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Evaluation of leishmanicidal and trypanocidal activities of phenolic compounds from Calea uniflora Less. a

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Tamires C. Lima , Rafaela J. Souza , Alan D.C. Santos , Milene H. c

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Moraes , Nicole E. Biondo , Andersson Barison , Mário Steindel & Maique W. Biavatti

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Departamento de Ciências Farmacêuticas, CCS, Universidade Federal de Santa Catarina (UFSC), Florianópolis, SC, Brazil b

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Departamento de Química, Universidade Federal do Paraná (UFPR), Curitiba, PR, Brazil c

Departamento de Microbiologia e Parasitologia, CCB, Universidade Federal de Santa Catarina (UFSC), Florianópolis, SC, Brazil Published online: 16 Apr 2015.

To cite this article: Tamires C. Lima, Rafaela J. Souza, Alan D.C. Santos, Milene H. Moraes, Nicole E. Biondo, Andersson Barison, Mário Steindel & Maique W. Biavatti (2015): Evaluation of leishmanicidal and trypanocidal activities of phenolic compounds from Calea uniflora Less., Natural Product Research: Formerly Natural Product Letters, DOI: 10.1080/14786419.2015.1030740 To link to this article: http://dx.doi.org/10.1080/14786419.2015.1030740

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Natural Product Research, 2015 http://dx.doi.org/10.1080/14786419.2015.1030740

Evaluation of leishmanicidal and trypanocidal activities of phenolic compounds from Calea uniflora Less. Tamires C. Limaa, Rafaela J. Souzaa, Alan D.C. Santosb, Milene H. Moraesc, Nicole E. Biondoc, Andersson Barisonb, Ma´rio Steindelc and Maique W. Biavattia* a

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Departamento de Cieˆncias Farmaceˆuticas, CCS, Universidade Federal de Santa Catarina (UFSC), Floriano´polis, SC, Brazil; bDepartamento de Quı´mica, Universidade Federal do Parana´ (UFPR), Curitiba, PR, Brazil; cDepartamento de Microbiologia e Parasitologia, CCB, Universidade Federal de Santa Catarina (UFSC), Floriano´polis, SC, Brazil (Received 9 December 2014; final version received 10 March 2015)

The phytochemical study of Calea uniflora led to the isolation of nine phenolic compounds identified as noreugenin (1), ethyl caffeate (2), a mixture of butein (3) þ orobol (4), a-hydroxy-butein (5), caffeic acid (6), butein 40 -O-glucopyranosyl (7), quercetin 3-O-glucopyranosyl (8) and 3,5-di-O-caffeoylquinic acid (9). The chemical identity of the isolates was established on the basis of NMR and physical data. The chemical shifts of 5 and 7 have been reassigned and all the isolates were tested against Leishmania amazonensis and Trypanosoma cruzi amastigotes. None of the metabolites showed promising leishmanicidal activity. However, 2 and the mixture of 3 and 4 demonstrated interesting trypanocidal effect with IC50 values of 18.27 and 26.53 mM, respectively. Besides, these compounds did not present cytotoxic effect towards THP-1 cells, and compound 2 was 3.5-fold more selective than the mixture of 3 þ 4. Keywords: Calea uniflora; phenolic compounds; leishmanicidal; trypanocidal

1. Introduction Calea uniflora Less. (Heliantheae, Asteraceae) is popularly known in Brazil as ‘erva-de-lagarto’ and ‘arnica-da-praia’ (Pio Correˆa 1978; Zank 2011). It is a native shrub with yellow flowers found in Uruguay and Southern Brazil (Ferraz et al. 2009). In the state of Santa Catarina (Brazil), the aerial parts of this species are used by local population for wound healing as well as for internal and external bruises. Few phytochemical and pharmacological studies have been conducted on C. uniflora, and earlier investigations on different parts of this plant revealed

*Corresponding author. Email: [email protected] q 2015 Taylor & Francis

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the presence of chromanones (Do Nascimento et al. 2007), p-hydroxyacetophenone derivatives (Do Nascimento et al. 2004) and flavonoid glycosides (Do Nascimento & Oliveira 2004), with the chromanones displaying leishmanicidal effect (Do Nascimento et al. 2007) and p-hydroxyacetophenone derivatives showing trypanocidal and antifungal activities (Do Nascimento et al. 2004). Phenolic compounds, including flavonoids, chromones, chalcones and phenolic acids, have displayed a broad range of biological properties such as antiproliferative (Pascoal et al. 2014), anti-inflammatory (Min & Cuong 2013), antioxidant (Charles & Venkata 2014), trypanocidal (Marin et al. 2011) and leishmanicidal (Ogungbe et al. 2014). In the course of our investigation, nine phenolic derivatives were isolated and identified from C. uniflora. The previous works reporting phenolic compounds as antiprotozoan metabolites prompted us to evaluate them against intracellular amastigote forms of Leishmania amazonensis and Trypanosoma cruzi.

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2. Results and discussion The dichloromethane and ethyl acetate fractions of the leaves from C. uniflora were successively chromatographed leading to nine phenolic compounds and their structures (Figure 1) were established by using NMR and their physical data, comparing with those previously reported. They were identified as: noreugenin (1) (Huang et al. 2010), ethyl caffeate (2) (Xiang et al. 2011), butein (3) (Chen et al. 2008), orobol (4) (Zheng et al. 2006), a-hydroxy-butein (5) (Metuno et al. 2008), caffeic acid (6) (Regasini et al. 2008), butein 40 -O-glucopyranosyl (7) (Zhu et al. 2009), quercetin 3-O-glucopyranosyl (8) (Dudek-Makuch & Matlawska 2011) and 3,5-diO-caffeoylquinic acid (9) (An et al. 2008). Compounds 3 and 4 were obtained as a mixture (1:1) and all the constituents, except 3,5-di-O-caffeoylquinic acid (Puebla et al. 2011), are described for the first time in the genus Calea. The published spectroscopic data of compounds 5 and 7 presented some inconsistencies and were herein revised and discussed. The first full 1H and 13C NMR assignment of 5 was recorded by Metuno et al. (2008) in CDCl3, but these data contain interchanged shift chemical assignments for some hydrogen and carbon atoms. The chemical shifts values reported by Metuno et al. are dC 113.8 (C-1) and dC 124.5 (C-10 ), dC 113.6 (C-30 ) and dC 98.4 (C-b); the

Figure 1. Chemical structure of the isolated compounds from C. uniflora.

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proton shifts dH 6.69 and 6.71 were assigned to H-30 and H-b, respectively. A diagnostic analysis of the NMR 2D data allowed the re-assignments of C-1 (dC 125.4), C-10 (dC 115.0), C-30 (dC 99.4) and C-b (dC 114.7). Likewise, protons H-30 and H-b were found at dH 6.72 and 6.696, respectively. We are describing for the first time the complete NMR data of a-hydroxy-butein and butein 40 -O-glucopyranosyl in CD3OD. The 1H NMR spectrum of compound 5 (a-hydroxy-butein, C15H12O6, m.p. 177.1 –178.38C) strongly suggested a diarylpropanoid structure consistent with a a-hydroxy-chalcone skeleton by the presence of six aromatic protons forming two ABX systems in the rings A and B: dH 7.61 (1H, d, J ¼ 8.4 Hz, H-60 ), dH 6.72 (1H, d, J ¼ 2.0 Hz, H-30 ), dH 6.699 (1H, dd, J ¼ 8.4, 2.0 Hz, H-50 ), dH 7.52 (1H, d, J ¼ 2.0 Hz, H-2), dH 6.84 (1H, d, J ¼ 8.3 Hz, H-5) and dH 7.24 (1H, dd, J ¼ 8.3, 2.0 Hz, H-6). Additionally, a singlet typical of olefinic proton resonating at dH 6.696 (1H, s) was ascribed to H-b to the carbonyl. The connectivities of the molecular fragments were determined by HMBC correlation experiment. The assignment of H-b was confirmed by its heteronuclear long-range correlations to C-2, C-6, C-a and C-b0 , and the 13C NMR resonance at dC 147.7 was attributed to C-a. The geometry of the olefinic carbons in compound 5 was determined to be in a transgeometry based on earlier studies (van Der Merwe et al. 1972; Ferreira et al. 1974; Malan & Roux 1974; Metuno et al. 2008). The occurrence of a-hydroxy-chalcones is extremely rare in the nature, only few examples having been described (Ferreira et al. 1974; Malan & Roux 1974). Complete NMR assignments for 7 were reported previously by Zhu et al. (2009) in DMSOd6. However, some NMR multiplicities are questionable, suggesting that these assignments need to be revised. The olefinic protons H-a and H-b were observed in the 1H NMR spectrum as two doublets with a coupling constant of 15.3 Hz (trans configuration) instead of two singlets (2H, s, dH 7.69) as reported for H-a and H-b (Zhu et al. 2009). The 1H NMR spectrum of compound 7 (butein 40 -O-glucopyranosyl, C21H24O10, m.p. 193.5– 195.58C) was consistent with the presence of a glycosylated chalcone scaffold. Resonances of the aglycone included typical signals of a,b-unsaturated ketone protons at dH 7.46 (1H, d, J ¼ 15.3 Hz, H-a) and dH 7.66 (1H, d, J ¼ 15.3 Hz, H-b); the aromatic ring A was found to be 1,3,4-trisubstituted since the protons resonate at dH 7.10 (1H, d, J ¼ 2.1 Hz, H-2), dH 7.03 (1H, dd, J ¼ 8.1, 2.1 Hz, H-6) and dH 6.73 (1H, d, J ¼ 8.1 Hz, H-5), while the ring B showed same substitution with protons at dH 7.93 (1H, d, J ¼ 9.0 Hz, H-60 ), dH 6.59 (1H, dd, J ¼ 9.0, 2.5 Hz, H-50 ) and dH 6.52 (1H, d, J ¼ 2.5 Hz, H-30 ). The geometry of the olefinic double bond was determined to be E on the basis of the coupling constant (J ¼ 15.3 Hz) between the protons a and b. The 1H NMR spectrum further displayed signal of an anomeric proton at dH 4.94 (1H, d, J ¼ 7.4 Hz, H-100 ). Its coupling constant value and the shifts of the remaining carbinols in the sugar moiety suggested a b-D -glucopyranosylated chalcone. Chemical shift value of anomeric carbon atom (dC 101.4) indicated that the linkage of the glucose occurred through an O-bond. Additionally, the attachment of the glucopyranosyl unit to the aglycone moiety was established by HMBC correlation between the anomeric proton and a quaternary carbon atom at dC 165.4 (C-40 ) in the ring B of the chalcone. The antiprotozoan activity of compounds 1 –9 was investigated against intracellular amastigotes of L. amazonensis and T. cruzi, the causative agents of cutaneous leishmaniasis and Chagas disease, respectively. The results of the in vitro leishmanicidal and trypanocidal activities were expressed in percentage of parasite growth inhibition and are summarised in Table 1. The ability of the compounds to inhibit the growth of the parasite was evaluated at concentration of 50 mM, and the IC50, CC50 and SI values were determined for the most active compounds (%growth inhibition . 50%). Amphotericin B 2 mM and Benznidazole 20 mM were used as positive controls, with 86.88% of inhibition against L. amazonensis and 82.67% against T. cruzi, respectively. DMSO 1% was used as negative control and did not show any growth inhibition.

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Table 1. Intracellular leishmanicidal and trypanocidal activities of isolated compounds from C. uniflora. Material tested concentration (50 mM)

%Growth inhibition ^ SD L. amazonensis amastigotes

1 2 Mixture of 3 þ 4 5 6 7 8 9 DMSO 1% Benznidazole 20 mM Amphotericin B 2 mM

10.94 (^ 1.29) 24.53 (^ 1.04) 24.66 (^ 3.40) 8.21 (^ 0.53) 9.97 (^ 1.20) 11.73 (^ 0.93) 8.59 (^ 2.72) 25.33 (^ 3.55) 0 – 86.88 (^ 3.83)

%Growth inhibition ^ SD T. cruzi amastigotes No activity 76.06 (^ 3.07) 73.34 (^ 0.34) 36.18 (^ 4.41) No activity No activity No activity No activity 0 82.67 (^ 0.88) –

Table 2. IC50 CC50 and SI values for the compound 2 and the mixture of 3 þ 4. Compound Compound 2 Mixture of 3 þ 4

IC50 ^ SD (mM) T. cruzi

CC50 ^ SD (mM) TPH-1 cells

SI

18.27 ( ^ 0.25) 26.53 ( ^ 0.48)

236.7 ( ^ 0.24) 95.91 ( ^ 0.22)

12.95 3.61

None of the phenolic compounds show promising leishmanicidal activity. Compounds 1, and 5 –8 exhibited weak or no activity, while compounds 2, 9 and the mixture of 3 þ 4 revealed moderate leishmanicidal activity, inhibiting 24.53%, 23.33% and 24.66% the parasite intracellular growth, respectively. Ethyl caffeate (2) was the most potent compound against T. cruzi, with 76.06% inhibition on the intracellular growth of the parasite. The mixture of 3 þ 4 revealed a 73.34% inhibitory effect on the growth of T. cruzi. The obtained results demonstrated that these compounds had almost similar effectiveness than the reference drug Benznidazole, which reduced 82.67% of intracellular amastigotes load of T. cruzi. Compounds 1 and 6– 9 did not displayed trypanocidal effect, while 5 exhibited moderate activity (36.18%). Furthermore, as the compound 2 and the mixture of 3 þ 4 showed percentage of inhibition higher than 50%, their IC50, CC50 and SI values were determined and are given in Table 2. Both ethyl caffeate (2) and the mixture of butein þ orobol (3 þ 4) exhibited a significant in vitro activity against the amastigote forms of T. cruzi, displaying IC50 values of 18.27 and 26.53 mM, respectively. The CC50 of compounds 2 and 3 þ 4 was of 236.7 and 95.9 mM, reaching a selectivity index (SI) of 12.95 and 3.61, respectively. These results show that compound 2 exhibited a 2.4 lower cytotoxic effect on THP-1 cells than butein þ orobol (3 þ 4). Additionally, compound 2 showed better selectivity index (SI ¼ 12.95) than 3 þ 4 (SI ¼ 3.61). This is the first report about the trypanocidal activity of ethyl caffeate, butein and orobol. Furthermore, ethyl caffeate, the most active metabolite obtained, may be a lead molecule to be transformed into different analogues in order to develop potent derivatives in antiprotozoal chemotherapy. 3. Experimental 3.1. General methods Melting point was measured with an MQAPF-301 apparatus. 1D and 2D NMR spectrums were recorded on Bruker AVANCE 400 MHz and/or Ascend 600 MHz spectrometers (Bruker BioSpin GmbH, Rheinstetten, Germany). Acetone-d6 or CD3OD was used as solvent, and TMS as internal reference standard (0.00 ppm).

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3.2. Plant material The leaves of C. uniflora were collected in Imbituba, Santa Catarina, Brazil, in October 2012. The identification of plant material was performed by Dr John F. Pruski (New York Botanical Garden), and a voucher specimen (MO-2383317) was deposited at the Missouri Botanical Garden Herbarium (MO), St. Louis, MO, USA. 3.3. Extraction and isolation of chemical constituents Fresh leaves from C. uniflora (2.3 kg) were extracted by maceration at room temperature (ca. 258C) with ethanol 92% for 15 days. Solvent was removed at reduced pressure, yielding 104.0 g of crude extract. Subsequently, crude extract was dissolved in H2O, extracted with n-hexane (Hex), dichloromethane (DCM) and ethyl acetate (EA) in a liquid –liquid partition to afford Hex (26.8 g, F1), DCM (3.2 g, F2) and EA (6.2 g, F3) fractions, as well as a residual aqueous fraction that was lyophilised to give 67.8 g of a hygroscopic solid (F4). F2 (3.2 g) was submitted to vacuum liquid chromatography (VLC) on SiO2 gel and eluted with Hex, DCM, EA and MeOH (pure or in gradient mixtures), yielding 12 sub-fractions (A –M). Sub-fraction F (661.0 mg) was submitted to SiO2 gel column chromatography (CC) and eluted with a gradient of Hex, EA and MeOH to give 240 fractions. The fraction F114– 144, eluted with Hex – EA (80:20), afforded 76.3 mg of compound 1. The fraction F69– 78 was combined and re-chromatographed over Sephadex LH-20 with acetone – MeOH (50:50) and 28 fractions were collected. Fractions F21 –23 were pooled together and yielded 17.9 mg of compound 2. Subsequently, F3 (6.2 g) was further chromatographed by VLC on SiO2 gel using Hex, EA, acetone and MeOH as mobile phase. Eight sub-fractions (A – H) were obtained and the subfraction D (2.5 g) was purified by CC using DCM-MeOH in increasing order of polarity to obtain 151 fractions. Fractions F40 –43 and F55– 67 were combined to give 61.9 mg of a 1:1 mixture of the compounds 3 and 4, and 122.7 mg of compound 5, respectively. In addition, fraction F77– 87 was subjected to a preparative TLC eluted with DCM-MeOH (85:15) to afford 6.0 mg of compound 6. The sub-fractions E and F were pooled (1.28 g) and submitted to a Medium Pressure Liquid Chromatography over reverse phase RP-18 using H2O –MeOH mixtures as mobile phase to yield 171 fractions. Fraction F122 –134, eluted with H2O –MeOH (70:30), gave 12.4 mg of compound 7, whereas F98– 110 was purified by preparative TLC with DCM-MeOH (70:30) as eluent to afford 5.0 mg of compound 8. Finally, fraction F10– 22 was further chromatographed on Sephadex LH-20 eluted with MeOH to yield compound 9 (70.6 mg). Compound 5: Yellowish solid. m.p: 177.1– 178.38C. 1H NMR (CD3OD, 600 MHz): dH 7.61 (d, J ¼ 8.4 Hz, H-60 ), 7.52 (d, J ¼ 2.0 Hz, H-2), 7.24 (dd, J ¼ 8.2, 2.0 Hz, H-6), 6.84 (d, J ¼ 8.2 Hz, H-5), 6.72 (d, J ¼ 2.0 Hz, H-30 ), 6.699 (dd, J ¼ 8.4, 2.0 Hz, H-50 ), 6.696 (s, H-b); 13 C NMR (CD3OD, 150 MHz): dC 125.4 (C-1), 118.7 (C-2), 146.8 (C-3), 149.5 (C-4), 116.7 (C-5), 126.5 (C-6), 115.0 (C-10 ), 169.7 (C-20 ), 99.4 (C-30 ), 168.5 (C-40 ), 114.0 (C-50 ), 126.9 (C-60 ), 147.7 (C-a), 114.7 (C-b), 184.6 (C-b0 ). Compound 7: Orangish powder. m.p: 193.5 – 195.58C. 1H NMR (CD3OD, 600 MHz): dH 7.93 (d, J ¼ 9.0 Hz, H-60 ), 7.66 (d, J ¼ 15.3 Hz, H-b), 7.46 (d, J ¼ 15.3 Hz, H-a), 7.10 (d, J ¼ 2.1 Hz, H-2), 7.03 (dd, J ¼ 8.1, 2.1 Hz, H-6), 6.73 (d, J ¼ 8.1 Hz, H-5), 6.59 (dd, J ¼ 9.0, 2.5 Hz, H-50 ), 6.52 (d, J ¼ 2.5 Hz, H-30 ), 4.94 (d, J ¼ 7.4 Hz, H-100 ), 3.81 (dd, J ¼ 12.1, 2.3 Hz, H-600 a), 3.62 (dd, J ¼ 12.1, 5.5 Hz, H-600 b), 3.39 (dm, J ¼ 7.4 Hz, H-200 ), 3.39 (m, H-300 ), 3.39 (m, H-400 ), 3.32 (ddd, 1H, J ¼ 9.2, 5.5, 2.3 Hz, H-200 ); 13C NMR (CD3OD, 150 MHz): dC 128.5 (C-1), 116.1 (C-2), 147.0 (C-3), 150.5 (C-4), 116.7 (C-5), 124.1 (C-6), 116.9 (C-10 ), 167.1 (C-20 ), 105.3 (C-30 ), 165.4 (C-40 ), 109.5 (C-50 ), 132.9 (C-60 ), 101.4 (C-100 ), 74.9 (C-200 ), 78.4 (C-300 ), 78.4 (C-400 ), 71.4 (C-500 ), 62.5 (C-600 ), 118.5 (C-a), 147.0 (C-b), 194.3 (C-b0 ).

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3.4. Leishmanicidal and trypanocidal screening (a brief description) Leishmanicidal and trypanocidal screening was performed against intracellular amastigotes of L. amazonensis (Schwende et al. 1996) and T. cruzi (Buckner et al. 1996), respectively. Compounds 1 –9 were solubilised in DMSO and serially diluted (50 – 1.56 mM). Infected cell layer was treated by addition of 20 mL of each sample in triplicate. Amphotericin B and Benznidazole were used as positive control for leishmanicidal and trypanocidal activities, respectively. DMSO 1% was utilised as negative control. Optical density was read at 570/630 nm. The cell viability was performed in THP-1 cells by the colorimetric 3-(4,5dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method and the optical densities was read at 540 nm. The complete biological protocol is described in the supplementary material.

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4. Conclusion The phytochemical study from fresh leaves of C. uniflora resulted in the isolation of nine phenolic compounds identified as noreugenin (1), ethyl caffeate (2), butein (3), orobol (4), a-hydroxy-butein (5), caffeic acid (6), butein 40 -O-glucopyranosyl (7), quercetin 3-Oglucopyranosyl (8) and 3,5-di-O-caffeoylquinic acid (9). To the best of our knowledge, this is the first report on the isolation of these compounds from the species C. uniflora. Furthermore, the biological investigation revealed that the isolated compounds were not promising against L. amazonensis; however, compound 2 and the mixture of 3 þ 4 exhibited an interesting trypanocidal effect against T. cruzi amastigote and 2 was 3.5 times more selective than the mixture of 3 þ 4. Supplementary material 1D and 2D NMR data of the compounds 5 and 7 (Figures S1– S9) are available in the supplementary material as well as the biological protocol. Acknowledgements The authors are grateful to Mr Ce´sar Simionato for the plant collection and Dr John Pruski for the identification. Part of this work was performed within the Research Network Natural Products against Neglected Diseases (ResNetNPND).

Disclosure statement No potential conflict of interest was reported by the authors.

Funding The authors thank CAPES/CNPq for financial support.

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Evaluation of leishmanicidal and trypanocidal activities of phenolic compounds from Calea uniflora Less.

The phytochemical study of Calea uniflora led to the isolation of nine phenolic compounds identified as noreugenin (1), ethyl caffeate (2), a mixture ...
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