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Evaluation of antiprotozoal and antimycobacterial activities of the resin glycosides and the other metabolites of Scrophularia cryptophila.

Introduction

Infectious diseases still pose a major and challenging health problem around the world. It is estimated that one-third of the world's population is infected with tubercle bacillus Mycobacterium tuberculosis, which causes 8 million new cases and 2 million deaths per year (WHO, 2004). The malaria parasite Plasmodium falciparum is responsible for 1-2 million deaths and 500 million new cases annually, primarily in Africa (WHO, 2000). Leishmaniasis is a group of prevalent diseases caused by several parasites belonging to the genus Leishmania. Visceral leishmaniasis (Kala-azar) caused by Leishmania donovani is endemic in many parts of the world and affects an estimated 15 million people worldwide (Ashford et al., 1992). African sleeping sickness caused by Trypanosoma brucei is endemic in 36 countries in sub-Saharan Africa. The global prevalence for this disease is currently estimated at 500,000. Chagas' disease, which is caused by Trypanosoma cruzi is widespread in Central and South America, with an estimated 18 million people infected (WHO, 1998). In the absence of effective vaccines, chemotherapy plays a critical role in the control of these diseases. However, standard drugs possess severe toxicity and suffer from inefficacy. Moreover, the emergence of drug-resistant strains of the causative organisms led to an increasing pressure on current chemotherapy regimes. Hence, the discovery of novel drugs and drug templates for the treatment of these diseases has become a priority.

Glycoresins, also known as resin glycosides, are uncommon secondary metabolites exclusive to the plants of the Convolvulaceae family. A particularly rich source for these compounds is the resins of Ipomoea (morning glory) species, from which a number of glycoresins, e.g., turpethinic acids (Ipomoea turpethum) (Wagner et al., 1978, 1983), murucins and murucoidins (I. murucoides) (Leon et al., 2005; Cherigo and Pereda-Miranda, 2006) operculinic acid and operculins (I. leptophylla) (Barnes et al., 2003) and stoloniferins (I. stolonifera) (Noda et al., 1998) have been obtained. Other Convolvulaceae genera containing resin glycosides are Convolvulus (Noda et al., 1990, 1992; Kogetsu et al., 1991), Cuscuta (Du et al., 1998, 1999) and Calystegia (Gaspar, 1999). Chemically, resin glycosides are composed of a linear tetra- or pentaglycosidic oligosaccharide unit and one or more fatty acid(s). In most cases, the sugar unit is attached to one of the secondary hydroxyl groups of the fatty acid. Sometimes, as in the case of murucins, tricolorins orizabins and arboresins, the carboxylic acid function of the fatty acid attacks the hydroxyl group of another sugar unit to generate a macrocyclic lactone structure. Oligosaccharide moiety often bears acylations with a wide range of organic acids, such as acetic, propanoic, butanoic, tigloic, methyl propanoic, 2-methylbutanoic or cinnamic acids. The most commonly encountered fatty acids within resin glycosides are undecanoic (C-11), 11-hydroxytetradecanoic (C-14), 11-hydroxypalmitic, 3,12-and 4,12-dihydroxypalmitic (C-16) acids. Glycoresins have been reported to possess a number of biological activities, such as antibacterial (Pereda-Miranda et al., 2006a), antituberculotic (Barnes et al., 2003), antitumoral (Cao et al., 2005; Leon et al., 2005), purgative (Pereda-Miranda et al., 2006b), antidepressant and anticonvulsant (Miron-Lopez et al., 2007).

In a recent communication, we reported crypthophilic acids A-C (1-3) from the aerial parts of Scrophularia cryptophila (Scrophulariaceae), an endemic plant for Turkish flora (Cahs et al., 2007). Compounds 1-3 have been identified as the tetraglycosides of (+)-3S, 12S-dihydroxypalmitic acid and represent the first non-convolvulaceous resin glycosides. Besides them, a number of known metabolites have also been isolated and characterized from the title plant. This included iridoid glycosides [harpagide (4), acetylharpagide (5), catalpol (8), aucubin (9) and methylcatalpol (10)], phenylethanoid glycosides [verbascoside (11), angoroside C (12)] as well as chlorogenic acid (13), L-tryptophan (6) and buddlejasaponin III (7). The main objective of this study was to investigate the growth-inhibitory activity of the new compounds 1-3 against a large panel of parasitic protozoa. Additionally, some of the known components (4-7), which have not been tested for their antiprotozoal activity before have also been investigated. Blood-stage forms of T. brucei rhodesiense, T. cruzi, L. donovani and P. falciparum were used as test organisms. The cytotoxicity of the compounds was assessed against primary rat skeletal myoblasts (L6 cells) in order to determine their therapeutic index. Finally, in vitro antimycobacterial effects of all 13 metabolites have also been evaluated on the causative agent of pulmonary tubercle, M. tuberculosis.

Materials and methods

Plant material, isolation and characterization of compounds 1-13 (Fig. 1, 1-7)

S. cryptophila Boiss. & Heldr. was collected in Ankara in June 2001 and all compounds were purified from the water-soluble portion of the MeOH extract obtained from the aerial parts of the plant as described (Cahs et al., 2007). Their structures were determined by spectroscopic and chemical means. The purity of compounds (>95%) was confirmed by [.sup.1.H] and [.sup.13.C] NMR.

In vitro assay for Plasmodium falciparum

Antiplasmodial activity was determined using the K1 strain of P. falciparum (resistant to chloroquine and pyrimethamine). A modification of the [[.sup.3.H]]-hypoxanthine incorporation assay was used (Matile and Pink, 1990). Briefly, infected human red blood cells in RPMI 1640 medium with 5% Albumax were exposed to serial drug dilutions in microtiter plates. After 48 h of incubation at 37 [degrees]C in a reduced oxygen atmosphere, 0.5 [micro]Ci [.sup.3.H]-hypoxanthine was added to each well. Cultures were incubated for a further 24 h before they were harvested onto glass-fiber filters and washed with distilled water. The radioactivity was counted using a BetaplateTM liquid scintillation counter (Wallac, Zurich, Switzerland). The results were recorded as counts per minute per well at each drug concentration and expressed as percentage of the untreated controls. From the sigmoidal inhibition curves [IC.sub.50] values were calculated. Artemisinin was used as reference compound (Table 1).

[FIGURE 1 OMITTED]

In vitro assays for Trypanosoma brucei rhodesiense, T. cruzi, Leishmania donovani and L6 cell cytotoxicity

Antiparasitic assays for T. b. rhodesiense, T. cruzi and the cytotoxicity assay against rat skeletal myoblasts (L6 cells) were performed as previously described (Sperandeo and Brun, 2003). The assay for L. donovani was done using the Alamar Blue assay as described for T. b. rhodesiense. Briefly, axenic amastigotes were grown in SM medium (Cunningham, 1977) at pH 5.4 supplemented with 10% fetal bovine serum. About 100 [micro]l of the culture medium with 105 amastigotes from axenic culture with or without a serial drug dilution was seeded in 96-well microtiter plates. After 72 h of incubation, 10 [micro]l of Alamar Blue was then added to each well and the plates incubated for another 2 h. Then the plates were read with a microplate fluorometer as previously described (Sperandeo and Brun, 2003). Benznidazole, melarsoprol, miltefosin and podophyllotoxin were used as positive controls. The [IC.sub.50] values of reference compounds are shown in Table 1.

In vitro assay for M. tuberculosis

[H.sub.37]Rv strain of M. tuberculosis (ATCC 27294, Rockville, MD) was grown to late log phase in Middlebrook 7H9 broth supplemented with 0.2% v/v glycerol, 0.05% Tween 80 and 10% v/v OADC. Cultures were centrifuged 15 min at 4 [degrees]C, washed twice and resuspended in PBS. Suspensions were then passed through an 8 [micro]m filter to remove clumps and aliquots were frozen at -80 [degrees]C. The cfu was determined by plating on 7H11 agar plates. The MIC for M. tuberculosis was assessed by the microplate alamar blue assay as previously described (Collins and Franzblau, 1997). The compounds were dissolved in DMSO and added to culture media to produce a maximum final concentration of 100 [micro]g/ml. Eight twofold serial dilutions of the test compounds were prepared in Middlebrook 7H12 medium and added to 96-well microplates in a volume of 100 [micro]l. Then M. tuberculosis (100 [micro]l continuing 2 x [10.sup.4] cfu) was added, yielding a final testing volume of 200 [micro]l. Cultures were incubated for 7 days at 37 [degrees]C after which 12.5 [micro]l of 20% Tween 80, and 20 [micro]l of Alamar Blue were added to cultures. After incubation at 37 [degrees]C for 24 h fluorescence was read (ex 530 nm, em 590 nm). The MIC was defined as the lowest concentration affecting a reduction in fluorescence of [greater than or equal to]90% relative to the mean of replicate bacteria-only controls. Rifampicin was used as positive controls. Table 1 displays the MIC values and percentage inhibition of M. tuberculosis whole cells at highest test concentration (100 [micro]g/ml) of compounds 1-13.

Results

Our earlier phytochemical studies on S. cryptophila (Calis et al., 2007) afforded three new resin glycosides (1-3) and 10 known metabolites (4-13). Since some of the isolates (6-11) have recently been isolated from endemic Scrophulariaceae and Lamiaceae plants and tested for antiprotozoal activity (Kirmizibekmez et al., 2004; Tasdemir et al., 2005), they were not tested again to avoid duplication. However, their activities were displayed in Table 1 in order to facilitate comparison. The antimycobacterial effects of all 13 compounds were also assessed. Table 1 shows the MIC values and percentage inhibition of M. tuberculosis whole cells at 100 [micro]g/ml concentration of compounds 1-13.

While crypthophilic acid A (1) and crypthophilic acid C (3) exerted promising antiprotozoal activities, crypthophilic acid B (2) was completely devoid of any biological activity. Also, the known compounds 4-7 were found to have remarkable antiparasitic potentials. All tested compounds, but 2, exhibited good in vitro trypanocidal activities against African trypanosomes (T.b. rhodesiense). In particular, tryptophan (6) and buddlejasaponin III (7) appeared to have strong trypanocidal effects with [IC.sub.50] values of 4.1 and 9.7 [micro]g/ml. It was noteworthy that the trypanocidal potency of crypthophilic acid C (3) was almost threefold of crypthophilic acid A (1) ([IC.sub.50] values 14.1 and 46.9 [micro]g/ml, respectively). Harpagide (4) and acetylharpagide (5) were almost equipotent ([IC.sub.50]'s 21.0 and 26.9 [micro]g/ml). In contrast, the growth-inhibitory activity of the compounds against American T. cruzi was very poor and only 3, 6 and 7 possessed some weak activity against this parasite ([IC.sub.50] values 43.4, 56.2 and 44.1 [micro]g/ml, respectively). The majority of the compounds exerted significant antileishmanial activity against L. donovani. The only exceptions were the compounds 2 and 6. Harpagide (4) emerged as the best leishmanicidal agent with [IC.sub.50] value of 2.0 [micro]g/ml. This was followed by 3 ([IC.sub.50] 5.8 [micro]g/ml), 7 ([IC.sub.50] 6.2 [micro]g/ml), acetylharpagide (5, [IC.sub.50] 6.9 [micro]g/ml) and 1 ([IC.sub.50] 12.8 [micro]g/ml). When tested against blood-stage forms of the drug-resistant K1 strain of the malaria parasite, P. falciparum, only crypthophilic acid C (3), L-tryptophan (6) and buddlejasaponin III (7) showed antimalarial activity with [IC.sub.50] values of 4.2, 16.6 and 22.4 [micro]g/ml. In target identification studies, none of the three compounds inhibited PfFabI, a key enzyme from the P. falciparum type II fatty acid cascade, FAS-II (data not shown). All compounds were found to be safe as they did not possess any cytotoxicity on mammalian L6 cells even at high concentrations ([IC.sub.50]'s >90 [micro]g/ml). When tested for antitubercular activity against M. tuberculosis, all 13 compounds exhibited minimum inhibitory concentration (MIC) values above 100 [micro]g/ml. Cryptophilic acid C (3) and chlorogenic acid (13) showed some marginal activity with 45% and 37% inhibition at 100 [micro]g/ml concentration.

Discussions

In continuation of our search for novel antiprotozoal agents from endemic Turkish plants, we evaluated the new resin glycosides 1-3, as well as the known metabolites 4-7, which were isolated from S. cryptophila (Calis et al., 2007). Although crypthophilic acid B (2) were inactive in all assays, the remaining glycoresins crypthophilic acid A (1) and crypthophilic acid C (3) exhibited promising antiprotozoal activities without causing toxicity on mammalian cells. Particularly, 3 emerged as a good candidate molecule, as it inhibited all four protozoa. Crypthophilic acid A (1), however, inhibited only T. b. rhodesiense and L. donovani. This differential activity profile exerted by compounds 1-3 is interesting. Crypthophilic acid B (2) is the isovaleroyl ester of 1, and the ester function resides on the lower terminal rhamnose unit (Rha-t1, position 4'"). The only difference between 2 and 3 is the presence of an additional acetyl group on the same position of the upper terminal rhamnose unit (Rha-t2, position 4""). Thus, it appears that a single esterification on Rha-t1 is not favored; however, introduction of a second ester function on the Rha-t2 increases the bioactivity significantly. It is interesting to note that compound 3 is the most apolar resin glycoside. A correlation between lipophilicity and biological activity has been observed with antibacterial Convolvulaceae resin glycosides (Pereda-Miranda et al., 2006a). The broad-spectrum antiprotozoal activity of 3 might be due to better penetration through erythrocyte and/or parasite membranes. Also a slight structural difference adopted by 3 might modify its interaction with the target membranes to cause a remarkable biological effect. Glycolipids and glycoproteins found on the membrane surface of parasitic protozoa play a crucial role in determining the specificity of the host-parasite interaction and in protecting the parasites within their respective hosts. Thus, inhibition of the biosynthetic steps of protozoal glycolipids is emerging as a realistic target for antiprotozoal drug discovery (McConville, 1995). Interestingly, none of the compounds (1-13) inhibited a crucial enzyme (PfFabI) from the FAS-II pathway of P. falciparum (data not shown), which is responsible from de novo biosynthesis of short (C10-C14) fatty acids. However, because of the structural similarities with parasitic cell surface glycolipids, one can speculate that resin glycosides 1 and 3 interfere and disrupt the surface glycolipid biosynthesis, thereby show their antiprotozoal activity. Given that some resin glycosides have been shown to possess antimycobacterial activity (Barnes et al., 2003), we have tested compounds 1-3 also against M. tuberculosis. Except for compounds 3 (and 13), which showed some growth inhibition at highest test concentration (100 [micro]g/ml concentration), none of the compounds exhibited significant activity towards M. tuberculosis. On the other hand, glycoresins have emerged to be non-toxic to mammalian cells. This is somehow consistent with the results of earlier studies, given the fact that the most cytotoxic glycoresins possess a macrocyclic lactone structure (Cao et al., 2005; Leon et al., 2005; Cherigo and Pereda-Miranda, 2006). However, lack of toxicity indicates a highly selective toxicity on parasitic protozoans.

Very little attention has been paid so far to the ability of iridoid and phenylethanoid glycosides to inhibit protozoal infections. Our previous studies on endemic Scrophularia lepidota (Scrophulariaceae) and Phlomis brunneogaleata (Lamiaceae) showed broad-spectrum antiprotozoal potential of several iridoid and phenylethanoid glycosides (including compounds 8-12), and also compound 13 for the first time (Kirmizibekmez et al., 2004; Tasdemir et al., 2005). Two additional iridoid glucosides investigated in the current study, harpagide (4) and acetylharpagide (5), also appeared as promising. Their activity profiles were similar, as both inhibited T. b. rhodesiense and L. donovani only. However, leishmanicidal potency of 4 was much higher than that of 5, which contains an acetoxyl function at C-8 position on the aglycone. The absence of antiplasmodial potential for acetylharpagide is consistent with a previous study reported by Kuria et al. (2002). The aminoacid tryptophan (6) inhibited three of the four parasite strains, and was most active against T. b. rhodesiense. A literature survey has shown that tryptophan itself has not been reported for its antiprotozoal activity. However, the importance of tryptophan residue for antiprotozoal activity of the natural peptides, e.g., apicidins has been acknowledged (Singh et al., 2002). Another very promising compound emerged from this study was the oleanane triterpen glycoside buddlejasa-ponin III (7), which inhibited the growth of all four parasites tested. The most encouraging activities observed for 7 were against L. donovani and T. b. rhodesiense. Emam et al. (1997) have previously reported the inhibitory effect of buddlejasaponin J isolated from S. scrodonia against Trichomonas vaginalis and L. infantum, but to our knowledge this is the first report of protozoocidal activity of buddlejasaponin III. Fortunately, compounds 4-7 were also non-toxic towards mammalian cells, indicating a large selectivity index. Not only the glycoresins 1-3, but also all remaining ten compounds showed no significant activity against M. tuberculosis cultures. As mentioned above, only compound 13 had some marginal activity at highest doses.

In summary, this study provides new insights into the real potential of resin glycosides as antimicrobial agents and adds a new line to the list of reported biological activities of this type of compounds. The mechanism(s) underlying the antiprotozoal activity of compounds 1 and 3 warrants further investigations. This is also the first study reporting the broad-spectrum antiprotozal activity of the remaining compounds, iridoid glucosides harpagide and acetylharpagide, aminoacid tryptophan and the triterpen glycoside buddlejasaponin III. The current study, in combination with our earlier studies on S. lepidota (Tasdemir et al., 2005) also suggests that Scrophularia species are useful sources for the discovery of new antiprotozoal agents.

Acknowledgment

The authors thank Dr. Ali A. Donmez (Department of Biology, Hacettepe University, Turkey) for collection and taxonomical identification of the plant.

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Deniz Tasdemir (a,*), Reto Brun (b), Scott G. Franzblau (c), Yukselen Sezgin (d), Ihsan Calis (d)

(a) Centre for Pharmacognosy and Phytotherapy, School of Pharmacy, University of London, 29-39 Brunswick Square, London WC1N 1AX, UK

(b) Department of Medical Parasitology and Infection Biology, Swiss Tropical Institute, Socinstrasse 57, CH-4002 Basel, Switzerland

(c) Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA

(d) Department of Pharmacognosy, Faculty of Pharmacy, Hacettepe University, Sihhiye, TR-06100 Ankara, Turkey

Received 24 April 2007; accepted 23 July 2007

*Corresponding author. Tel.: + 44 20 7753 5845; fax: + 44 20 7753 5909.

E-mail addresses: deniz.tasdemir@pharmacy.ac.uk, dtasdemir@hotmail.com (D. Tasdemir).
Table 1. In vitro antiprotozoal, antimycobacterial and cytotoxic effects
of S. cryptophila metabolites 1-13 (all [IC.sub.50] and MIC values are
in [micro]g/ml)

 T. b.
 rhodesiense T. cruzi L. donovani P. falciparum
Compound [IC.sub.50] [IC.sub.50] [IC.sub.50] [IC.sub.50]

Reference 0.0098 (a) 1.06 (b) 0.102 (c) 0.0022 (d)
 1 46.9 > 90 12.8 > 50
 2 > 90 > 30 > 30 > 50
 3 14.1 43.4 5.8 4.2
 4 21.0 > 90 2.0 > 50
 5 26.9 > 90 6.9 > 50
 6 4.1 56.2 > 30 16.6
 7 9.7 44.1 6.2 22.4
 8 54.8 (g) > 90 (g) 10.4 (g) > 50 (g)
 9 51.1 (g) > 90 (g) 10.9 (g) > 50 (g)
10 32.5 (g) > 90 (g) 8.3 (g) > 50 (g)
11 14.2 (h) > 90 (h) 8.7 (h) > 50 (h)
12 29.3 (g) > 90 (g) 8.0 (g) > 50 (g)
13 18.9 (h) > 90 (h) 7.0 (h) > 50 (h)

 Cytotoxicity M. tb. %
 L6 cells M. tuberculosis inhibition at
Compound [IC.sub.50] MIC 100 [micro]g/ml

Reference 0.08 (e) 0.061 (f)
 1 > 90 > 100 8
 2 > 90 > 100 0
 3 > 90 > 100 45
 4 > 90 > 100 14
 5 > 90 > 100 19
 6 > 90 > 100 16
 7 > 90 > 100 12
 8 > 90 (g) > 100 8
 9 > 90 (g) > 100 8
10 > 90 (g) > 100 2
11 37.1 (h) > 100 12
12 > 90 (g) > 100 19
13 > 90 (h) > 100 37

Reference compounds: (a) melarsoprol, (b) benznidazole, (c) miltefosine,
(d) artemisinin, (e) phodophyllotoxin and (f) rifampicin.
(g) These results are from our earlier studies (Tasdemir et al., 2005).
(h) These results are from our earlier studies (Kirmizibekmez et al.,
2004).
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Author:Tasdemir, Deniz; Brun, Reto; Franzblau, Scott G.; Sezgin, Yukselen; Calis, Ihsan
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Geographic Code:4EUUK
Date:Mar 1, 2008
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