
127.	Chlorogenic acid	E. grijisii	R		Dong et al., 2008a
128.	Cynarin	E. grijisii	R		Dong et al., 2008a
129.	Rutin	E. heterophyllus	AP		Mahmood and Khadeem, 2013
		E. albicaulis	AP		Kiyekbayeva et al., 2017
130.	(+)-4-(3-methylbutanoyl)-2,6-di(3,4-dimethoxy)phenyl-3,7-dioxabicyclo[3.3.0]octane	E. giganteus	R		Tene et al., 2004
131.	(+)-4-hydroxy-2,6- di(3,4-dimethoxy)phenyl-3,7-dioxabicyclo[3.3.0]octane	E. giganteus	R		Tene et al., 2004
		E. giganteus	Rz		Sandjo et al., 2016
		E. giganteus	Rz	Cytotoxic	Kuete et al., 2013
132.	Hexacosyl-(E)-ferulate	E. nanus	R		Nakano et al., 2012
133.	Umbelliferone	E. integrifolius	WP		Senejoux et al., 2013
134.	Syringin	E. grijisii	R		Dong et al., 2008a
135.	1,5-dicaffeoylquinic acid	E. galalensis	AP	Hepato-protective	Abdallah et al., 2013
136.	3,5-dicaffeoylquinic acid			Hepato-protective
137.	3,4-dicaffeoylquinic acid			Hepato-protective
138.	4,5-dicaffeoylquinic acid			Hepato-protective
Alkaloids
139.	Echinopsine (1-methyl-4-quinolone)	E. echinatus	AP		Chaudhuri, 1987
		E. nanus	R		Nakano et al., 2012
		E. albicaulis	AP		Kiyekbayeva et al., 2017
		E. orientalis	Sd	Antioxidant	Erenler et al., 2014
140.	Echinozolinone	E. echinatus	AP		Chaudhuri, 1987
Alkaloids
141.	Echinopsidine	E. echinatus	AP		Chaudhuri, 1987
142.	7-hydroxyechinozolinone	E. echinatus	F		Chaudhuri, 1992
143.	1-Methyl-4(1H)-quinolinone	E. heterophyllus	Sd		Khadim et al., 2014
144.	1-methyl-4-methoxy-8-(ß-D-glucopyranosyloxy)-2(1H)-quinolinone	E. gmelinii Turcz.	AP		Su et al., 2004
145.	4-methoxy-8-(-D-glucopyranosyloxy)-2(1H)-quinolinone	E. gmelinii	AP		Su et al., 2004
146.	Echinorine	E. albicaulis	AP		Kiyekbayeva et al., 2017
Lipids
147.	Triacontane	E. integrifolius	R		Karimov and Aisa, 2013
148.	Heptacosane	E. integrifolius	R		Karimov and Aisa, 2013
149.	Lignoceric acid	E. integrifolius	R		Karimov and Aisa, 2013
150.	Tetrahydrofurano-ceramide	E. giganteus	Rz	Cytotoxic	Sandjo et al., 2016
151.	Ritroyne A	E. ritro	R		Li et al., 2019

AP, Aerial part; F, Flower; L, Leaf; R, Root; Rd, Radix; Rz, Rhizome; Sd, Seed; WP, Whole plant.

Figure 1.

Structural formulae of secondary metabolites isolated from members of the genus Echinops.

Thiophenes

Thiophenes, the main bioactive constituents of the genus Echinops, are biosynthetically derived from fatty acids and reduced sulphur (Arroo et al., 1997). Majority of the thiophenic compounds comprise an acetylenic functional group and most of the thiophenes comprised two thiophene rings in their structure. The most abundant thiophenes which were reported from nine species were 5-(but-3-en-1-ynyl)-2,2'-bithiophene (1) and α-terthiophene (2). 5-(4-hydroxybut-1-ynyl)- 2-(pent-1,3-diynyl)-thiophene (5), 5-(penta-1,3-diynyl)-2-(3,4-dihydroxybut-1-ynyl)-thiophene (14), and 5-(4-hydroxy-1-butynyl)-2,2'-bithiophene (31) were isolated from five species. Thiophenes were detected in essential oils obtained from the different plants of this genus. 5-(3-buten-1-ynyl)-2,2'-bithienyl was detected in essential oils obtained from the roots of E. grijsii Hance, E. bannaticus, and E. sphaerocephalus L.

The biological activities of thiophenes were evaluated mainly in vitro and they have an insecticidal, anti-proliferative, and anti-fungal potential effects.

Terpenoids

Sesqui- and triterpenoids were reported mainly from the whole plant and aerial parts of the genus Echinops. Most of the sesquiterpenoids contain lactones. Sesquiterpene lactones are also the most prevalent secondary metabolites in the family of Asteraceae (Chadwick et al., 2013). Most triterpenoids exist in various forms including lactones, esters, and sterols along with their glycosides. The common sesquiterpenoid reported was costunolide (61), which was isolated from three species whereas lupeol (86) and lupeol acetate (94) were the common triterpenoids. Many sesquiterpenoids were also detected from the essential oils of the genus.

Flavonoids and Other Phenolic Compounds

Flavonoids from the genus Echinops were mainly flavones and mostly isolated from the whole plant and aerial parts of the members. Apigenin (105) is the most common flavonoidal aglycone and it was isolated from the flower and whole plant of E. niveus Wall., E. echinatus, E. integrifolius Kar. & Kir., and E. albicaulis Kar. & Kir. ( Table 2 ). In addition to flavonoids, phenolic compounds including coumarins, phenylpropanoids, and lignans were reported (Tene et al., 2004; Dong et al., 2008a; Senejoux et al., 2013).

Alkaloids

The first alkaloids isolated from the genus Echinops were echinopsine (139), echinozolinone (140), and echinopsidine (141) from the aerial parts of E. echinatus (Chaudhuri, 1987). Later on, another alkaloid, 7-hydroxyechinozolinone (142), was isolated from the flowers of the same plant (Chaudhuri, 1992). Additional four alkaloids of which two were in glycosidic form were reported ( Table 2 ). The alkaloids were mainly isolated from the aerial parts of the plants. The predominant alkaloid, which was isolated from four different species, was 1-methyl-4-quinolone (139).

Essential Oils and Lipids

The genus Echinops is rich in bioactive essential oil constituents, which were mainly found in the roots. Various reports indicated the presence of terpenoids and thiophenes.

The root of E. grijisii was found to contain cis-β-farnesene and 5-(3-buten-1-ynyl)-bithiophene as main components (Guo et al., 1994). Essential oils from root, stem, leaf, and flowers of E. ellenbeckii comprised mainly β-maaliene, cyperene, caryophyllene oxide, and β-selinene from the respective plant parts (Hymete et al., 2004). The fresh inflorescences of E. graecus and E. ritro yielded methyl chavicol and (E)-2-hexenal, 1,8-cineole, and p-cymene as major constituents, respectively (Papadopoulou et al., 2006).

Essential oils from the root of E. bannaticus and E. sphaerocephalus were reported to contain 5-(3-buten-1-ynyl)-2,2'-bithienyl and α-terthienyl as major constituents, and also triquinane sesquiterpenoids (Radulović and Denić, 2013). The most abundant compounds from E. giganteus have been reported to be tricyclic sesquiterpenoids such as silphiperfol-6-ene and presilphiperfolan-8-ol followed by presilphiperfol-7-ene, cameroonan-7-α-ol, and (E)-caryophyllene (Pavela et al., 2016).

Ceramides, sulf-polyacetylene ester, and simple hydrocarbons were the nonpolar constituents from the genus ( Figure 1 ). The ethyl acetate extract of E. integrifolius contained lupeolacetate, 1,3-butadiene-1-carboxylic acid, lupeol, (1R,3R,4R,5R)-(–)-quinic acid, palmitic acid, and D-threo-O-ethylthreonine as the main constituents (Karimov and Aisa, 2012). In a related study, GS-MS analysis of petroleum ether extract of the aerial part of E. integrifolius indicated the presence of methyl esters of fatty acids as well as saturated hydrocarbons such as octacosane, hentriacontane, hexacosane, tetratetraacontane, eicosane, and nonadecane. Trace amount of 2-octanone and 4,8,12,16-tetramethyl heptadecan-4-olide were also detected in E. integrifolius (Karimov and Aisa, 2013).

Biological Activities

Anti-Microbial Activity

The genus Echinops is traditionally used to treat different infectious diseases including trachoma, sepsis, typhoid, gonorrhea, and ulcerative lymphangitis. It is also used to treat different ailments that might be caused by bacterial/fungal infections including fever, respiratory diseases, toothache, leucorrhoea, and earache. Thus, they have been investigated for their anti-microbial activities. Anti-bacterial and anti-fungal activities of extracts from the genus with their respective minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBI), minimum fungicidal concentration (MFC), and zone of inhibitions are presented in Table 3 . These studies showed that both Gram-positive and Gram-negative bacteria were sensitive to the extracts/isolated compounds obtained from the genus.

Table 3.

In vitro antibacterial and antifungal activities of some Echinops species.

Echinops species	Extract(Plant part)	Strain (ID)	Type	MIC	MBC	Zone of inhibition (mm) (Conc.) (mg/mL)	Ref.
E. adenocaulos Bioss.	Zamzam water	Streptococcus pneumonia (MDR)	I	780 µg/mL	–	–	Saleh Fares et al., 2013
E. amplexicaulis	Ether (R)	Mycobacterium tuberculosis (MDR)	I	50 µg/mL	50 µg/mL	41.0 (50)	Kevin et al., 2018
		M.tuberculosis (H37Rv)	S	12 µg/mL	10 µg/mL	40.3 (50)
		M. bovis (BCG strain)	S	45 µg/mL	50 µg/mL	40. 7 (50)
E. echinatus	70% Ethanol (AP)	Bacillus subtilis	S			14.7 (0.8)	Ahmad, 2012
		S. aureus	S			12.7 (0.8)
		Pseudomonas aeruginosa	S			20.7 (0.8)
		Salmonella typhi	S			27.3 (0.8)
		Shigella sonnei	S			17.3 (0.8)
		Escherichia coli	S			24 (0.8)
E. ellenbeckii	80% Methanol (L)	S. aureus (ATCC 6538)	S	–	–	23.0 (10)	Hymete et al., 2005a
E. giganteus	Methanol (R)	Klebsiella pneumonia (K24)	LC	32 µg/mL	–	–	Fankam et al., 2011
		M. tuberculosis (H37Rv)	CC	32 µg/mL	128 µg/mL		Tekwu et al., 2012
		M. tuberculosis (H37Ra)	CC	16 µg/mL	128 µg/mL
E. kebericho	Water/Ethanol/Methanol (R)	S. aureus	S	100/3.1/3.1 µg/mL	> 100/6.3/9.4 µg/mL	8.3/19.3/18(0.08)	Ameya et al., 2016
	Ethanol/Methanol (R)	E. fecalis	S	12.5/12.5 µg/mL	18.75/18.75 µg/mL	11.66/14.1(0.08)
		E. coli	S	25/25 µg/mL	37.5/37.5 µg/mL	9.66/8.66 (0.08)
	Essential oils (R)	Listeria monocytogenes	S	0.2 µL/mL	0.4 µL/mL	–	Belay et al., 2011
		S. aureus		0.2 µL/mL	0.4 µL/mL
		S. pyogenes		0.2 µL/mL	0.8 µL/mL
		P. aeruginosa		0.2 µL/mL	0.4 µL/mL
		Shigella dysenteriae		6.3 µL/mL	6.3 µL/mL
		K. pneumonia		0.1 µL/mL	0.2 µL/mL
		Proteus mirabilis		25 µL/mL	25 µL/mL
		Bacillu scereus		0.4 µL/mL	0.8 µL/mL
E. longisetus	80% Methanol (L)	S. aureus (ATCC 6538)	S	–	–	23.0 (10)	Hymete et al., 2005a
	80% Methanol (St)	S. aureus (ATCC 6538)	S	–	–	23.3 (10)
E. ritro	Essential oil (AP)	S. aureus (ATCC 25923)	S	150 µg/mL			Jiang et al., 2017
		Salmonella Enteritidis (CICC21513)	S	600 µg/mL
E. spinosissimus	Methanol (AP)	B. cereus	I	–	–	12 (6)	Rahman et al., 2011
	Methanol (AP)	S. aureus	I	–	–	12 (6)
	Methanol (AP)	S. aureus	I	–	–	10 (6)
	Methanol (AP)	S. aureus	I	–	–	32 (6)
	Hexane (AP)	S. sepidermis	I	–	–	16 (6)
	Methanol (AP)	E. coli	I	–	–	11 (6)
	Methanol (AP)	Klebsiella oxytoca	I	–	–	12(6)
	Hexane (AP)	Yersinia enterocolitica ss. Entero colitica (ATCC 23715)	CC			20 (6)
Echinops species	Extract(plant part)	Strain (ID)	Type	MIC	MFC	Zone of inhibition (mm) (Conc.) (mg/mL)	Ref.
E. cephalotes	Ethanol/Methanol/Water	C. albicans	I			18.9/16.3/18(7.8)	Heshmati et al., 2016
	Ethanol	C. glabrata	I			15.7(7.8)
E. ellenbeckii	80% Methanol (L)	C. albicans	I	–	–	18.9 (10)	Hymete et al., 2005a
E. kebericho	Ethanol/methanol (R)	A. flavus	I	12.5/6.25 µg/mL	22.92/12.5 µg/mL	17.33/18.66 (0.08)	Ameya et al., 2016
		C. albicans	I	6.25/3.12 µg/mL	12.5/6.25 µg/mL	18.66/20.33 (0.08)
E. pinosissimus	Methanol (AP)	C. albicans	S	–	–	18 (23)	Abd-Ellatif et al., 2011

AP, Aerial part; F, Fruit; L, Leaf; R, Root; St, Stem; WP, Whole plant; MDR, Multidrug resistant; I, Isolate; S, Standard. All studies resulting in MIC values over 1 mg were not included as such dosages cannot be applied in vivo.

Out of the tested strains, M. tuberculosis (H37Rv) showed higher sensitivity to the ether root extract of E. giganteus and methanolic extract of E. amplexicaulis Oliv. with MIC of 12 µg/mL and 32 µg/mL, respectively (Tekwu et al., 2012; Kevin et al., 2018). The methanolic root extract of E. amplexicaulis also showed a promising effect against a multidrug-resistant strain of M. tuberculosis with a MIC of 50 µg/mL (Kevin et al., 2018). The ethanolic root extract and essential oils obtained from E. kebericho Mesfin showed relatively strong effect against Staphylococcus aureus (Ameya et al., 2016) and Klebsiella pneumoniae (Belay et al., 2011). These results might justify the traditional application of E. kebericho in treating respiratory disease, toothache, and fever. The essential oil from E. ritro L. exhibited anti-bacterial effect and antibiofilm and disruption of the bacterial membrane were suggested as mechanisms of actions (Jiang et al., 2017).

Different extracts from members of the genus having anti-bacterial effect were analyzed for their chemical constituents. The unsaponifiable matter from the hexane extract of E. spinosissimus contained mainly taraxasterol, lupeol, pseudotaraxasterol, α-amyrin, β-amyrin, pseudotaraxasteryl acetate, lup-22(29)-en-3-yl acetate, β–sitosterol, and stigmasterol. The hexane extract showed anti-bacterial activity with MIC values of less than 125 µg/mL against different bacterial strains (Bacillus amyloliquefaciens, Micrococcus luteus, Bacillus subtilis, and Salmonella enteric) (Bouattour et al., 2016). Thiophens (31, 46, 54, and 59) isolated from the root of E. ritro possessed anti-bacterial effect against S. aureus with a MIC value of 8 µg/mL. This was similar to the effect observed for the positive control, levofloxacin. The anti-bacterial effects of thiophenes 31, 46, 55, 57, and 59 against Escherichia coli with a MIC of 64, 32, 64, 64, and 8 µg/mL, respectively, were also described (Li et al., 2019).

In addition to those described in Table 3 , the root extract of Echinops spp from Ethiopia showed anti-bacterial activity through growth inhibition (Ashebir and Ashenafi, 1999). The study did not delineate the specific name of the plant, MIC/MBC, and zone of inhibitions which makes it challenging to compare with other study results. Methanolic extract of the whole plant of E. polyceras improved the effect of tetracycline on resistant strains of Pseudomonas aeruginosa (Aburjai et al., 2001). The effect of the plant without tetracycline however was not studied. The leaf and flower extracts of E. viscosus subsp. bithynicus were described to have anti-bacterial properties against E. coli, Micrococcus luteus, S. aureus, Mycobacterium smegmatis, P. aeruginosa, Enterobacter cloacae, and Bacillus megaterium. Even though the concentration of the extracts is not well defined in the study, the flower extract of E. microcephalus has been reported to have greater zone of inhibition than the standard drug, vancomycin (30 µg/disc) (Toroğlu et al., 2012).

Most of the anti-fungal studies on the genus revealed that the extracts/isolated compounds were effective mainly against Candida albicans with the most potent effect observed for the root methanolic extract of E. kebericho (MIC = 3.12 µg/mL) (Ameya et al., 2016).

Thiophenes (1, 2, 5, 18, 22, 23, 31, 38, and 39) from E. ritro have been described to possess significant anti-fungal activity against different fungal isolates. The most active thiophenes were 1 (IC₅₀ = 4.2 µM) against Colletotrichum gloeosporioides, 2 (IC₅₀ = 1.9 µM), and 5 (IC₅₀ = 1.1 µM) against C. fragariae (Fokialakis et al., 2006a). A recent study also showed that thiophenes (31, 46, and 55) isolated from E. ritro exhibited anti-fungal effect against C. albicans with the MIC of 64, 32, and 64 µg/mL, respectively (Li et al., 2019). The anti-fungal activity of extracts obtained from E. viscosus subsp. bithynicus and E. microcephalus leaves and flowers were found to be active against Saccharomyces cerevisiae, Rhodotorula rubra, Mucor pusillus, and Kluyveromyces fragilis (Toroğlu et al., 2012).

Effect on Cancer Cell Lines

The traditional use of the genus Echinops in the treatment of cancer is not common nevertheless the species in this genus were explored for cytotoxic activity. The methanolic extract of E. kotschyi Boiss. against MOLT-4 and K562 cancer cell lines (Afshaki et al., 2012) and essential oils obtained from E. kebericho, which consist of 43 compounds predominantly dehydrocostus lactone, showed cytotoxic activity against human monocytic leukemia cell line (THP-1) with an IC₅₀ value of 0.4 µg/L (Tariku et al., 2011).

Four thiophens isolated from E. latifolius Tausch., 5-(3,4-dihydroxybut-1-ynyl)-2,2'-bithiophene (15), 5-(4-hydroxy-1-butynyl)-2,2'-bithiophene (31), 5-{4-[4-(5-pent-1,3-diynylthiophene-2-yl)-but-3-yny}-2,2'-bithiophene (40), and 5-(4-hydroxybut-1-one)-2,2'-bithiophene (41) were tested against human malignant melanoma (A375-S2) and human cervical carcinoma (HeLa) cell lines. The four compounds displayed cytotoxic activity and the effect was more when the mixture of cell lines and compounds were exposed to ultraviolet A (UVA) light for 30 min. The effects of the four compounds were higher against HeLa cell line with IC₅₀ values of 5.2, 10.2, 3.1, and 6.5 µmol/L, respectively (Wang et al., 2007).

Jin et al. (2008) illustrated the in vitro cytotoxic activity of the dichloromethane fraction of the crude ethanolic root extract of E. grijisi and thiophenes (1, 2, 9, 18, 23, 34, 39, and 42) isolated from this fraction. The fraction, as well as the isolated compounds showed different effects towards human hepatocarcinoma (HepG2 and MFC-7), human acute myeloid leukemia (HL-60), and human chronic myelogenous leukemia (K562) cell lines. The highest activities were observed for the dichloromethane fraction against HL-60 (IC₅₀ = 5 µg/mL), 5-(4-isovaleroyloxybut-1-ynyl)-2,2'-bithiophene (18) against HepG2 (IC₅₀ = 2 µg/mL), 5-(3-acetoxy-4-isovaleroyloxybut-1-ynyl)-2,2′-bithiophene (34) against HepG2 and K562 (IC₅₀ = 1.8 and 7 µg/mL), and 5-(prop-1-ynyl)-2-(3,4-diacetoxybut-1-ynyl)-thiophene (42) against HL-60 (IC₅₀ = 8 µg/mL). The dichloromethane fraction was tested in mice and did not show anti-tumor effect.

Similarly, Zhang et al. (2009) evaluated the cytotoxic effect of thiophenes isolated from E. grijisii on human cancer cell lines, HL60 and K562. Significantly potent effect was achieved with 5 (IC₅₀ = 0.23 and 0.47 µg/mL) and 14 (IC₅₀ = 0.27 and 0.43 µg/mL) against HL60 and K562, respectively. The thiophenes showed better activity against HL-60. A compound isolated from the root of E. grijsii, 5-(5,6-dihydroxy-hexa-1,3-diynyl)-2-(prop -1-ynyl)-thiophene (13), possessed anti-proliferative activity against human colon cancer cells, SW620, SW480, and HCT116 with IC₅₀ values of 19.5 µM, 10.5 µM, and 27.7 µM, respectively, at 24 h. The proposed mechanism of action for the thiophene (13) was mitochondrial-mediated apoptosis (Zhang and Ma, 2010; Xu et al., 2015).

The methanolic extract from the underground part of E. giganteus also exhibited cytotoxic activity with an IC₅₀ values of 9.84, 6.68, and 7.96 µg/mL against prostate cancer (Mia PaCa2) and two leukemia cells (CCRF-CEM and CEM/ADR5000), respectively (Kuete et al., 2011). In addition, the crude extract showed strong activity against breast cancer (MDA-MB-231-pcDNA3) with an IC₅₀ value of 4.17 µg/mL. The secondary metabolites (5, 97, 126, and 131) from the methanolic extract of this plant were tested for their cytotoxic effect and showed lower effect than that of the crude extract (Kuete et al., 2013). In continuation of this study, 5-(3,4-dihydroxybut-1-ynyl)-2-(penta-1,3-diynyl)-thiophene (14), echinopsolide A (98), and tetrahydrofurano-ceramide (150) were isolated from E. giganteus. These three compounds tested against leukemia showed the highest activity on CCRF-CEM (IC₅₀ values of 46.96, 36.78, and 9.83 µM, respectively) and CEM/ADR5000 (IC₅₀ values of 21.09, 38.57, and 6.12 µM, respectively) cell lines (Sandjo et al., 2016).

Macrochaetosides A and B (80 and 81) and cyclostenol (104), isolated from aerial parts of E. macrochaetus Boiss., were tested for their cytotoxic activity. The activity was observed on cell lines of breast adenocarcinoma (MCF-7) (IC₅₀ = 2.1 and 0.18 μM), human hepatocellular carcinoma (HepG2) (IC₅₀ = 2.9 and 3.3 μM), and colorectal adenocarcinoma (HCT-116) (IC₅₀ = 3.6 and 2.3 μM) for cyclostenol and macrochaetosides A, respectively. Macrochaetoside B only showed a cytotoxic activity against MCF-7 with an IC₅₀ of 6.9 μM (Zamzami et al., 2019).

The vehicle used to dissolve the compounds for the cytotoxicity study is not mentioned in some of the reports (Sandjo et al., 2016; Zamzami et al., 2019). In one study, α-terthiophene (2) was used as a positive control against A375-S2 (IC₅₀ = 10.6 µmol/L) and HeLa (IC₅₀ = 6.3 µmol/L) cell lines (Wang et al., 2007). Similarly α-terthiophene showed cytotoxic effect towards K562 (IC₅₀ = 50 µg/mL) and HepG2 (IC₅₀ = 10µg/mL) (Jin et al., 2008).

The above-described effects on cancer cell lines could be mainly due to thiophenes. Terpenoids and ceramides were the other secondary metabolites having a cytotoxic effect. Among the cell lines tested, leukemia cell lines were comparatively more sensitive in which 5-(4-hydroxybut-1-ynyl)-2-(pent-1,3-diynyl)-thiophene (5) showed the most potent effect.

Even though the extracts and isolated compound from the genus showed promising effects against different cancer cell lines, the effects are ought to be further investigated using in vivo models.

Hepato-Protective and Anti-Oxidant Activities

Members of the genus Echinops were also shown to have hepatoprotective and anti-oxidant activities. Most of the studies were conducted in carbon tetrachloride (CCl₄)-induced liver damage, in which biomarkers of liver function like aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured.

The methanolic root extract, as well as n-butanol and aqueous fractions of E. grijsii, showed hepatoprotective activity in CCl₄-induced liver damage in rats. The effect was prominent in the aqueous and butanol fractions, at a dose of 300 mg/kg, that markedly decreased AST and ALT levels (Lin et al., 1993). A study conducted by Eram et al. (2013) in CCl₄-intoxicated rabbits justified the traditional claim of E. echinatus to treat jaundice (Gupta et al., 2010). The ethanolic aerial parts extract of E. echinatus at 500 and 750 mg/kg resulted in a significant decrease of ALT and AST, of which the lower dose (500 mg/kg) showed a higher effect (Eram et al., 2003). As presented in Table 1 , flavonoids were isolated from the root of E. grijsii and the whole plant of E. echinatus. These might be responsible for the hepatoprotective effects of the extracts (Wang et al., 2015; Zang et al., 2017) and further investigations are required on phytoconstituents of the plants.

The hepatoprotective effect of compounds isolated from members of the genus Echinops was also investigated along with crude extracts. The protective effects of E. galalensis Schweinf. as well as isolated compounds β-sitosterol (89), apigenin-7-O-β-D-glucoside (109), 3β-acetoxy-taraxast-12,20(30)-diene-11α-21α–diol (100), α-amyrin (101), erythrodiol (102), lup-20(29)-ene-1,3-diol (103), and dicaffeoyl-quinic acid derivatives (135-138) on human hepatoma cell line (Huh7) have also been established. The highest protection was exhibited by 100, 102, and 103 and they significantly decreased the level of ALT. Except for the crude extract, all the tested samples decrease the level of AST and 89, 101, and 135 showed the highest effect (Abdallah et al., 2013). According to Abdallah et al. (2013), the protective effect of the extract and isolated compounds was suggested to be partly due to anti-oxidant effects of the samples.

Methotrexate-induced hepatotoxicity was also used to evaluate the hepatoprotective effect of some of the plants. Using this model, the protective effect of ethanolic aerial part extract and flavonoid fraction of E. heterophyllus P.H. Davis was established in rabbits. The crude ethanolic extract (250 mg/kg) significantly decreased the serum proteins, liver enzymes, and oxidative stress markers than the flavonoid fraction (Abdulmohsin et al., 2019).

In liver diseases, excessive oxidative stress undoubtedly contributes to the progression and pathological expression of the disease and serves as a prognostic indicator (Zhu et al., 2012). The methanolic root extract of E. giganteus showed in vitro free radical scavenging effect with 12.54 mg equivalent weight of trolox per 100 g (Bouba et al., 2010). The aqueous extracts of E. ritro, E. tournefortii Ledeb. possessed 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging effect with inhibitions more than 80% and 70%, respectively, at 1 mg/mL (Aydın et al., 2016). A study that compared different types of extraction methods on antioxidant activity reported that hot extraction using methanolic-ethyl acetate of E. persicus showed higher in vitro free radical scavenging effect (89.14%) against DPPH (Mohseni et al., 2017). The free radical scavenging effect of crude seed and leaf extracts E. orientalis Trautv. as well as isolated compounds β-sitosterol (89) and 1-methylquinolin-4(1H)-one (139) from seeds and apigenin-7-O-β-D-glucoside (109) and apigenin-7-O-(6"-trans-p-coumaroyl-β-D-glucopyranoside (124) from leaf methanolic extract was demonstrated. The extracts showed a significant effect (> 60% at 40 µg/mL) while the effect of the isolated compounds was not significant against 2,2-diphenyl-1-picrylhydrazyl (DPPH). However, the two flavonoids (109 and 124) showed better scavenging effect towards 3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radical cation than the extracts and the other two compounds (89 and 139), with IC₅₀ of 3 and 5 µg/mL (Erenler et al., 2014).

Active cell cultures of human peripheral blood mononuclear cells were also used to evaluate the anti-oxidant effect of aqueous methanolic extract of E. albicaulis aerial parts. The study showed that the active oxygen species (ROS) generation in the cells was significantly reduced at concentrations of 1, 20, and 50 mg/mL of the extract; however, the extract induced overproduction ROSs at higher concentrations (Kiyekbayeva et al., 2017).

Regardless of the effects described, the anti-oxidant activity evaluations are not still sufficient. In most of the reports the IC₅₀ value for the in-vitro anti-oxidant effect are not mentioned. No single in vivo anti-oxidant model was employed. In some of the hepatoprotective effect studies standard drugs were not utilized and comparison was made only with the negative control ( Table 5 ). The hepatoprotective effect of traditionally used plant, E. spinosus L. (Akdime et al., 2015), has not been scientifically investigated yet.

Table 5.

Other biological effects of members of the genus Echinops.

Hepatoprotective and antioxidant activities
Plant/compound name (Plant)	Effects Model	Positive control	Negative control	Dose/Concentration (Rout of administration)	Activity	References
100, 102, and 103 (E. galalensis)	Hepatoprotective 2	Silymarin	PBS	100 mg/ml	↓ ALT	Abdallah et al., 2013
100, 102, and 103 (E. galalensis)	Hepatoprotective 2	Silymarin	PBS	100 mg/ml	↓ AST	Abdallah et al., 2013
109 (E. orientalis)	Anti-oxidant 2	Trolox	NM		IC50 = 3 µg/mL	Erenler et al., 2014
131 (E. orientalis)	Anti-oxidant 2	Trolox	NM		IC50 = 5 µg/mL	Erenler et al., 2014
E. albicaulis	Anti-oxidant 2	N-acetylcysteine	NM	1, 20, and 50 mg/mL	↓ Generation of ROSs	Kiyekbayeva et al., 2017
E. echinatus	Hepatoprotective 1	Silymarin	Normal saline	500 mg/kg (p.o.)	↓ AST and ALT	Eram et al., 2013
E. giganteus	Anti-oxidant 2	Trolox	Distilled water		12.54 mg equivalent weight of trolox per 100 g	Bouba et al., 2010
E. grijsii	Hepatoprotective 1	NM	Normal saline	300 mg/kg (p.o.)	↓ AST and ALT	Lin et al., 1993
E. heterophyllus	Hepatoprotective 1	NM	Distilled water	250 mg/kg (p.o.)	↓ AST, ALT, and Aalkaline phosphatase(ALP)	Abdulmohsin et al., 2019
E. orientalis	Anti-oxidant 2	Trolox	NM	40 µg/mL	> 60%	Erenler et al., 2014
E. persicus	Anti-oxidant 2	NM	Methanol		89.1%	Mohseni et al., 2017
E. ritro	Anti-oxidant 2	BHT (Dibutylhydroxytoluene)	Distilled water	1 mg/mL	> 80%	Aydın et al., 2016
E. tournefortii	Anti-oxidant 2	BHT	Distilled water	1 mg/mL	> 70%	Aydın et al., 2016
Anti-inflammatory, analgesic, anti-pyretic and wound healing activities
132 (E. echinatus)	Anti-inflammatory 1	Phenylbutazone	1% gumacacia	200 mg/kg (i.p.)	Inh = 68.3%	Singht et al., 1991
43 (E. latifolius)	Inhibition of LPS-induced NOproduction 2	Aminoguanidine and Indomethacin	NM		IC50 = 12.8 µM	Jin et al., 2016
44 (E. latifolius)	Inhibition of LPS-induced NOproduction 2	Aminoguanidine and Indomethacin	NM		IC50 = 28.2 µM	Jin et al., 2016
45 ( E. latifolius)	Inhibition of LPS-induced NOproduction 2	Aminoguanidine and Indomethacin	NM		IC50 = 30.9 µM	Jin et al., 2016
46 (E. latifolius)	Inhibition of LPS-induced NOproduction 2	Aminoguanidine and Indomethacin	NM		IC50 = 48.6 µM	Jin et al., 2016
47 (E. latifolius)	Inhibition of LPS-induced NOproduction 2	Aminoguanidine and Indomethacin	NM		IC50 = > 100 µM	Jin et al., 2016
48 (E. latifolius)	Inhibition of LPS-induced NOproduction 2	Aminoguanidine and Indomethacin	NM		IC50 = > 100 µM	Jin et al., 2016
83 (E. latifolius)	Inhibition of LPS-induced NOproduction 2	Aminoguanidine and indomethacin	NM		IC50 = > 100 µM	Jin et al., 2016
Chloroform fraction (E. grijissi)	Anti-inflammatory	Indomethacin	Normal saline	300 mg/kg (i.p.)	Inh = 56%	Lin et al., 1992
E. echinatus	Anti-inflammatory 1	Phenylbutazone	1% gumacacia	800 mg/kg (i.p.)	Inh = 67.5%	Singh et al., 1989
E. echinatus	Analgesic 1	Pentazocine	Distilled water	500 mg/kg (p.o)	↑ Reactionary time	Patel et al., 2011b
E. echinatus	Antipyretic 1	Paracetamol	NM	750 mg/kg	↓ Rectal temperature	Alam et al., 2016
E. heterophyllus	Wound healing 1	NM	NM	NM	Facilitated epithelialization	Abdulrasool et al., 2013
Flavonoids (E. latifolius)	Inhibition of rheumatoid arthritis 1	NM	Phosphate-buffered saline (PBS)	50, 100 and 150 mg/kg	↓ Arthritis and paw swelling score	Miao et al., 2015
Anti-protozoal and anti-helmentic activities
10 (E.hoehnelii)	Anti-malarial 1	Chloroquine	7% Tween 80/3% ethanol	100 mg/kg	Inh = 32.7%	Bitew et al., 2017
14 (E.hoehnelii)	Anti-malarial 1	Chloroquine	7% Tween 80/3% ethanol	100 mg/kg	Inh = 50.2%	Bitew et al., 2017
E. ellenbeckii	Anti-helmentic 2	Niclosamide	Tap water	500 µg/mL	Mortality rate = 100%	Hymete et al., 2005a
E. kebericho	Anti-malaria 1	Chloroquine	(3% of Tween 80	500 mg/kg	Inh = 57.3%	Toma et al., 2015
E. kebericho	Anti-helmentic 2	Niclosamide	Tap water		LD50 = 57 µg/mL	Hymete and Kidane 1991
E. longisetus	Anti-helmentic 2	Niclosamide	Tap water	500 µg/mL	Mortality rate = 100%	Hymete et al., 2005a
E. polyceras	Anti-malarial 2	NM	Distilled water	0.2% (w/v)	Inh = 96%	Sathiyamoorthy et al., 1999
Essential oil (E. giganteus)	Anti-trypanosomal 2	Suramin	DMSO		IC50 = 10.5 µg/mL	Kamte et al., 2017
Essential oil (E. kebericho)	Anti-leishmanial 2	Amphotericin B	1% DMSO		EC50 = 0.24 µg/mL	Tariku et al., 2011
Essential oil (E. kebericho)	Anti-helmentic 2	Thiabendazole	0.5% Tween 80 in PBS	1% (v/v)	Inh = 81.8%	Hussien et al., 2011
Effects on insects and termites
1 (E. grijsii)	Larvicidal 2	Rotenone	0.25% Tween 40		LC50 = 0.12 µg/mL	Zhao et al., 2017
1, 2 (E. ritro and E. spinosissimus)	Termicidal 2	NM	Distilled water	1% (w/w)	Mortality rate = 100%	Fokialakis et al., 2006b
10 (E. transiliensis)	Larvicidal 2	Permethrin	DMSO		LC50 = 14.71 µg/mL	Nakano et al., 2014
14 (E. transiliensis)	Larvicidal 2	Permethrin	DMSO		LC50 = 12.45 µg/mL	Nakano et al., 2014
15 (E. transiliensis)	Larvicidal 2	Permethrin	DMSO		LC50 = 9.89 µg/mL	Nakano et al., 2014
18 (E. grijsii)	Larvicidal 2	Rotenone	0.25% Tween 40		LC50 = 0.33 µg/mL	Zhao et al., 2017
2 (E. grijsii)	Larvicidal 2	Rotenone	0.25% Tween 40		LC50 = 1.38 µg/mL	Zhao et al., 2017
2 (E. transiliensis)	Larvicidal 2	Permethrin	DMSO		LC50 = 0.16 µg/mL	Nakano et al., 2014
39 (E. transiliensis)	Larvicidal 2	Permethrin	DMSO		LC50 = 4.22 µg/mL	Nakano et al., 2014
51 (E. transiliensis)	Larvicidal 2	Permethrin	DMSO		LC50 = 7.45 µg/mL	Nakano et al., 2014
52 (E. transiliensis)	Larvicidal 2	Permethrin	DMSO		LC50 = 19.97 µg/mL	Nakano et al., 2014
8 (E. transiliensis)	Larvicidal 2	Permethrin	DMSO		LC50 = 18.55 µg/mL	Nakano et al., 2014
9 (E. transiliensis)	Larvicidal 2	Permethrin	DMSO		LC50 = 17.95 µg/mL	Nakano et al., 2014
Butanol fraction (E. echinatus)	Anti- hyperplasia 1	Finasteride	2% Tween 80	50, 100, and 200 mg/kg (p.o.)	↓ Prostatic/body weight ratio	Agrawal et al., 2012
Butanol fraction (E. echinatus)	5α-reductase inhibitory effect 2	Finasteride	Ethanol		IC50 = 0.22 mg	Agrawal et al., 2012
E. echinatus	Anti-fertility 1	NM	Distilled water	50, 100, and 200 mg/kg	↓ sizes of testes, epididymis, ventral prostate, vas deferens, and seminal vesicle	Chaturvedi et al., 1995
Essential oil (E. giganteus)	Larvicidal 2	NM	DMSO		LC50 = 227.4 µL/L	Pavela et al., 2016
Effects on the reproductive system
Terpenoidal fraction (E. echinatus)	Effect on male reproductive parameters 1	NM	1% Tween 80	60 mg/kg (p.o.)	↓ Seminiferous tubular diameter and germinal epithelial cell thickness	Padashetty and Mishra, 2007
Other activities
14 (E. grijsii)	NQO1 inducing activity 2	4'-Bromoflavone	NM	40 µM	Induction = 3.1X of the control	Shi et al., 2010
14 (E. grijsii)	NQO1 inducing activity 2	4'-Bromoflavone	NM	2.87 µg/mL	Induction = 2X of the control	Zhang and Ma, 2010
5 (E. grijsii)	NQO1 inducing activity 2	4'-Bromoflavone	NM	1.86 µg/mL	Induction = 2X of the control	Zhang and Ma, 2010
9 (E. grijsii)	NQO1 inducing activity 2	4'-Bromoflavone	NM	2.58 µg/mL	Induction = 2X of the control	Zhang and Ma, 2010
E. echinatus	Anti-diabetic 1	Sitagliptin	Normal saline	200 mg/kg (p.o.)	↓ Blood glucose level	Fatima et al.2017
E. echinatus	Anti-diabetic 1	MetforminHCl	1% Tween 80 in saline	200 mg/kg (p.o.)	↓ Blood glucose level	Sarvaiya et al., 2017
E. echinatus	Diuretic	Furosemide	Normal saline	500 mg/kg (p.o.)	↑ Urine volume and electrolyte excretion	Patel et al., 2011a
E. ellenbeckii	Molluscicidal 2	NM	De-chlorinated tap water	20.25 µg/mL	Mortality rate = 100%	Hymete et al., 2005a
E. giganteus	Amylase inhibitory 2	NM	Distilled water	NM	> 75%	Etoundi et al., 2010
E. lasiolepis	Immunomodulating activity	NM	DMSO	1 µg/mL	Inhibited PBMCs proliferation	Asadi et al., 2014
E. longisetus	Molluscicidal 2	NM	De-chlorinated tap water	45 µg/mL	Mortality rate = 100%	Hymete et al., 2005a
E. persicus	Anti-ulcer	NM	Distilled water	500 mg/kg (p.o./i.p.)	↓ Number and level of stomach ulcer	Rad et al., 2010

DMSO, Dimethyl sulfoxide; NM, Not mentioned; p.o., Per os (Oral); i.p., intraperitoneal; ¹, In vivo; ², In vitro.

Anti-Inflammatory, Analgesic, Anti-Pyretic, and Wound Healing Activities

Traditionally, members of the genus Echinops are documented to have been used to treat inflammation, pain, and fever. Accordingly, several species have been explored for anti-inflammatory, analgesic, and anti-pyretic activities.

The whole plant ethanolic extract of E. echinatus showed anti-inflammatory activity against carrageenan and formaldehyde induced edema in rats with inhibitions of 67.5% and 51.8% at a dose of 800 mg/kg administered intraperitoneally and orally, respectively (Singh et al., 1989). A triterpenoid isolated from this plant, taraxasterol acetate (88), showed anti-inflammatory activity on carrageenan-induced pedal edema in rats with the highest inhibition of 68.3% and 63.2% at 200 mg/kg administered by the intraperitoneal and oral route, respectively (Sing et al., 1991). Flavanone glycoside, 5,7-dihydroxy-8,4'-dimethoxyflavanone-5-O-α-L-rhamno-pyranosyl-7-O-β-D-arabinopyranosyl (1→4)-O-β-D-glucopyranoside (125) isolated from E. echinatus, showed anti-inflammatory activity (Yadava and Singh, 2006). The methanolic root and aerial part extract of the plant showed analgesic properties in both hotplate and tail immersion models. The aerial part exhibited the highest activity by increasing the reaction time in both models to 7.99 and 7.77 sec, respectively, at 500 mg/kg, and it was comparable with the standard drug, pentazocine (Patel et al., 2011b). The ethanolic leaf and stem extract of E. echinatus showed antipyretic effect at a dose of 750 mg/kg in rabbits (Alam et al., 2016).

The methanolic root extracts of E. spinosus, E. grijissi, and E. latifolius exhibited significant anti-inflammatory activity (Lin et al., 1992; Rimbau et al., 1999). The ethyl acetate, chloroform, and n-hexane fractions obtained from the crude extract of E. grijissi showed significant anti-inflammatory activities in carrageenan-induced edema in rats, of which the chloroform fraction, at a dose of 300 mg/kg, exhibited inhibitory effect (56.7%) higher than that of indomethacin (Lin et al., 1992). Flavonoids, extracted from E. latifolius, were tested on rheumatoid arthritis using rats and inhibited the synovium proliferation through fibroblast-like synoviocytes apoptosis at 150 mg/kg (Miao et al., 2015).

A study was conducted to evaluate the anti-inflammatory activity of compounds isolated from E. latifolius, 5-(1,2-dihydroxy-ethyl)-2-(Z)-hept-5-ene-1,3-diynylthiophene (43), 5-(1,2-dihydroxyethyl)-2-(E)-hept-5-ene-1,3-diynylthiophene (44), 6-methoxy-arctinol-b (45), arctinol-b (46), latifolanone A (82), arctinol (47), methyl [5'-(1-propynyf)-2,2'-bithienyl-5-yl] carboxylate (48), and atractylenolide-II (83) on inhibition of lipopolysaccharide (LPS)-induced nitric oxide (NO) production. In the order of presented compound names, thiophenic compounds numbered 43-46 inhibited the NO production with IC₅₀ ranging from 12.8–42.7 µM, whereas the IC₅₀ of 47, 48, and 83 were reported to be more than 100 µM (Jin et al., 2016).

The whole plant extract of E. heterophyllus and the alkaloidal faction facilitated epithelialization and left no scars in rabbits (Abdulrasool et al., 2013). This is the only wound healing activity reported on members of this genus although the dose, vehicle, and the standard drug are not described.

The in vivo anti-inflammatory effects of the genus seemed to be not promising since the plants resulted in an inhibition of edema at higher doses. In spite of the studies stated above, scientific data justifying the traditional claim of E. bovei (Boiss.) Maire., E. cornigerus, E. kebericho, E. longifolius A. Rich., E. macrochaetus, and E. spinosissimus to treat rheumatism and pain are not provided yet.

Anti-Protozoal and Anti-Helmentic Activities

As presented in Table 3 , E. hoehnelii Schweinf. and E. kebericho have been used in traditional treatment of malaria. These plants along with other species showed anti-malarial activity.

Aqueous extract of the aerial parts of E. polyceras exhibited strong (96%) in vitro growth inhibitory activity against Plasmodium falciparum. Nevertheless, the concentration of the extract used for the test and the standard drug used as positive control has not been reported (Sathiyamoorthy et al., 1999). A study on 70% ethanolic root extract E. kebericho resulted in an inhibition of parasitemia by 57.3% at a dose of 500 mg/kg in mice against Plasmodium berghei (Toma et al., 2015). A recent study conducted on the 70% methanolic extract from roots of E. kebericho exhibited 49.5% of inhibition at 1000 mg/kg in mice (Biruksew et al., 2018). This might suggest that the potency of E. kebericho extract could be dependent on the extraction solvent.

Dichloromethane faction of the 80% methanolic extract of E. hoehnelii, and thiophens (5-(penta-1,3-diynyl)-2-(3-chloro-4-acetoxy-but-1-ynyl)-thiophene (10), and 5-(penta-1,3-diynyl)-2-(3,4-dihydroxybut-1-ynyl)-thiophene (14)) possessed anti-malarial activity. The two compounds showed parasitemia inhibition of 32.7% and 50.2% at a dose of 100 mg/kg, respectively, against P. berghei in mice (Bitew et al., 2017).

Different studies showed that essential oils possess strong anti-protozoal effects. The essential oil isolated from E. kebericho displayed a strong activity against two Leishmania strains (L. aethiopica and L. donovani) with an EC₅₀ values of 0.24 and 0.5 µg/mL (Tariku et al., 2011). Essential oil obtained from E. giganteus had anti-protozoal effect against Trypanosoma brucei with an IC₅₀ of 10.5 µg/mL and GC-MS analysis of the oil revealed the presence of modheph-2-ene, presilphiperfolan-8-ol, presilphiperfol-7-ene, cameroonan-7-α-ol, and (E)-caryophyllene as the main constituents of the oil (Kamte et al., 2017).

The anti-helminthic effects of members of the genus were also described. The root 80% methanolic extract of E. kebericho showed higher anti-helmentic effect (LD₅₀ = 57µg/mL) than niclosamide (LD₅₀ = 84.5 µg/mL) against earthworms (Hymete and Kidane, 1991). The root 80% methanolic extracts of E. ellenbeckii as well as E. longisetus A. Rich. were active against earthworms with 100% mortality at 500 µg/mL (Hymete et al., 2005a). Essential oil from the root of E. kebericho showed lethal effect (81.8%) at a concentration of 1% (v/v) towards Haemonchus contortus (Hussien et al., 2011).

Effects on Insects and Termites

The leaves of Echinops spp, which are commonly known as “Kebericho” in Ethiopia, had a mosquito repellant effect against Anopheles arabiensis with the effectiveness of 92.47% as a smoke (Karunamoorthi et al., 2008).

The activity of thiophenes (2, 8, 9, 10, 14, 15, 39, 51, and 52) isolated from E. transiliensis Golosk. against Aedes aegypti was reported and the toxic effect increased with the number of thiophene moieties in the molecule. Strong activity was observed for 2''-terthiophene (2) with an LC₅₀ value of 0.16 µg/mL (Nakano et al., 2014). Similarly, the root extract of E. grijsii possessed significant larvicidal activity against Aedes albopictus, Anopheles sinensis, and Culex pipienspallens with LC₅₀ values of 2.65, 3.43, and 1.47 µg/mL, respectively.

Bioactivity-directed chromatographic separation of the essential oil obtained from E. grijsii led to the isolation of thiophenes. The larvicidal effects of the isolated compounds, 5-(3-buten-1-yn-1-yl)-2,2′-bithiophene (1) (LC₅₀ 0.34, 1.36, and 0.12 µg/mL), α-terthienyl (2) (LC₅₀ 1.41, 1.79, and 1.38 µg/mL), and 5-(4-isovaleroyloxybut-1-ynyl)-2,2'-bithiophene (18) (LC₅₀ 0.45, 5.36, and 0.33 µg/mL) against the three organisms mentioned above was described (Zhao et al., 2017). On the contrary, the larvicidal activity of essential oils from E. giganteus against Culex quinquefasciatus was relatively low (LC₅₀ = 227.4 μL/L) (Pavela et al., 2016).

Fokialakis et al. (2006b) evaluated the termicidal effect of eight thiophenes (1, 2, 5, 10, 18, 23, 31, and 39) isolated from E. ritro, E. spinosissimus, E. albicaulis, and E. transiliensis on Coptotermes formosanus. The study revealed that all the thiophenes showed termicidal activity and 100% morality was observed after application of 5-(3-buten-1-ynyl)-2,2-bithiophene (1) and 2''-terthiophene (2) for 9 days at 2% and 1% (w/w), respectively. However, the exact concentrations of the compounds were not mentioned.

Effects on the Reproductive System

A number of species have been used for the management of various reproductive health problems ( Table 1 ). In spite of the traditional claims, only E. echinatus has been evaluated for these biological activities.

Corresponding to its traditional use, the terpenoidal fraction from E. echinatus displayed anti-fertility properties at doses of 30 and 60 mg/kg in male rats (Padashetty and Mishra, 2007). Earlier studies also indicated that the root ethanolic extract of E. echinatus has anti-fertility properties through decrement in sizes of testes, epididymis, ventral prostate, vas deferens, and seminal vesicle at doses of 50, 100, and 200 mg/kg. In addition, the extract also decreased sperm motility and density with an inhibition of sepermatogenesis in rats (Chaturvedi et al., 1995). The butanol fraction of the root extract demonstrated a protective effect on testosterone-induced prostatic hyperplasia at a dose of 100 mg/kg in rats. The butanol fraction also showed better 5α-reductase inhibitory effect (IC_{50 =} 0.22 mg/mL) than of the crude extract and other fractions followed by the water soluble fraction (IC_{50 =} 0.43 mg/mL) (Agrawal et al., 2012). Similarly, the root petroleum ether extract of E. echinatus inhibited 5α-reductase. The enzyme plays an important role in the pathogenesis of benign prostatic hyperplasia (BPH), prostatic cancer, acne, alopecia, baldness in men, and hirsutism in women (Nahata and Dixit, 2014).

Other Activities

A study showed that 5-(penta-1,3-diynyl)-2-(3,4-dihydroxybut-1-ynyl)-thiophene (14), isolated from the root of E. grijsii, has an induction effect on nicotinamide adenine dinucleotide phosphate (NAD(P)H): quinone oxidoreductase1 (NQO1), an enzyme that is involved in detoxification of toxic quinones. The induction effect was dose-dependent and the maximum effect was observed at a concentration of 40 μM and it was 3.1 folds of the control, 4'-bromoflavone (Shi et al., 2010). Similarly, compounds 5, 9, and 14, from the root of E. grijisii, had a strong NQO1-inducing effect and the concentrations that caused a twofold induction were 1.86, 2.58, and 2.87 μg/mL, respectively. Compounds 5 and 14 were found to have an alkylating effect on cysteine residues in NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) (Zhang and Ma, 2010).

The 70% hydro-alcoholic root extract of E. echinatus was reported to have significant anti-diabetic activity on alloxan-induced diabetic rats. The the extract treated animals (200 mg/kg) showed lower blood glucose level (164 mg/dL) compared to the negative control (277.6 mg/dL) after 21 days of treatment. In addition, the extract exhibited the ability to regenerate pancreatic islet cells and normal structure of glomeruli and proximal and distal convoluted tubules in kidneys (Fatima et al., 2017). Similarly, the methanolic root extract of E. echinatus exhibited a significant anti-diabetic effect at doses of 100 and 200 mg/kg on alloxan induced diabetic rats. The extract was also able to decrease serum cholesterol, serum triglyceride, serum low-density lipoprotein, serum very low-density lipoprotein, and serum alkaline phosphate significantly while it increased high-density lipoproteins (Sarvaiya et al., 2017).

The molluscicidal activities of 80% methanolic root extracts of E. ellenbeckii and E. longisetus with a 100% mortality rate at 20.25 and 45 µg/mL, respectively, was described (Hymete et al., 2005a). The pancreatic amylase inhibitory activity (> 75%) of aqueous root extract of E. giganteus was reported although the exact concentration of the extract was not mentioned (Etoundi et al., 2010). The latex of E. persicus at 500 mg/kg resulted in lower number and level of stomach ulcer compared to the negative control in rats (Rad et al., 2010). The methanolic extract of root and aerial parts of E. echinatus significantly increased urine volume and excretion at doses of 250 and 500 mg/kg (Patel et al., 2011a). The immunomodulating activity of aerial parts methanolic extract of E. lasiolepis Bunge has been reported. The extract at different concentrations (0.1, 1, 10, 100, and 200 µg/mL) inhibited peripheral blood mononuclear cells (PBMCs) proliferation of which 1 µg/mL showed optimum proliferation (30.66%) (Asadi et al., 2014).

Biological effects evaluated on genus Echinops and the doses with maximum effect are summarized in Tables 3 –5.

Table 4.

In vitro cytotoxic effect of members of the genus Echinops.

Plant/fraction/compound name (Plant)	Cell line	Positive control	Negative control	IC50	References
Essential oils(E. kebericho)	Human monocytic leukemia (THP-1)	Amphotericin B	1% DMSO	0.4 µg/mL	Tariku et al., 2011
15 (E. latifolius)	Human cervical carcinoma (HeLa)	α-terthienyl	DMSO	5.2 µmol/L	Wang et al., 2007
31 (E. latifolius)	HeLa	α-terthienyl	DMSO	10.2 µmol/L	Wang et al., 2007
40 (E. latifolius)	HeLa	α-terthienyl	DMSO	3.1 µmol/L	Wang et al., 2007
41 (E. latifolius)	HeLa	α-terthienyl	DMSO	6.5 µmol/L	Wang et al., 2007
Dichloromethane fraction (E. grijisi)	Human acute myeloid leukemia (HL-60)	Platinol	DMSO	5 µg/mL	Jin et al., 2008
18 (E. grijisi)	Human hepatocarcinoma (HepG2)	Adriamycin	DMSO	2 µg/mL	Jin et al., 2008
34 (E. grijisi)	HepG2	Adriamycin	DMSO	1.8 µg/mL	Jin et al., 2008
34 (E. grijisi)	Human chronic myelogenous leukemia (K562)	Adriamycin	DMSO	7 µg/mL	Jin et al., 2008
42 (E. grijisi)	HL-60	Platinol	DMSO	8 µg/mL	Jin et al., 2008
5 (E. grijisi)	HL-60	Platinol	DMSO	0.23 µg/mL	Zhang et al., 2009
5 (E. grijisi)	K562	Adriamycin	DMSO	0.47µg/mL	Zhang et al., 2009
14 (E. grijisi)	HL-60	Platinol	DMSO	0.27 µg/mL	Zhang et al., 2009
14 (E. grijisi)	K562	Adriamycin	DMSO	0.43 µg/mL	Zhang et al., 2009
13 (E. grijisi)	Colon cancer (SW480)	4′-Bromoflavone	DMSO	19.5 µM	Zhang and Ma, 2010
13 (E. grijisi)	Colon cancer (SW480)	4′-Bromoflavone	DMSO	10.5 µM	Zhang and Ma, 2010
13 (E. grijisi)	Colon cancer (HCT116)	4′-Bromoflavone	DMSO	27.7µM	Zhang and Ma, 2010
E. giganteus	Prostate cancer (Mia PaCa2)	Doxorubicin	DMSO	9.84 µg/mL	Kuete et al., 2011
E. giganteus	Leukemia (CCRF-CEM)	Doxorubicin	DMSO	6.68 µg/mL	Kuete et al., 2011
E. giganteus	Leukemia (CEM/ADR5000)	Doxorubicin	DMSO	7.96 µg/mL	Kuete et al., 2011
14 (E. giganteus)	CCRF-CEM	Doxorubicin	NM	46.96 µM	Sandjo et al., 2016
14 (E. giganteus)	CEM/ADR5000	Doxorubicin	NM	21.09 µM	Sandjo et al., 2016
98 (E. giganteus)	CCRF-CEM	Doxorubicin	NM	36.78 µM	Sandjo et al., 2016
98 (E. giganteus)	CEM/ADR5000	Doxorubicin	NM	38.57 µM	Sandjo et al., 2016
150 (E. giganteus)	CCRF-CEM	Doxorubicin	NM	9.83 µM	Sandjo et al., 2016
150 (E. giganteus)	CEM/ADR5000	Doxorubicin	NM	6.12 µM	Sandjo et al., 2016
80 (E. macrochaetus)	Breast adenocarcinoma (MCF-7)	Doxorubicin	NM	0.18 µM	Zamzami et al., 2019
80 (E. macrochaetus)	HepG2	Doxorubicin	NM	3.3 µM	Zamzami et al., 2019
80 (E. macrochaetus)	MCF-7	Doxorubicin	NM	2.1 µM	Zamzami et al., 2019
104 (E. macrochaetus)	HepG2	Doxorubicin	NM	2.9 µM	Zamzami et al., 2019
104 (E. macrochaetus)	MCF-7	Doxorubicin	NM	6.9 µM	Zamzami et al., 2019

DMSO, Dimethyl sulfoxide; NM, Not mentioned.

Conclusion

The genus Echinops is well known for its use to treat pain and respiratory manifestations. The traditional claims were justified by different biological evaluations. Findings from in vitro studies indicated that members of the genus have a potential effect against different cancer lines, microbial strains, and insects. They also showed significant in vivo anti-inflammatory, analgesic, and hepatoprotective activities. Some of the extracts and isolated compounds showed promising effects. This includes the anticancer activity of compounds 5 and 14, antioxidant potential of 109, anti-leishmanial and anti-helmentic effects of E. kebericho, and the larvicidal effect of compound 1. The safety and efficacy of secondary metabolites responsible for the in vitro effects of extracts/fractions should further be investigated in in vivo models. The most abundant bioactive secondary metabolites in members of the genus are thiophenes and terpenoids which are also mentioned as responsible for the cytotoxic effect observed. In the current review, it has been observed that the potential uses of the species in the removal of kidney stones and use to solve nerve-related problems have not been scientifically addressed yet. Investigation of the anti-microbial activity of isolated compounds seems to be limited. We believe this review will provide summarized information to the scientific community working on the genus.

Author Contributions

HB developed concept of the review, conducted the literature review, extracted relevant information to the study, and drafted the manuscript. AH guided the literature search and edited the manuscript. Both authors have read and approved the manuscript.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.