The genus Scrophularia: a source of iridoids and terpenoids with a diverse biological activity.

CONTEXT: Scrophularia genus (Scrophulariaceae) includes about 350 species commonly known as figwort. Many species of this genus grow wild in nature and have not been cultivated yet. However, some species are in danger of extinction.
OBJECTIVE: This paper reviews the chemical compounds, biological activities and the ethnopharmacology of some Scrophularia species.
MATERIALS AND METHODS: All information was obtained through reported data on bibliographic database such as Scopus, United States National Agricultural Library, Biological Abstracts, EMBASE, PubMed, MedlinePlus, PubChem and Springer Link (1934-2017). The information in different Pharmacopoeias on this genus was also gathered from 1957 to 2007.
RESULTS: The structures of 204 compounds and their biological activity were presented in the manuscript: glycoside esters, iridoid glycosides and triterpenoids are the most common compounds in this genus. Among them, scropolioside like iridoids have shown potential for anti-inflammatory, hepatoprotective and wound healing activity. Among the less frequently isolated compounds, resin glycosides such as crypthophilic acids have shown potent antiprotozoal and antimicrobial activities.
CONCLUSION: The Scrophularia genus seems to be a rich source of iridoids and terpenoids, but isolation and identification of its alkaloids have been a neglected area of scientific study. The diverse chemical compounds and biological activities of this genus will motivate further investigation on Scrophularia genus as a source of new therapeutic medications.

Introduction

The Scrophulariaceae family consists of 220 genera. Scrophularia genus is one of the large genera of the Scrophulariaceae. Distribution of these genera occurs mainly through mountainous regions (e.g., Scrophularia farinosa Boiss. and Scrophularia amplexicaulis Benth.) to rarely in deserts (e.g., Scrophularia deserti Delile). This genus is represented by 60 species in the flora of Iran and can be used as heart stimulant, circulatory stimulant and diuretic. Other traditional uses of this genus include antipyretic, febrifuge, antibacterial, anti-erythema, anticonstipation, antifurunculosis, ulcerous stomatitis and tonsillitis treatment.

Among these traditional uses of the Scrophularia, anti-inflammatory and anti-infections’ treatment in different types of diseases is common (Viola 1966; Swiatek and Dombrowicz 1975). The therapeutic potential of the Scrophularia has led researchers to focus on the isolation and determination of their bio-active compounds. Some of these species are characterized mainly by glycoside esters or phenylpropanoid glycosides (Calis et al. 1988b; de Santos et al. 2000; Li et al. 2000, 2009), saponins, and iridoids (Çalis et al. 1993a; Yamamoto et al. 1993; Pachaly et al. 1994; Maksudov et al. 1996; Bhandari et al. 1997; Chen et al. 2007; Chebaki et al. 2011). According to some findings, phenylpropanoid glycosides and iridoids are the major part of Scrophularia genus secondary metabolites, which showed apparent therapeutic potential in numerous investigations (Figure 1). Several biological effects of phenylpropanoid such as antioxidants, hepatoprotective, antitumor, anti-inflammatory and other useful effects have been studied over the past few years (Garrido et al. 2004; Korkina et al. 2007). Another main class of secondary metabolites is iridoids compounds which constitute the most chemical and biological diversity in Scrophularia genus. The several reported biological activities of these compounds have led to increased inclination for the isolation of these classes of chemical compounds (Garg et al. 1994; Giner et al. 2000; Kim and Kim 2000; Kim et al. 2002a; Lee et al. 2002; Stevenson et al. 2002; Kim et al. 2003a; Tasdemir et al. 2005; Valiyari et al. 2012). Based on data extracted from different studies, most biological activities of iridoids include anti-inflammatory, anticancer and antiprotozoal (Dinda et al. 2009). This review presents a brief case for the medicinal uses and the phytochemical and pharmacological properties of the Scrophularia genus.

Figure 1.

Comparison between chemical compounds isolated from investigated Scrophularia species. Part (A) shows investigated species percentage against the total species. Part (B) shows the relative percent of the various phytochemical class isolated from investigated Scrophularia species.

Materials and methods

All information regarding the chemical and biological activity of the plants were obtained through reported data from 1934 to 2017 on bibliographic database such as Scopus, United States National Agricultural Library, Biological Abstracts, EMBASE, PubMed, MedlinePlus, PubChem and Springer Link. The search keywords without any language limitation were Scrophularia, biological activity, traditional uses, iridoids, phenylethanoids, alkaloids, resin glycosides, triterpenoid glycoside, essential oils and diterpenoids. The gathered information was then compared with data reported in recent publications (the last 17 years, 2000–2017), and the Pharmacopoeia of the People's Republic of China. Also, data collection on different Pharmacopeias including British Herbal Pharmacopoeia, the Japanese Pharmacopoeia, the French Pharmacopoeia and the Pharmacopoeia of the Royal College of Physicians at Edinburgh (1957–2007) was carried out in order to create a pharmaceutical overview about these species.

Results

Biology and ethnopharmacology

Most Scrophularia species are annual or perennial herbaceous plants, with woody base and rarely suffruticose, and can also be spinose in rare cases. However, a few of this genus are sub-shrubs. Flowers are urceolate or tubulose. The length of corolla ranges from 3 to 20 mm. Lips are equal or unequal, which is one of the important characteristics for distinguishing species. With thyrse inflorescence or in rare cases, racemose with one or two flower in each cyme, mostly have four-angled stems and opposite leaves. Some Scrophularia species are widely used as traditional medicine. Several countries, including China, Korea and Japan, have used these species as traditional therapeutics as anti-inflammatory and anticancer remedies. Roots of S. ningpoensis Hemsl. “Xuan Shen”, S. buergeriana Miquel, Ann. Mus. Bot. Lugduno-Batavi. “Beixuan Shen” and S. nodosa L. (common figwort) have been used as therapeutic remedies in fever, swelling, constipation, pharyngitis, neuritis and laryngitis. In Europe, other species, such as S. aquatica L. (water figwort), are used as laxatives, heart stimulants, circulatory stimulants and diuretics. In ancient Iranian medicine, roots and aerial parts of S. lucida L. “Sinderitis” and S. chryasanthemifolia Bory & Chaub. “Heterasinderitis” are used as heart and circulatory stimulants. Table 1 shows Scrophularia species which are used traditionally as therapeutic remedy.

Table 1.

The traditional use of Scrophularia species mentioned in different pharmacopoeias.

Name	Plant medicinal part	Traditional uses	Pharmacopeia	Other references
S. ningopoensis “Xuan Shen” (Chinese figwort)	Roots	Anti-inflammatory, treatment of cancer and antioxidant	Pharmacopoeia of the People’s Republic of China (Commission 2005)Society of Japanese Pharmacopoeia (Pharmacopoeia 2006)	Marty (1999), Wang et al. (2005) and Zhu (1998)
S. aquatica (water figwort) S. marilandica (late figwort)	Roots and aerial parts	Laxative, heart stimulant, circulatory stimulant and diuretic	The Pharmacopoeia of the Royal College of the Physicians at Edinburgh, Materia Medica (Lewis et al. 1748)French Pharmacopoeia (Ministry of Health 2012)	Marty (1999)
S. buergeriana “Bei xuan shen”	Roots	Treatment of fever, swelling, constipation, pharyngitis, neuritis and laryngitis	Pharmacopoeia of the People’s Republic of China (Commission 2005)	Pinkas et al. (1994) and Wang et al. (2005)
S. dentata “Ye-Xin-Ba” (Tabatian figwort)	Aerial parts	Treatment of smallpox, measles, high-heat plague and poisoning	Pharmacopoeia of the People’s Republic of China (Commission 2005)	Zhang et al. (2014)
S. nodosa (common figwort)	Roots and aerial parts	Treatment of Fever, swelling, constipation, pharyngitis, neuritis and laryngitis	French Pharmacopoeia (Ministry of Health, 2012)British Herbal Pharmacopoeia (Willoughby et al. 1996)	Zhu (1998)
S. lucida L. ”Sinderitis”	Roots and aerial parts	Heart stimulant, circulatory stimulant, diuretic	–	Goodyer and Gunther (1968)
S. chryasanthemifolia L. (Hetera sinderitis)	Roots and aerial parts	Heart stimulant, circulatory stimulant and diuretic	–	Goodyer and Gunther (1968)
S. canina “a ruta salvacce” (Ruta canina)	Roots	Treatment of dermatitis and rheumatoid arthritis	–	Berdini et al. (1991), Guarrera and Lucia (2007) and Pieroni et al. (2004)

Phytochemistry

From the genus Scrophularia, chemical compounds such as flavonoids, phenylethanoids and glycoside esters, phenolic acids, C9 iridoid, glycosides, resin glycosides and fatty acids derivatives, triterpenes, triterpenoid glycosides, alkaloids, diterpenoids and essential oils can be isolated (Tables 2 and 3 and Figure 1). As mentioned above, some of these chemical substances produce bioactivities in various models (Table 4).

Table 4.

Pharmacological activities of some Scrophularia species.

Species	Biological activity	Responsible compound or extract	References
S. amplexicaulis	Antibacterial (aginest S. aureus)	Essential oil	Pasdaran et al. (2012, 2016)
	Antimalarial	Methanolic extract & fractions
	Free radical scavengering activities and general toxicity	Methanolic extract & fractions
S. dentata	Anti-inflammatory activity significantly inhibited CoA-induced splenocyte proliferation	Iridoids & Scrodentoids A–E, scropoliosides	Zhang et al. (2014, 2015b)
S. auriculata	Antibacterial	Phenolic acids	Cuéllar et al. (1998) and Giner et al. (2000)
	Anti-inflammatory	Iridoids and saponins, Hydroalcoholic extract
S. buergeriana	Neuroprotective & Anti-amnestic	Chloroformic & methanolic extracts from roots, harpagoside and 8-O-E-p-methoxycinnamoylharpagide Phenylpropanoids & Phenolic acids	Kim and Kim (2000), Lee et al. (2002), Kim et al. (2003b), Jeong et al. (2008), and Kim et al. (2011, 2012b)
	Hepatoprotective
	Anti-inflammatory
S. canina	Insecticidal activity	Plant, phenolic acids	Germinara et al. (2011)
S. cryptophila	Antiprotozoal and antimycobacterial activities	Crypthophilic acid A, C & buddlejasaponin III, acetylharpagide	Tasdemir et al. (2008)
S. deserti	inhibiting an enzyme or enzymes of Type II fatty acid synthesis (FAS)	Unsaturated fatty acids, ethanolic extract	Ahmed et al. (2003), Stavri et al. (2006) and Bahmani et al. (2013)
	Anti-inflammatory	Scropolioside-D2 & harpagoside B
	Antidiabetic	Scropolioside-D2 & harpagoside B
S. frutescens	Antibacterial	Aerial part aqueous extract, phenolic acids	Fernandez et al. (1996, 1998) and Garcia et al. (1998)
	Anti-inflammatory	Phenolic acids, Iridoids
	Cytostatic activity	Phenolic acids
S. grossheimi	Hepatoprotective	1,6-di-O-caffeoyl-β-D-glucopyranose & flavonoids	Akhmadov et al. (1969), Akhmedov and Litvinenko (1969) and Galindez et al. (2001)
S. koelzii	Hepatoprotective & immunostimulant	Scropolioside-A, koelzioside, harpagoside, 6-O-(3″-O-p-Methoxy-cinnamoyl)-α-L-rhmanopyranosyl catalpol, chloroform fraction of the aerial parts	Garg et al. (1994)
S. lepidota	Anti-protozoal & Antiplasmodial	Ningpogenin, sinuatol	Tasdemir et al. (2005)
S. ningpoensis	Cardioprotective	Trans-caffeic acid methyl ester & 4-methylcatechol, 6″-O-caffeoylharpagide, 6″-O-(p-coumaroyl) harpagide, harpagoside and Phenylethanoide glycosides	Chen et al. (2008) and Zhu et al. (2013)
	Anti-inflammatory	Ningpogenin, ningpogoside A and ningpogoside B and hydrophilic extract	Qian et al. (1991)
	Antibacterial	Scrokoelziside A and ethanolic leave extract	Li et al. (2009)
S. nodosa	Wound healing activity	Scopolioside A, scrophuloside A4 and scrovalentinoside	Stevenson et al. (2002)
S. oxysepala	Insecticidal activity	Essential oil, methanolic fractions	Pasdaran et al. (2013, 2017) and
	Apoptosis	Dichloromethane and methanol extracts	Valiyari et al. (2012) and Orangi et al. (2013)
	CytotoxicFree radical scavenging	Methanolic fractions, scropolioside D, harpagoside B &2-(4-chlorobenzyl amino) ethanol	Pasdaran et al. (2017)
S. striata	Wound healing and Anti-inflammatory	Ethanolic extract, ethyl acetate extract	Hajiaghaee et al. (2007) and Azadmehr et al. (2009)
	Antibacterial	Ethanolic extract	Benito et al. (1998) and Bahrami and Ali (2010)
	Antioxidant	Ethanolic extract	Díaz et al. (2004)
S. scorodonia	Anti-inflammatory	Angoroside A, angoroside C, angoroside D, acteoside, isoacteoside, Buddlejasaponin I& Saikosapoinin I, II
	Antiviral	Scorodioside, Buddlejasaponin IV	Bermejo et al. (2002)
S. takesimensis	Strong aldose reductase (AR) inhibitory activity	Acacetin	Kim et al. (2012a)

Flavonoids and flavonoid glycosides

Although flavonoids are the major compounds in plants, and consist of the most dominant compounds in many of the plants family, Scrophularia genus is an exceptional case regarding the existence of flavonoids. Very negligible flavonoids compounds, such as quercetin (1), isorhamnetin-3-O-rutinoside (2), nepitrin (3) and haemoplantaginin (4) have been isolated from S. striata Boiss. O-methylated flavone and acacetin (5) have been isolated from endangered Korean species of S. takesimensis Nakai (Li et al. 2009; Monsef-Esfahani et al. 2010; Kim et al. 2012a). Other flavonoids such as scrophulein (6) and homoplantaginin (9) have been isolated from S. grossheimii Schischk. and S. ningpoensis, respectively (Akhmedov and Litvinenko 1969). An investigation on the bioactive compounds of S. ilwensis K.Koch. resulted in the isolation of quercetin-3-O-rutinoside (7) and kaempferol-3-O-rutinoside (8) from polar extract (Çalis et al. 1993a). Many bioactivities such as antioxidant, antibacterial, anti-inflammatory and antinociceptive activities have been reported of these compounds or flavonoid-rich extracts (Mahboubi et al. 2013; Nasri et al. 2013) (Table 2 and Figure 2).

Table 2.

Compounds isolated from the genus Scrophularia (the structure of the compounds illustrated in text).

Plant name	Compound	No.	Ref.
S. auriculata	Scrovalentinoside	130	(Giner, et al. 2000, Giner et al. 1998)
	Verbascosaponin A	188
	Scropolioside A	134
	Ilwensisaponin A	177
	Verbascoside	48
S.amplexicaulis	Scropolioside D	131	(Pasdaran, et al. 2016)
	Scrophuloside B4	117
	Salidroside	75
	Verbascoside	48
	Eugenol	200
	Eugenol acetate	203
	1-Octen-3-ol	204
S. buergeriana	Buergerinin F	78	(Kim and Kim 2000, Lin, et al. 2000, Kim, et al. 2002b, Kim, et al. 2003b, Jeong et al. 2008, Yan and Xie 2011)
	Buergerinin G	79
	Buergerinin E	80
	Ningpogenin	86
	Buergerinin D	82
	Buergerinin C	84
	Buergerinin B	85
	8-O-E-p-methoxycinnamoyl harpagide	102
	8-O-Z-p-methoxycinnamoyl harpagide	103
	6′-O-E-p-methoxycinnamoyl harpagide	104
	6′-O-Z-p-methoxycinnamoyl harpagide	105
	Trans-cinnamic acid	11
	(E)-p-methoxycinnamic acid	12
	(E)-p-methoxycinnamic acid methyl ester	40
	(E)-o-methoxycinnamic acid	10
	(E)-p-coumaric acid	16
	(E)-caffeic acid	41
	(E)-ferulic acid	42
	Homovanilline alcohol	36
	Buergeriside A1	67
	Buergeriside B1	66
	Buergeriside B2	65
	Buergeriside C1	64
	Harpagoside	113
S. canina	7,8-Didehydro-6b,10-dihydroxy-11-noriridomyrmecin	83	(Berdini, et al. 1991, Venditti et al. 2015)
	8-epi-Loganic acid	138
	Verbascoside	48
	(E)-Phytol	174
S. cryptophila	Crypthophilic acid A	171	(Tasdemir, et al. 2008)
	Crypthophilic acid B	172
	Crypthophilic acid C	173
	Buddlejasaponin III	182
	8-O-Acetyl harpagide	100
	Harpagide	114
S. dentata	Scrodentoside A	139	(Zhang, et al. 2015b, Zhang, et al. 2014)
	Scrodentoside B	140
	Scrodentoside C	141
	Scrodentoside D	142
	Scrodentoside E	143
	Scrodentoside F	154
	Scrodentoside G	155
	Scrodentoside H	156
	Scropolioside G	157
	Scropolioside H	158
	Saccatoside	159
	6-O-Methyl catalpol	94
	Catalpol	93
	6′-O-E-p-feruloyl harpagide	107
	Scropolioside D	131
	Cis-harpagoside	144
	Harpagoside	113
	Laterioside	101
	Scorodioside	145
	6-O-α-L-(4″-O-trans-cinnamoyl)-rhamnopyranosylcatalpol	146
	6-O-α-L-(4″-O-trans-p-coumaroyl)-rhamnopyranosylcatalpol (Scropolioside F)	147
	lagotisoside D	148
	8-O-Acetyl harpagide	100
	7-Deoxygardoside	149
	Ajugoside	89
	8-epi-deoxyloganic acid	150
	6′-O-p-Coumaroyl harpagide	151
S. dentata (continued)	10-Deoxygeniposidic acid	152
	Geniposidic acid	153
	Ajugol	90
	Harpagide	114
	Scrodentoid A	195
	Scrodentoid B	196
	Scrodentoid C	197
	Scrodentoid D	198
	Scrodentoid E	199
	Lipedosides A-I	51
	Osmanthuside B	52
	Martynoside	53
	Diacetylmartynoside	54
	Verbascoside	48
	Isoverbascoside	49
	3-O-trans-Feruloylrhamnopyranose	76
	2-O-trans-Feruloylrhamnopyranose	77
S. deserti	3-(R)-1-Octan-3-yl-3-O-β-D-glucopyranoside	169	(Ahmed, et al. 2003, Stavri, et al. 2006)
	3(ζ)-Hydroxy-octadeca-4(E), 6(Z)-dienoic acid	170
	6-O-α-L-rhamnopyranosylcatalpol	97
	Buddlejoside A8	98
	Harpagoside B	99
	8-O-Acetyl harpagide	100
	Koelzioside	132
	Scropolioside D	131
	Scropolioside D2	133
	Scropolioside B	135
	Scrospioside A	136
	Laterioside	101
S. frutescens	(Z)-p-Coumaric acid	13	(Fernandez, et al. 1998, Garcia, et al. 1998)
	(Z)-Caffeic acid	14
	(Z)-Isoferulic acid	15
	(Z)-p-Methoxycinnamic acid	16
	(E)-p-coumaric acid	17
	(E) 3, 4-Dimethoxy cinnamic acid	18
	(Z) Ferulic acid	19
	(Z)-Methoxycinnamic acid methyl ester	20
	Syringic acid	21
	Gentisic acid	22
	Protocatechuic acid	23
	Isovanillic acid	24
	Catalpinic acid	25
	Vanillic acid	26
S. ilwensis	Ilwensisaponin A (Mimengoside A)	177	(Çalis, et al. 1993a, Çalis, et al. 1993b)
	Ilwensisaponin B	178
	Ilwensisaponin C	179
	Ilwensisaponin D	180
	Karsoside	116
	Scropolioside D	131
	Aucubin	109
	Harpagide	114
	8-O-Acetylharpagide	100
	Ajugol	90
	Angoroside C	46
	Quercetin-3-O-rutinoside	7
	Kaempferol-3-O-rutinoside	8
S. kakudensis	Songarosaponin A	189	(Yamamoto A 1993)
	Saksisaponin A	181
	Buddlejasaponin I	182
	Buddlejasaponin II	183
	Buddlejasaponin III	184
	Scrophulasaponin II	185
	Scrophulasaponin III	186
	Scrophulasaponin IV	187
S. koelzii	Koelzioside	132	(Bhandri et al. 1992, Garg, et al. 1994, Bhandari, et al. 1996, Bhandari, et al. 1997)
	Scropolioside A	134
	Scropolioside B	135
	6-O-(3”-O-p-Methoxy-cinnamoyl)-α-L-rhmanopyranosylcatalpol	161
	Scrokoelziside A	175
	Scrokoelziside B	176
S. lepidota	Ajugoside	89	(Tasdemir, et al. 2005)
	Ajugol	90
	Sinuatol	91
	6-O-β-D-Xylopyranosylaucubin	92
S. lepidota (continued)	Catalpol	93
	6-O-Methyl catalpol	94
	3,4-Dihydro-methyl catalpol	95
	1-Dehydroxy-3,4-dihydro aucubigenin	96
	Scrolepidoside	137
	Aucubin	109
	Angoroside C	46
	Ningpogenin	86
S. ningpoensis	Haemoplantaginin	4
	8-Hydroxycoumarin	38
	6-Hydroxyindan-1-one	39
	4-Methylcatechol	35
	trans-Cinnamic acid	10
	3-Methylphenyl-O-β-xylopyranosyl-(1→6)-O-β-glucopyranoside	70	(Kajimoto, et al. 1989, Qian, et al. 1991, Qian et al. 1992, Li, et al. 2000, Nguyen, et al. 2005, Chen, et al. 2007, Chen et al. 2008, Li, et al. 2009, Niu, et al. 2009, Zhang et al. 2012, Zhu et al. 2013, Zhang, et al. 2015a)
	4-Hydroxybenzaldehyde	27
	3′-Hydroxyacetophenone	28
	Scrokoelziside A	175
	Buergeriside A1	67
	Sibirioside A	68
	Cistanoside F	69
	Cistanoide D	43
	6′-O-Caffeoyl harpagide	106
	6′-O-E-p-Feruloyl harpagide	107
	6″-O-β-Glucopyranosylharpagoside	108
	8-O-Acetyl harpagide	100
	β-Sitosterol	192
	β-Sitosterol glucoside	193
	Angoroside C	46
	Nepitrin	3
	Buergerinin A	81
	Aucubin	109
	Ningpogenin	86
	Ningpogoside A	87
	Ningpogoside B	88
	4′-hydroxyacetophenone	30
	3′,5′-Dimethoxy-4′-hydroxyacetophenone	31
	3′-Methoxy-4′-hydroxyacetophenone	32
	(Z)-4-Hydroxycinnamic acid methyl ester	34
	(E)-p-Methoxycinnamic acid	11
	trans-Caffeic acid methyl ester	33
	Scropolioside B	135
	Scrophularianine A	164
	Scrophularianine B	165
	Scrophularianine C	166
	2,6-Dimethoxy-4-methoxymethylphenol	37
	Homovanillic alcohol	36
	Scrophuloside B4	117
	Scrophuloside A4	118
	6-O-Feruloylb-fructofuranosyl-(2→1)-O-α-glucopyranosyl-(6→1)-O-α-glucopyranoside	74
	Scrokoelziside B	176
	6-O-cinnamoyl b-fructofuranosyl-(2→1)-O-α-glucopyranosyl-(6→1)-O-α-glucopyranoside	73
	Ningposide A	61
	Ningposide B	62
	Homoplantaginin	9
	Eurostoside	115
	2-(3-Hydroxy-4-methoxyphenyl)ethyl-O-α-arabinopyranosyl-(1→6)-O-α-rhamnopyranosyl-(1→3)-O-β-Glucopyranoside	72
	PhenylO-β-xylopyranosyl-(1→6)-O-β-glucopyranoside	71
	Ningpoensines B/C	163
	Vanillin	29
	6-O-Methyl catalpol	94
	8- O-Feruloylharpagide	110
	8-O-(2-Hydroxycinnamoyl) harpagide	111
	6-O-α-D-Galactopyranosylharpagoside	112
	Harpagoside	113
	Harpagide	114
	Ningposide C	60
	Ningposide D	63
	Buergeriside C1	64
	Buergeriside B2	65
	Buergeriside B1	66
	Ningpoensine A	162
S. oxysepala	Scrokoelziside A	175	(Orangi et al. 2013, Orangi et al. 2016, Valiyari et al. 2012)
	Scrokoelziside B	176
	Verbascosaponin	177
	Harpagoside B	99
	Scropolioside D	131
	2-(4-chlorobenzyl amino) ethanol	167
	Eugenol	200
	Dehydroeugenol	201
	Methyl benzyl alcohol	202
	1-Octen-3-ol	204
S. nodosa	Jionoside D	50	(Miyase and Mimatsu 1999, Stevenson et al. 2002, Swiatek 1972)
	Scrovalentinoside	130
	Angoroside C	46
	Scrophuloside A2	120
	Scrophuloside A4	118
	Scrophuloside A5	121
	Scrophuloside A6	122
	Scrophuloside A7	123
	Scrophuloside A8	124
	Scrophuloside A1	119
	Buddlejoside A5	126
	Buddlejoside A3	127
	Buddlejoside A4	129
	Pulverulentoside II	125
	Scrophuloside A3	160
	Verbascoside A	128
	Scrophuloside B1	57
	Scrophuloside B2	58
	Purpureaside C	56
	Verbascoside	48
	Angoroside A	44
	cis-Verbascoside	59
S. scopolii	Angoroside A	44	(Calis et al. 1988a, Calis, et al. 1988b)
	Angoroside B	45
	Angoroside C	46
	Angoroside D	47
	Verbascoside	48
	Isoverbascoside	49
	ScropoliosideA	134
	ScropoliosideB	135
S. striata	Quercetin	1	(Monsef-Esfahani, et al. 2010)
	trans-cinnamic acid	11
	Isorhamnetin-3-O-rutinoside
	Nepitrin	3
	Verbascoside	48
	1-Octen-3-ol	204
S. scorodonia	8-O-Acetyl harpagide	100	(Emam et al. 1997, de Santos, et al. 2000, Bermejo, et al. 2002, Díaz, et al. 2004)
	Scrolepidoside	137
	Saikosapoinin I (Buddlejasaponin IV)	190
	Saikosapoinin II (Sandrosaponin I)	191
	Isoangoroside C	55
	Buddlejasaponin I	182
S. takesimensis	Isorhamnetin-3-O-rutinoside	2	(Kim, et al. 2012a)
	Nepitrin	3
	β-Sitosterol	192
	α-Spinasterol 3-O-β-D-glucopyranoside	194
	5-Hydroxypyrrolidin-2-one	168
	trans-Cinnamic acid	11
	(E)-p-Methoxycinnamic acid	12
	(E)-o-Methoxycinnamic acid	10
	Acacetin	5
S. trifoliata	Catalpol	93	(Ramunno et al. 2006)
	Aucubin	109

Figure 2.

Isolated flavonoids and flavonoid glycosides from Scrophularia genus.

Phenolic acids

Thirty-two (10–42) phenolic acid compounds with various substitutions were isolated from S. frutescens L. var frutescens, S. canina L., S. takesimensis and S. grosheimii (Akhmadov and Kharchenko 1969; Swiatek 1972; Swiatek and Dombrowicz 1975; Fernandez et al. 1996, 1998; Garcia et al. 1998).

E-p-Methoxycinnamic acid and E-isoferulic acid isolated from S. buregeriana significantly improved memory deficit, induced by scopolamine in mice (Kim et al. 2003a). E-p-Methoxycinnamic acid (Table 2 and Figure 3) also has a protective role against NMDA and glutamate-induced neurotoxicity (Kim et al. 2002b). In another experiment, m- and p-methoxycinnamic acid and ferulic acid showed hepatoprotective activities against carbon tetrachloride (CCl4) in animal tests (Lee et al. 2002a; Kim et al. 2011).

Figure 3.

Phenolic acids compounds reported from Scrophularia plants.

Phenylethanoid glycosides

Phenylethanoid as one of the main phytochemical compounds plays specific role in biological activity of these plants. Many biological activities such as antimicrobial, anti-inflammatory, antitumor, heart function improvement and neuroprotective activities are attributed to these compounds (Zhu 1998; Koo et al. 2005; Deyama et al. 2006; Georgiev et al. 2011). Previous studies revealed that one of the main constituents of Scrophularia plants is phenylethanoid glycosides, and many of the therapeutic potentials can be attributed to them (Zhang and Li 2011).

Sixteen phenylethanoid glycosides compounds (43–59, Figure 4) have been isolated from Scrophularia (Calis et al. 1988b; de Santos et al. 2000; Li et al. 2000; Lee et al. 2002a). Some of these compounds showed cytotoxicity upon investigations, for example, angoroside compounds which are isolated from S. scopolii Hoppe ex Pers. Among these isolated compounds, angoroside A (39) showed most cytotoxic activity compared with angoroside B (40) and angoroside C (41). The relationship between compound structures and their activities were elucidated.

Figure 4.

Phenylethanoid glycosides isolated from Scrophularia plants.

The methoxy group on carbon (3) position in angoroside B and (3′) in angoroside C reduced cytotoxic activity compared with angoroside A (Saracoglu et al. 1997). In other research on anti-inflammatory activities of phenylpropanoids, acteoside (43), angoroside A (39) and angoroside C (41) have shown significant effects in TXB2-release assay. In addition, angoroside A (39), angoroside D (42), acteoside (43) and isoacteoside (44) significantly inhibited LPS-induced PGE2, NO and TNF-α (Dı´az et al. 2004). An investigation on S. dentata showed that phenylethanoid glycosides such as acteoside (43), isoacteoside (44), lipedosidesA-I (51), osmanthuside B (52), martynoside (53) and diacetylmartynoside (54) were isolated from this species. Phenylethanoid glycosides isolated from Scrophularia genus are listed in Table 2.

Glycoside esters

Several glycoside esters (60–77, Figure 5) with various substitutions have been isolated from S. ningpoensis and S. buregeriana (Chen et al. 2007) phenylpropanoid esters of rhamnose, buergerisides A1, B1, B2 and C1 isolated from S. buregeriana, exhibited significant neuroprotective effects against glutamate-induced neurotoxicity (Kim and Kim 2000). Another isolated glycoside ester, ningposide D (63) isolated from S. ningpoensis, demonstrated a mild cytotoxic effect on human cancer cell line K662 on investigation (Nguyen et al. 2005). Isolated glycoside esters from various Scrophularia plants are listed in Table 2.

Figure 5.

Chemical structures of Scrophularia glycoside esters.

C9 iridoid

Several C9 iridoids (78–88) have been isolated from S. buregeriana and S. ningpoensis. These compounds are in glycosides and non-glycosides forms (Lin et al. 2000, 2006; Niu et al. 2009). C9 iridoids isolated from these plants are listed in Table 2 and Figure 6.

Figure 6.

Chemical structures of Scrophularia C9 iridioides.

Iridoid glycosides

Using different chromatography methods such as reverse phase column chromatography (RP-HPLC), size exclusion chromatography and thin layer chromatography yielded 72 iridoid glycosides from various species of Scrophularia (Table 2 and Figure 7) (Sticher et al. 1980; Calis et al. 1988b; Kajimoto et al. 1989; Berdini et al. 1991; Qian et al. 1991; Pachaly et al. 1994; Maksudov et al. 1996; Bermejo et al. 2002; Niu et al. 2009; Chebaki et al. 2011). Many of these compounds demonstrated various pharmacological activities such as hepatoprotective and anti-inflammatory activities (Table 4). Among the chemical compounds isolated from S. koelzii Pennell. such as harpagoside (113), koelzioside (132) and scropolioside A (134), scropolioside A demonstrated maximum hepatoprotective activity against thioacetamide-induced hepatotoxicity in animal model (Garg et al. 1994). Research on S. deserti led to the isolation of scropolioside D2 (133) and harpagoside B (99), which have significant antidiabetic and anti-inflammatory activities (Ahmed et al. 2003).

Chemical structures of isolated Scrophularia iridoid glycosides.

Among the various bioactivities observed of these compounds, anti-inflammatory effect is the most investigated. Zhu et al. (2015), in working on anti-inflammatory activity of isolated iridoid glycosides from S. dentata Royle ex Benth. and comparison between their potentials, reported their anti-inflammatory activities against LPS-induced NF-κB activity, cytokines mRNA expression, IL-1β secretion and cyclooxygenase-2 activity depending on whether the 6-O-substituted cinnamyl moiety was linked to C″ 2-OH, C″ 3-OH or C″ 4-OH, and on the number of moieties linked, which is closely related to the enhancement of anti-inflammatory activity (Pieroni et al. 2004). Structural diversity of iridoid glycosides in this genus can be categorized into three classes including (a) moieties which exist on cyclopentane ring, (b) moieties which exist on different position of glucose attached in [c] pyran ring and (c) moieties which exist on different position of rhamnose that are attached in C6 cyclopentane ring. Among these structural classes, diversity of iridoid glycosides with moieties in rhamnose attached in C6 cyclopentane ring position is more than other classes. Subsequently, structures with moieties are placed in different positions of cyclopentane ring, and finally structures with moieties in different positions of glucose are attached in [c] pyran ring. Table 2 shows various isolated Scrophularia iridoid glycosides.

Alkaloids

Several pyridine alkaloids are isolated from Scrophularia (Table 2 and Figure 8), three novel zwitterionic alkaloids-ningpoensine A (162) and ningpoensines B/C (163) (pair of epimers) were isolated from the root of S. ningpoensis (Zhang et al. 2015a). Ningpoensines B/C can promote wound closure in human embryonic keratinocytes in researches (Maksudov et al. 1996). In another research, three new monoterpene pyridine alkaloids, scrophularianines A–C (164–166) with cyclopenta [c] pyridine skeleton, were reported from S. ningpoensis. Other unusual new halogenated alkaloids, [2-(4-chlorobenzyl amino) ethanol] (167) with cytotoxic effects, were also isolated from S. oxysepala Boiss. (Orangi et al. 2016). Another cyclic alkaloid is 5-hydroxypyrrolidin-2-one (168) isolated from Korean species, S. takesimensis (Kim et al. 2012a).

Figure 8.

Alkaloids, resin glycosides and fatty acids derivatives of Scrophularia plants.

Resin glycosides and fatty acids derivatives

Six resin glycosides and fatty acids derivatives were isolated from Scrophularia (Figure 8) (Stavri et al. 2006; Çalis et al. 2007). Among these compounds, crypthophilic acids A–C (171–173) isolated from S. cryptophila Boiss. were examined for antiprotozoal and antimycobacterial activities. Crypthophilic acids A and C showed activity against Trypanosoma brucei rhodesiense and Leishmania donovani (Kajimoto et al. 1989). In another research on traditional remedy, where S. deserti was used as an antipyretic in Middle East countries, two unsaturated fatty acid compounds including 3(ζ)-hydroxy-octadeca-4(E), 6(Z)-dienoic acid (170) and 3R-1-octan-3-yl-3-O-β-d-glucopyranoside (169) were isolated. Among these compounds, 6(Z)-dienoic acid showed antibacterial activity against both Staphylococcus aureus and mycobacteria (Table 2; Ahmed et al. 2003).

Triterpenoid glycosides and sterols

Oleanane-type triterpenoid glycoside is a major triterpenoid in Scrophularia species (Çalis et al. 1993b; Bhandari et al. 1996, 1997). Verbascosaponin A (188) as an oleanane-type triterpenoid was isolated from S. auriculata ssp. pseudoauriculata (Sennen) O. de Bolòs & J. Vigo which showed an excellent anti-inflammatory activity in the acute 12-O-tetradecanoylphorbol 13-acetate (TPA) model (Giner et al. 2000). In addition, three saikosaponin homologs, scrophulasaponins II–IV were isolated from S. kakudensis Franch. (Figure 9) (Yamamoto et al. 1993). Other isolated triterpenoid glycoside and their origin species are listed in Table 2.

Chemical structures of triterpenoid glycosides and sterols of Scrophularia species.

Diterpenoids

Five new 19(4→3)-abeo-abietane diterpenoids, scrodentoids A–E (195–199) were isolated from S. dentata, which is a famous traditional remedy for the treatment of smallpox, measles, high-heat plague and poisoning (Zhang et al. 2015a). These compounds are isolated from low-polar extract of S. dentata by column chromatography and reversed-phase HPLC techniques. The anti-inflammatory, immunosuppressive, antifertility, anticystogenesis and anticancer activities of 19(4→3)-abeo-abietane diterpenoids have been previously reported (Zhang et al. 2015b). Scrodentoids A–E were investigated for immunosuppressive effect and cytotoxic effects, especially against B16 and MCF-7 cells line. According to this investigation, scrodentoids A (195) and D (198) showed the most potential in this biological test (Table 2 and Figure 10).

Figure 10.

Diterpenoids and some of the essential oil major compositions of Scrophularia species.

Essential oils

The essential oils of a few Scrophularia species have been investigated until now. The essential oil of S. oxysepala, an endemic plant of western and central regions of Iran, was characterized by the presence of high percent of eugenol (200), dehydroeugenol (201) and methyl benzyl alcohol (202) as phenolic compounds. In addition, a high amount of eugenol (200) and eugenol acetate (203) have been reported from the essential oil of S. amplexicaulis Benth, another endemic plant of Iran, which showed antimicrobial activity against S. aureus (Pasdaran et al. 2012, 2013). According to research on S. oxysepala, S. amplexicaulis, S. striata and S. frigida Boiss, it was indicated that probably, 1-octen-3-ol (204) is a chemical compound marker in Scrophularia species (Table 3 and Figure 10) (Miyazawa and Okuno 2003; Amiri et al. 2011).

Table 3.

Some of the Scrophularia species essential oil major compounds.

Species	Major compounds
S. oxysepala	Methyl benzaldehyde, methyl benzyl alcohol, 1-octen-3-ol, eugenol and phytol
S. amplexcaulis	Eugenol, 1-cten-3-ol, anethole, caryophyllene oxide and eugenol acetate
S. striata	1-octen-3-ol, banzyl banzoat, benzaldehyde, linalool and phytol
S. frigida	Oxygenated monoterpenes, L-linalool, geraniol, α-terpineol, and 1-octen-3-ol

Biological activity

Anti-inflammatory

Scrophularia denata “Ye-Xin-Ba” a traditional Chinese herbal medicine is native to Tabatian region. The iridoids isolated from this plant showed anti-inflammatory effects in NF-κB-mediated reporter gene luciferase assay. Scropolioside B (135) and scropolioside D (131) had significant inhibitory effect against nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation with an IC50 value of 43.7 and 1.02 μM, respectively (Zhang et al. 2014). Zhu et al. (2015) investigated the anti-inflammatory potential of various scropoliosides isolated from S. denata against LPS-induced NF-κB activity, cytokines mRNA expression, interleukin 1β (IL-1β) secretion and cyclooxygenase-2 activity. Scropoliosides B (135), F (147) and G (157) and 6-O-methylcatapol (94) significantly reduced IL-1β maturation, and secretion in the cultured medium of the THP-1 cells. Other scropoliosides A (134), B (135) and D (131) also inhibited IL-1β mRNA expression. Scrodentosides A and B inhibited cyclooxygenase 2 (COX-2) activity (Zhu et al. 2015). In working on S. auriculata ssp. pseudoauriculata, compounds such as verbascosaponin A (188) and verbascosaponin (177) were isolated, verbascosaponin inhibited the carrageenan paw oedema and ear oedema induced by 12-O-tetradecanoylphorbol 13-acetate (TPA test). Results showed that verbascosaponin A (188) and verbascosaponin (177) with an ID50 value of 0.32 and 0.18 µmol/ear, respectively, in comparison with indomethacin 0.35 µmol/ear have an excellent anti-inflammatory effects (Giner et al. 2000). The ethanol–water extracts of aerial parts of S. auriculata L. and roots of S. buergeriana display significant inhibition against oxazolone-induced contact-delayed hypersensitivity mouse ear oedema (DTH) and release of histamine, tumour necrosis factor-α (TNF-α), IL-4 in inflammation model, respectively (Giner et al. 2000; Kim et al. 2012b). During the investigation of S. deserti anti-inflammatory potential, five iridoid glycosides, including scropolioside D2 (133), harpagoside B (99), scropolioside D (131), koelzioside (132) and 8-O-acetylharpagide (100) were isolated and characterized (Zhu et al. 2015). Scropolioside D (131) and harpagoside B (99) isolated from S. deserti possess significant anti-inflammatory activity in carrageenan paw oedema (Ahmed et al. 2003). Fernandez et al. (1996, 1998) reported the anti-inflammatory activity of different extracts from S. frutescens L. In further screening for finding active compounds, several phenolic acids were remarkably active in the TPA test, among these isolated phenolic acid compounds, ferulic (19), gentisic (22), protocatechuic (23) and syringic (21) acids significantly inhibited oedema (protocatechuic with 71.59% inhibition; syringic with 74.43% inhibition and ferulic with 71.02% inhibition) (Fernandez et al. 1998). The roots of S. ningpoensis “Xuan Shen” as Chinese traditional medicine which is used against swelling, laryngitis and neuritis, consist of several iridoids and phenylethanoids, hydrophilic extract of this plant showed significant inhibitory effect (ED50 20 mg/kg) on this animal model (Qian et al. 1991). Scrophularia striata, an Irano-Turanian region endemic plant, showed that in several anti-inflammatory models, ethyl acetate extract of S. striata inhibits IL-1β, TNF-α and prostaglandin E2 (PGE2) secretion in mouse peritoneal macrophages induced by lipopolysaccharide (LPS) (Figures 11 and 12; Azadmehr et al. 2013).

Studies on biological actives of Scrophularia spp. phytochemicals.

The ratio of biological activities reported for Scrophularia spp.

Antimicrobial and antiprotozoal

Essential oil of Iranian endemic plant, S. amplexicaulis, showed antibacterial activity against S. aureus in the well diffusion method. The essential oil of this plant is characterized by a high content of eugenol (53.8%) and eugenol acetate (24.5%), and the antibacterial activity of these compounds has been identified previously (Didry et al. 1994; Pasdaran, et al. 2012). In another research on methanolic extract and fractions of S. amplexicaulis, 80% and 60% (IC50 0.827, 0.431 mg/mL) methanol in water of solid-phase extraction (SFE) showed significant activity in haeme biocrystallization assay for potential antimalarial property (Pasdaran et al. 2016). Tasdemir et al. (2005, 2008) investigated the antiprotozoal and antimycobacterial activities of the chemical compounds of S. cryptophila, tryptophan and buddlejasaponin III (184) which showed growth-inhibitory effect against Trypanosoma brucei (IC50 4.1 and 9.7 mg/mL). Harpagide (114) and crypthophilic acid C (173) showed the best leishmanicidal activity (IC50 2.0 and 5.8 mg/mL) in comparison with other isolated compounds. In antimalarial activity against Plasmodium falciparum, crypthophilic acid C (173), tryptophan and buddlejasaponin III (184) showed antimalarial activity with IC50 values of 4.2, 16.6 and 22.4 mg/mL, respectively (Tasdemir et al. 2008). Investigation on the ethanol extract of S. deserti showed that plant have antibacterial potential against Brucellla melitensis, in other studies related to this plant, three isolated compounds including 3(ζ)-hydroxy-octadeca-4(E), 6(Z)-dienoic acid (170), ajugoside (89) and scropolioside B (135) exhibited moderate antibacterial activity against multidrug and methicillin-resistant S. aureus (MRSA) as well as mycobacteria with minimum inhibitory concentration (MIC) values, ranging from 32 to 128 µg/mL (Stavri et al. 2006; Bahmani et al. 2013). Fernandez et al. investigated the antibacterial and active fraction of S. frutescens and S. sambucifolia L. on several micro-organisms such as Bacillus cereus, Bacillus megaterium, Bacillus subtilis, S. aureus, Escherichia coli, Serratia marcescens, Salmonella typhimurium and Moraxella lacunata. Results of this investigation indicated that the phenolic fractions of both species showed more activity against Gram-positive bacteria, specifically against Bacillus sp. (Fernandez et al. 1996). The 70% ethanol extracts of leaves and scrokoelziside A (175) which were isolated from S. ningpoensis “Xuan Shen” showed anti-bacterial activity against beta-haemolytic streptococci (Figures 11 and 12; Li et al. 2009).

Hepatoprotective and neuroprotective

E-p-Methoxycinnamic acid (12) isolated from S. buergeriana showed anti-amnesic activity and protective effect on cultured neuronal cells against neurotoxicity induced by glutamate (Kim et al. 2003a). Future investigations for finding other active compounds of S. buergeriana in neuroprotection led to the isolation of 10 phenylpropanoid esters from roots of this plant, although all isolated phenylpropanoid esters exerted significant protective effects against glutamate-induced neurodegeneration, but buergeriside A1 (67), buergeriside B1(66) and (E)-p-methoxycinnamic acid (12) exhibited better protection (Kim and Kim 2000). In the continuous isolation of other neuroprotective compounds, 8-O-E-p-methoxycinnamoyl harpagide (102) and harpagide (114), 8-O-Z- p-methoxycinnamoyl harpagide (103), 6′-O-E-p-methoxycinnamoy lharpagide (104), 6′-O-Z-p-methoxycinnamoyl harpagide (105) E-harpagoside and Z-harpagoside were isolated from these plants and tested for the reduction of glutamate-induced neurotoxicity in rat. According to the result, these compounds demonstrated protective effect on cultured neurons against glutamate-induced oxidative stress (Kim and Kim 2000; Kim et al. 2002a, 2003b). Isolated phenylpropanoids from roots of S. buergeriana exhibit hepatoprotective effect in CCl4-induced toxicity (Kim et al. 2002a). Chloroformic fraction of the alcoholic extract of the aerial parts of S. koelzii showed hepatoprotective activity. Further investigation led to the isolation of several iridoid glycosides, and among these compounds, scropolioside A showed maximum hepatoprotective activity in thioacetamide hepatotoxicity model (Figures 11 and 12; Garg et al. 1994).

Conclusion

Recently, the amount of research on metabolites, pharmacological activities and traditional uses of the various Scrophularia species has increased significantly. According to reviewed literatures, several reasons could contribute to the screening of this genus which include (1) some of the species have been used as a traditional or local therapeutic remedy especially in Asia and Europe for long time, and the effectiveness and safety of these species have been established. Therefore, such sources have generated much interest and new field for easier search of potential compounds. (2) Iridoid glycosides, phenolic acids and triterpenoid glycosides have been identified as the three main chemical compositions of Scrophularia. Among them, scropoliosides like iridoid structures have shown potential for anti-inflammatory, hepatoprotective and wound healing activity effects. Among the less frequently isolated compounds, resin glycosides such as crypthophilic acids have shown good properties in antiprotozoal and antibacterial assays. Therefore, chemical compounds of this genus will motivate further investigation on Scrophularia, and have great potential as sources of finding new therapeutic medications. (3) Only 17 of the approx. 350 species have been studied in some detail. Among the isolated metabolites from Scrophularia spp., only a few of them has been investigated for their biological activities. Many of the conducted researches on isolation or biological screening have been conducted on iridoids and phenylethanoids while other classes of phytochemicals such as alkaloids, diterpenoids and flavonoids have been less considered by researchers.

On one hand, most of the studies on the isolated compounds have been carried and in vitro/in vivo and we could not find any clinical trials on biological activities of Scrophularia. Thus, pharmacokinetic and metabolism of these metabolites are unclear in human body. On the other hand, the exact mechanism of the active isolated molecules is still unknown. Considering these issues, there is huge gap between the current situation and the final goal which is developing approved drug from the isolated molecules or even developing supplements from the Scrophularia spp. extracts. Conducting ADME (absorption, distribution, metabolism and excretion) studies on the isolated bioactive compound of the genus seems to be essential.

In most cases, quantitative analysis of bioactive compounds has not been considered which might guide researchers to find other species of Scrophularia with more content of bioactive compounds. Despite the presence of some Scrophularia species in different pharmacopeias and their application in tradition or folk medicine of different societies, lack of analytical investigations on the bioactive compounds of these species resulted in difficulties in quality control and standardizations of these herbs.

Some metabolites, such as iridoids which also demonstrated some biological activities, are common between these plants and it is possible to consider them as biomarkers for Scrophularia spp.

Conducting complementary studies on isolated bioactive compound from this genus, such as Quantitative structure–activity relationship (QSAR) studies on the isolated bioactive compounds as well as preparing semi-synthetic derivatives, may result in more active metabolites.