Journal of Ethnopharmacology 155 (2014) 796–800
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Research Paper
Antitubercular activity of Arctium lappa and Tussilago farfara extracts and constituents Jinlian Zhao a, Dimitrios Evangelopoulos b,1, Sanjib Bhakta b, Alexander I. Gray a, Véronique Seidel a,n a
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK Mycobacteria Research Laboratory, Department of Biological Sciences, Institute of Structural and Molecular Biology, Birkbeck, University of London, London, UK b
art ic l e i nf o
a b s t r a c t
Article history: Received 13 February 2014 Received in revised form 28 May 2014 Accepted 14 June 2014 Available online 20 June 2014
Ethnopharmacological relevance: Arctium lappa and Tussilago farfara (Asteraceae) are two plant species used traditionally as antitubercular remedies. The aim of this study was (i) to screen Arctium lappa and Tussilago farfara extracts for activity against Mycobacterium tuberculosis and (ii) to isolate and identify the compound(s) responsible for this reputed anti-TB effect. Materials and methods: The activity of extracts and isolated compounds was determined against Mycobacterium tuberculosis H37Rv using a high throughput spot culture growth inhibition (HTSPOTi) assay. Results: The n-hexane extracts of both plants, the ethyl acetate extract of Tussilago farfara and the dichloromethane phase derived from the methanol extract of Arctium lappa displayed antitubercular activity (MIC 62.5 μg/mL). Further chemical investigation of Arctium lappa led to the isolation of n-nonacosane (1), taraxasterol acetate (2), taraxasterol (3), a (1:1) mixture of β sitosterol/stigmasterol (4), isololiolide (5), melitensin (6), trans-caffeic acid (7), kaempferol (8), quercetin (9), kaempferol-3-Oglucoside (10). Compounds isolated from Tussilago farfara were identified as a (1:1) mixture of β sitosterol/stigmasterol (4), trans-caffeic acid (7), kaempferol (8), quercetin (9), kaempferol-3-Oglucoside (10), loliolide (11), a (4:1) mixture of p-coumaric acid/4-hydroxybenzoic acid (12), p-coumaric acid (13). All compounds were identified following analyses of their physicochemical and spectroscopic data (MS, 1H and 13C-NMR) and by comparison with published data. This is the first report of the isolation of n-nonacosane (1), isololiolide (5), melitensin (6) and kaempferol-3-O-glucoside (10) from Arctium lappa, and of loliolide (11) from Tussilago farfara. Amongst the isolated compounds, the best activity was observed for p-coumaric acid (13) (MIC 31.3 μg/mL or 190.9 μM) alone and in mixture with 4-hydroxybenzoic acid (12) (MIC 62.5 μg/mL). Conclusions: The above results provide for the first time some scientific evidence to support, to some extent, the ethno-medicinal use of Arctium lappa and Tussilago farfara as traditional antitubercular remedies. & 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Antitubercular activity Arctium lappa Tussilago farfara Mycobacterium tuberculosis
1. Introduction Tuberculosis (TB) is a major global health problem and currently the leading bacterial killer worldwide. The World Health Organisation has estimated that Mycobacterium tuberculosis, the causative agent of TB, was responsible for 8.6 million new cases n
Corresponding author. Tel.: þ 44 141 548 2751; fax: þ 44 141 552 2562. E-mail address:
[email protected] (V. Seidel). 1 Current address: Centre for Clinical Microbiology, Department of Infection, Royal Free Campus, University College London, London, UK. http://dx.doi.org/10.1016/j.jep.2014.06.034 0378-8741/& 2014 Elsevier Ireland Ltd. All rights reserved.
and 1.3 million deaths in 2012. The current recommended treatment involves a long course of a combination of antibiotics and is associated with poor patient compliance, which has led to the emergence of multi-drug resistant (MDR) and extensively-drug resistant (XDR) forms of TB (WHO, 2013). The treatment of MDRTB requires expensive second-line drugs and XDR-TB is often incurable. There is now an urgent need to discover and develop new anti-TB agents (Zumla et al., 2013). This has led to a renewed interest in the screening and purification of novel anti-TB agents from natural sources (Guzman et al., 2012; Santhosh and Suriyanarayanan, 2014).
J. Zhao et al. / Journal of Ethnopharmacology 155 (2014) 796–800
Arctium lappa (burdock) is a biennial herbaceous plant traditionally used for its diuretic, carminative, anti-inflammatory, antiseptic and detoxifying properties (Kamkaen et al., 2006; Park et al., 2007). Burdock roots, seeds and leaves are also used as a traditional anti-TB medicine (Ritchason, 1995). Burdock is known to contain some lignans (Ming et al., 2004; Kamkaen et al., 2006; Park et al., 2007), terpenoids (Costa et al., 1993; Tsuneki et al., 2005), sterols (Ming et al., 2004; Mizushina et al., 2006), flavonoids (Ferracane et al., 2010; Chen et al., 2011), hydroxycinnamic acid derivatives (Maruta et al., 1995; Ferracane et al., 2010) and polyacetylenes (Takasugi et al., 1987). Burdock extracts have anti-inflammatory (Lin et al., 1996) and anti-diabetic properties (Cao et al., 2012). Burdock leaf, fruit and root extracts display antimicrobial activity ( Pereira et al., 2005; Keyhanfar et al., 2011; He et al., 2012 ). Tussilago farfara (coughwort) is a perennial herbaceous plant used to treat sore throats and lung ailments such as bronchitis, asthma and chronic cough including TB (Allen and Hatfield, 2004; Liu et al., 2006). It is also used for its detoxifying properties and for gout, skin, liver and kidney diseases (Darwin, 1996). Coughwort contains sesquiterpene lactones (Liu et al., 2006; Park et al., 2008), triterpenes (Yaoita and Masao, 1998; Liu et al., 2006), flavonoids (Liu et al., 2006), alkaloids (Luethy et al., 1980; Liu et al., 2006) and hydroxycinnamic acid derivatives (Liu et al., 2007). Coughwort extracts have antimicrobial (Dulger and Gonuz, 2004; Turker and Usta, 2008; Kačániová et al., 2013), anti-inflammatory (Benoit et al., 1976; Jeong et al., 2013), cardiostimulatory (Li and Wang, 1988), neuroprotective and anti-oxidative activity (Cho et al., 2005). To the best of our knowledge, there has been no published report on the antitubercular screening of neither burdock nor coughwort extracts. We report, herein, a chemical and biological investigation on the aerial parts of burdock and coughwort for the presence of compounds with whole-cell antitubercular activity.
2. Materials and methods 2.1. General Solvents were from Fisher Scientific (UK) except for NMR deuterated (99.9%) solvents (Sigma-Aldrich, UK). TLC analysis was carried out on silica gel 60 PF254 pre-coated plates (VWR International, UK). Compounds on TLC plates were detected under short (λ ¼254 nm) UV light and visualised by spraying plates with either p-anisaldehyde or vanillin sulphuric acid reagent, followed by heating until coloured spots appeared. Silica gel 60H (VWR International, UK) was used for vacuum liquid chromatography (VLC). Open column chromatography (CC) was carried out using silica gel 60 (mesh size, 0.063–0.200 mm) (VWR International, UK) and gel filtration was performed using Sephadexs (LH-20-100) (Sigma-Aldrich, UK). 1H and 13C NMR experiments were carried out on JEOL (JNM LA400) 400 MHz, Bruker 500 or 400 MHz instruments. Unless otherwise stated, HMBC experiments used a time delay of 0.07 s (e.g. JCH ¼7 Hz). All spectra were referenced on the residual solvent peaks and processed using Mestre Novas (MNova) software version 8.0.0 (Mestrelab Research SL, Spain). High resolution electron impact (HREI) mass spectra were recorded on a JEOL 505HA spectrometer using direct probe at elevated temperature (110–160 1C) at 70 eV. Positive ion and negative ion mode ESI experiments were performed on a Thermo Finnigan LCQ-Deca Iontrap or Orbitrap HRESI mass spectrometer. 2.2. Plant material Dried aerial parts of Arctium lappa L. (Asteraceae) and Tussilago farfara L. (Asteraceae) were purchased from G. Baldwin & Co Ltd.
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(London, UK) in 2011. The plants were ground to a fine powder prior to extraction. 2.3. Extraction and isolation Arctium lappa (988 g) was Soxhlet extracted successively with n-hexane (yield: 3% w/w), EtOAc (yield: 3% w/w) and MeOH (yield: 4% w/w). The n-hexane extract (30 g) was subjected to VLC eluting with hexane:EtOAc mixtures and then EtOAc:MeOH mixtures of increasing polarity. Fractions eluted with 2–10% EtOAc in n-hexane were pooled (2.8 g) based on a similar TLC profile and subjected to gel filtration eluting with 5% n-hexane in dichloromethane followed by CC. Elution on CC with 0–5% EtOAc in hexane afforded 1 (156.9 mg). Elution with 10% EtOAc in hexane yielded 91 subfractions (F1–F91). F1–F7 were combined and subjected to further CC eluting with 5% EtOAc in hexane to afford 2 (97.4 mg). F31–F37 were combined and further subjected to gel filtration (5% n-hexane in dichloromethane) to afford 3 (41.8 mg). F56–F91 were pooled to afford 4 (43.3 mg). The EtOAc extract (30 g) was subjected to VLC eluting with hexane:EtOAc mixtures and then EtOAc:MeOH mixtures of increasing polarity. The MeOH extract (40 g) was partitioned between dichloromethane, n-butanol and water. The dichloromethane phase (5.1 g) was subjected to VLC eluting with hexane:EtOAc mixtures of increasing polarity. The fraction eluted with 50% EtOAc in hexane was subjected to gel filtration in MeOH followed by CC eluting with 25% EtOAc in hexane to yield 5 (8.9 mg). Further CC elution with 30% EtOAc in hexane and subsequent gel filtration in EtOAc afforded 6 (25.5 mg). The butanol phase (13.5 g) was subjected to VLC eluting with hexane:EtOAc mixtures of increasing polarity. The fractions eluted with up to 10% MeOH in EtOAc were pooled and subjected to gel filtration in MeOH and gave 7 (18 mg), 8 (1 mg) and 9 (3 mg). The fractions eluted with 15–25% MeOH in EtOAc were pooled and subjected to CC. Elution with 10% MeOH in EtOAc afforded 10 (18 mg). Tussilago farfara (995 g) was Soxhlet extracted successively with n-hexane (yield: 2.3% w/w), EtOAc (yield: 1.4% w/w) and MeOH (yield: 9.1% w/w). The n-hexane extract (23 g) was subjected to VLC eluting with hexane:EtOAc mixtures of increasing polarity. Gel filtration (5% n-hexane in dichloromethane) of the fractions eluted with 30% EtOAc in n-hexane and 80% EtOAc in n-hexane yielded 4 (99.7 mg) and 11 (10.8 mg), respectively. The EtOAc extract (14 g) was subjected to VLC eluting with hexane: EtOAc mixtures and then EtOAc:MeOH mixtures of increasing polarity. Gel filtration (in MeOH) of the fraction eluted with 60% EtOAc in n-hexane afforded 8 (42.2 mg), 12 (27.6 mg) and 13 (1 mg). Gel filtration (in MeOH) of the fraction eluted with 80% EtOAc in n-hexane yielded 7 (1 mg) and 9 (4 mg). Gel filtration (in MeOH) of the fraction eluted with 20% MeOH in EtOAc gave 10 (12.1 mg). The MeOH extract (91 g) was partitioned between dichloromethane, n-butanol and water. All extracts and isolated compounds were stored at 20 1C prior to testing. 2.4. Screening against Mycobacterium tuberculosis Antitubercular activity was determined in vitro against Mycobacterium tuberculosis H37Rv (ATCC27294) using a high-throughput version of the spot culture growth inhibition (HT-SPOTi) assay (Evangelopoulos and Bhakta, 2010; Gupta and Bhakta, 2012; Guzman et al., 2013). Briefly, Mycobacterium tuberculosis H37Rv was initiated from a cryopreserved glycerol stock, passaged twice for growth uniformity and grown at 37 1C in 10 mL Middlebrook 7H9 liquid medium supplemented with 10% (v/v) oleic acid/albumin/dextrose/catalase (OADC) until the log phase (OD600E0.7). Mycobacterial cultures were first checked for quality control using cold Ziehl–Neelsen staining. The mycobacterial suspension was
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then prepared by dilution to achieve 1 105 CFU/mL inoculum for further use. Extracts/compounds were dissolved in DMSO. Serial dilution was performed in a sterile, thin 96-well frosted subskirted microtitre plate. A column containing only DMSO was also included as negative control. 2 μL of each of the diluted extracts/compounds was then transferred into sterile 96-well plates. The plates were filled up to 200 μL with Middlebrook 7H10 agar medium enriched with 10% (v/v) OADC using the MultidropCombi microplate dispenser (Thermo-Fisher Scientific). Plates were dried and 2 μL prepared mycobacterial suspension was spotted (105 CFU/mL) at the centre of each well by either the use of a single pipettor or by using the MultidropCombi. Then the plates were incubated in sealed bags at 37 1C for 2 weeks. MICs were determined as the lowest concentration of extracts/compounds showing no visible mycobacterial growth. The first-line anti-TB drugs isoniazid and rifampicin were included as antibiotic controls. Each sample was assayed in two biological replicates.
Table 1 Activity of Arctium lappa extracts and isolated compounds against Mycobacterium tuberculosis H37Rv in the HT-SPOTi assay.
μg/mL (μM)
Sample
MICs
n-hexane extract Ethyl acetate extract Methanol extract/dichloromethane phase Methanol extract/butanol phase Methanol extract/water phase n-nonacosane (1) Taraxasterol acetate (2) Taraxasterol (3) β-sitosterol/stigmasterol (1:1) mix (4) Isololiolide (5) Melitensin (6) Isoniazid Rifampicin
62.5 125 62.5 NAa NAa NAb NAa NAa 125 NAb NAb 0.01 (0.07) 0.01 (0.01)
a b
NA: no activity at 125 μg/mL. NA: no activity at 500 μg/mL.
3. Results and discussion Compounds isolated from Arctium lappa were identified as n-nonacosane (1) (Chen et al., 2008 ), taraxasterol acetate (2) (Khalilov et al., 2003), taraxasterol (3) (Mahato and Kundu, 1994), β sitosterol/stigmasterol in a (1:1) mixture (4) (Wright et al., 1978), isololiolide (5) (Kimura and Maki, 2002), melitensin (6) (Medjroubi et al., 2003), trans-caffeic acid (7) (Durust et al., 2001), kaempferol (8) (Xiao et al., 2006; Lee et al., 2009), quercetin (9) (Xiao et al., 2006; Xiang et al., 2011), kaempferol-3-O-glucoside (10) (Xiao et al., 2006; Lee et al., 2009). Compounds isolated from Tussilago farfara were identified as β sitosterol/stigmasterol in a (1:1) mixture (4), trans-caffeic acid (7), kaempferol (8), quercetin (9), kaempferol-3-O-glucoside (10), loliolide (11) (Kimura and Maki, 2002; Lee et al., 2009), p-coumaric acid/4-hydroxybenzoic acid in a (4:1) mixture (12) (Ou et al., 2011), p-coumaric acid (13) (Durust et al., 2001; Kuddus et al., 2010; Ou et al., 2011). All compounds were identified following analysis of their physicochemical and spectroscopic data (MS, 1H, 13 C-NMR, COSY, NOESY, HMBC, HSQC) and by comparison with published data. This is the first report of the isolation of nnonacosane (1), isololiolide (5), melitensin (6) and kaempferol-3O-glucoside (10) from Arctium lappa. Although kaempferol (8) has previously been isolated from Arctium lappa roots (Chen et al., 2011), this is the first report of its presence in the aerial parts. This is also the first report of the isolation of loliolide (11) from Tussilago farfara. The results of the antitubercular screening of Arctium lappa extracts and selected compounds are reported in Table 1. Among the tested extracts, only the n-hexane extract and the dichloromethane phase derived from the methanol extract displayed anti-TB activity (MIC 62.5 μg/mL). The ethyl acetate extract was moderately active at 125 μg/mL. Among the compounds isolated from the n-hexane extract, only the β-sitosterol/stigmasterol mixture (4) revealed activity (MIC ¼125 μg/mL). Taraxasterol acetate (2) and taraxasterol (3) were inactive at 125 μg/mL, whilst nnonacosane (1), isololiolide (5) and melitensin (6) had no activity at 500 μg/mL. The activity observed for the n-hexane extract was stronger than that observed for isolated compounds, suggesting that the activity could either be attributable to other (nonpurified) phytochemical(s) or to compounds acting synergistically. The activity of (4) in the HT-SPOTi assay correlated well with previous studies reporting the antitubercular activity of β-sitosterol, stigmasterol, and a (1:1) mixture in the MABA assay (Gutierrez-Lugo et al., 2005; Tan et al., 2008). It has been reported that the relatively polar “head groups” and flexible non-polar “phytyl tails” of sterols cause disruption in the mycobacterial cell
Table 2 Activity of Tussilago farfara extracts and isolated compounds against Mycobacterium tuberculosis H37Rv in the HT-SPOTi assay.
μg/mL (μM)
Sample
MICs
n-hexane extract Ethyl acetate extract Methanol extract/dichloromethane phase Methanol extract/butanol phase Methanol extract/water phase β-sitosterol/stigmasterol (1:1) mix (4) Caffeic acid (7) Kaempferol (8) Quercetin (9) Kaempferol -3-O-glucoside (10) Loliolide (11) p-coumaric acid/4-hydroxybenzoic acid (4:1) mix (12) p-coumaric acid (13) Isoniazid Rifampicin
62.5 62.5 500 NAa NAa 125 250 (1387.7) NAa 500 (1654.3) NAa 250 (1273.9) 62.5 31.3 (190.9) 0.01 (0.07) 0.01 (0.01)
a
NA: no activity at 500 μg/mL.
wall and that their antimycobacterial activity depends on the type of substituents present on the phytyl moiety (Rugutt and Rugutt, 2002, 2012). To the best of our knowledge, this is the first time that n-nonacosane (1), taraxasterol acetate (2), isololiolide (5) and melitensin (6) are screened for anti-TB activity. The results of the antitubercular screening of Tussilago farfara extracts and compounds are reported in Table 2. The n-hexane and ethyl acetate extracts showed the highest activity (MIC 62.5 μg/ mL). The β-sitosterol/stigmasterol mixture (4) and loliolide (11) isolated from the n-hexane extract were active at 125 and 250 μg/ mL, respectively, suggesting that the activity of the n-hexane extract may be attributable in part to these compounds. This is the first time that loliolide (11) is screened for anti-TB activity. Among the compounds isolated from Tussilago farfara ethyl acetate extract, quercetin (9) had an MIC of 500 μg/mL, whilst kaempferol (8) and kaempferol-3-O-glucoside (10) were both inactive at the highest concentration of 500 μg/mL. The best activity was observed for p-coumaric acid (13) (MIC 31.3 μg/mL) alone and in mixture with 4-hydroxybenzoic acid (12) (MIC 62.5 μg/mL). It should be mentioned that p-coumaric acid was previously reported as inactive (MIC 4128 μg/mL) in a study using the MABA assay (Gutierrez-Lugo et al., 2005). The latter is a microplate-based colorimetric assay which provides a rapid high-throughput
J. Zhao et al. / Journal of Ethnopharmacology 155 (2014) 796–800
screening of compounds against mycobacteria (Collins and Franzblau, 1997). However, its main drawback is that, unlike the HT-SPOTi assay, it is prone to contamination of samples during experiments and to inter-laboratory variations of results (Evangelopoulos and Bhakta, 2010). Substituted carboxylic acids (including benzoic and p-coumaric acid) have recently been identified as inhibitors of the β-class carbonic anhydrases from Mycobacterium tuberculosis (Maresca et al., 2013). These findings provide for the first time some scientific evidence to support, to some extent, the ethnomedicinal use of Arctium lappa and Tussilago farfara as traditional antitubercular remedies.
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