Hostname: page-component-586b7cd67f-2brh9 Total loading time: 0 Render date: 2024-11-22T18:17:04.382Z Has data issue: false hasContentIssue false
  • English
  • Français

Morita-Baylis-Hillman adduct shows in vitro activity against Leishmania (Viannia) braziliensis associated with a reduction in IL-6 and IL-10 but independent of nitric oxide

Published online by Cambridge University Press:  04 August 2012

F. M. AMORIM ,
Y. K. S. RODRIGUES ,
T. P. BARBOSA ,
P. L. N. NÉRIS ,
J. P. A. CALDAS ,
S. C. O. SOUSA ,
J. A. LEITE ,
S. RODRIGUES-MASCARENHAS ,
M. L. A. A. VASCONCELLOS  and
M. R. OLIVEIRA
F. M. AMORIM
Affiliation:
Universidade Federal da Paraíba, Centro de Ciências Exatas e da Natureza, Programa de Pós-Graduação em Biologia Celular e Molecular, João Pessoa, Paraíba, Brazil Universidade Federal da Paraíba, Departamento de Biologia Molecular, Laboratório Biologia de Leishmania, João Pessoa, Paraíba, Brazil
Y. K. S. RODRIGUES
Affiliation:
Universidade Federal da Paraíba, Centro de Ciências Exatas e da Natureza, Programa de Pós-Graduação em Biologia Celular e Molecular, João Pessoa, Paraíba, Brazil Universidade Federal da Paraíba, Departamento de Biologia Molecular, Laboratório Biologia de Leishmania, João Pessoa, Paraíba, Brazil
T. P. BARBOSA
Affiliation:
Universidade Federal da Paraíba, Centro de Ciências Exatas e da Natureza, Departamento de Química, Laboratório de Síntese Orgânica Medicinal, João Pessoa, Paraíba, Brazil
P. L. N. NÉRIS
Affiliation:
Universidade Federal da Paraíba, Departamento de Biologia Molecular, Laboratório Biologia de Leishmania, João Pessoa, Paraíba, Brazil Universidade Federal da Paraíba, Centro de Ciências da Saúde, Programa de Pós-Graduação em Produtos Naturais e Sintéticos Bioativos, João Pessoa, Paraíba, Brazil
J. P. A. CALDAS
Affiliation:
Universidade Federal da Paraíba, Departamento de Biologia Molecular, Laboratório Biologia de Leishmania, João Pessoa, Paraíba, Brazil Universidade Federal da Paraíba, Centro de Ciências da Saúde, Programa de Pós-Graduação em Produtos Naturais e Sintéticos Bioativos, João Pessoa, Paraíba, Brazil
S. C. O. SOUSA
Affiliation:
Universidade Federal da Paraíba, Centro de Ciências Exatas e da Natureza, Departamento de Química, Laboratório de Síntese Orgânica Medicinal, João Pessoa, Paraíba, Brazil
J. A. LEITE
Affiliation:
Universidade Federal da Paraíba, Centro de Ciências da Saúde, Programa de Pós-Graduação em Produtos Naturais e Sintéticos Bioativos, João Pessoa, Paraíba, Brazil Universidade Federal da Paraíba, Centro de Biotecnologia, Laboratório de Imunofarmacologia, João Pessoa, Paraíba, Brazil
S. RODRIGUES-MASCARENHAS
Affiliation:
Universidade Federal da Paraíba, Centro de Ciências da Saúde, Programa de Pós-Graduação em Produtos Naturais e Sintéticos Bioativos, João Pessoa, Paraíba, Brazil Universidade Federal da Paraíba, Centro de Biotecnologia, Laboratório de Imunofarmacologia, João Pessoa, Paraíba, Brazil
M. L. A. A. VASCONCELLOS
Affiliation:
Universidade Federal da Paraíba, Centro de Ciências Exatas e da Natureza, Departamento de Química, Laboratório de Síntese Orgânica Medicinal, João Pessoa, Paraíba, Brazil
M. R. OLIVEIRA*
Affiliation:
Universidade Federal da Paraíba, Centro de Ciências Exatas e da Natureza, Programa de Pós-Graduação em Biologia Celular e Molecular, João Pessoa, Paraíba, Brazil Universidade Federal da Paraíba, Departamento de Biologia Molecular, Laboratório Biologia de Leishmania, João Pessoa, Paraíba, Brazil Universidade Federal da Paraíba, Centro de Ciências da Saúde, Programa de Pós-Graduação em Produtos Naturais e Sintéticos Bioativos, João Pessoa, Paraíba, Brazil
*
*Corresponding author: Laboratório Biologia de Leishmania, Departamento de Biologia Molecular, Centro de Ciências Exatas e da Natureza, Universidade Federal da Paraíba, Campus I, Castelo Branco, João Pessoa, Paraíba, Brasil, CEP 58059-900. Tel: +55 83 3216 7436. E-mail: [email protected]
Get access Rights & Permissions [Opens in a new window]

Summary

Current treatments for different clinical forms of leishmaniasis are unsatisfactory, highly toxic and associated with increasing failure rates resulting from the emergence of resistant parasites. Leishmania (Viannia) braziliensis is the main aetiological agent of different clinical forms of American tegumentary leishmaniasis, including the mucosal form for which treatment has high failure rates. The aim of this work was to investigate the activity of the Morita-Baylis-Hillman adduct, methyl 2-{2-[hydroxy(2-nitrophenyl)methyl])acryloyloxy} benzoate in vitro against isolates of L. (V.) braziliensis obtained from patients with different clinical manifestations of tegumentary leishmaniasis: localized cutaneous leishmaniasis, mucosal leishmaniasis and disseminated cutaneous leishmaniasis. The adduct effectively inhibited the growth of promastigotes of the different isolates of L. (V.) braziliensis (IC50 ⩽ 7·77 μg/ml), as well as reduced the infection rate of macrophages infected with these parasites (EC50 ⩽ 1·37 μg/ml). It is remarkable to state that the adduct was more effective against intracellular amastigotes (P ⩽ 0·0045). The anti-amastigote activity correlated with an immunomodulatory effect, since the adduct was able to decrease the production of IL-6 and IL-10 by the infected macrophages. However, its effect was independent of nitric oxide production. This work demonstrates the anti-leishmanial activity of methyl 2-{2-[hydroxy(2-nitrophenyl)methyl])acryloyloxy} benzoate and suggests its potential in the treatment of human infections caused by L. (V.) braziliensis.

Keywords

Leishmania (Viannia) braziliensisMorita-Baylis-Hillman adductmacrophageIL-6IL-10nitric oxide
Type
Research Article
Information
Parasitology , Volume 140 , Issue 1 , January 2013 , pp. 29 - 38
Copyright
Copyright © Cambridge University Press 2012

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

REFERENCES

Astelbauer, F. and Walochnik, J. (2011). Antiprotozoal compounds: state of the art and developments. International Journal of Antimicrobial Agents 38, 118–124. doi: 10.1016/j.ijantimicag.2011.03.004.CrossRefGoogle ScholarPubMed
Barbosa, T. P., Junior, C. G. L., Silva, F. L., Lopes, H. M., Figueiredo, L. R. F., Sousa, S. C. O., Batista, G. N., Silva, T. G., Silva, T. M. S., Oliveira, M. R. and Vasconcellos, M. L. A. A. (2009). Improved synthesis of seven aromatic Baylis-Hillman adducts (BHA): Evaluation against Artemia salina Leach and Leishmania chagasi. European Journal of Medicinal Chemistry 44, 4, 1726–1730. doi: 10.1016/j.ejmech.2008.03.016.CrossRefGoogle ScholarPubMed
Barbosa, T. P., Sousa, S. C., Amorim, M. F., Rodrigues, Y. K. S., Assis, P. A. C., Caldas, J. P. A., Oliveira, M. R. and Vasconcellos, M. L. A. A. (2011). Design, synthesis and antileishmanial in vitro activity of new series of chalcones-like compounds: a molecular hybridization approach. Bioorganic and Medicinal Chemistry 19, 4250–4256. doi: 10.1016/j.bmc.2011.05.055.CrossRefGoogle ScholarPubMed
Basavaiah, D., Rao, K. V. and Reddy, R. J. (2007). The Baylis–Hillman reaction: a novel source of attraction, opportunities, and challenges in synthetic chemistry. Chemical Society Reviews 36, 1581–1588. doi: 10.1039/B613741P.CrossRefGoogle ScholarPubMed
Baud, V. and Karin, M. (2001). Signal transduction by tumor necrosis factor and its relatives. Trends in Cell Biology 11, 372–377. doi: 10.1016/S0962-8924(01)02064-5.CrossRefGoogle ScholarPubMed
Boeck, P., Falcão, C. A. B., Leal, P. C., Yunes, R. A., Filho, V. C., Torres-Santos, E. C. and Rossi-Bergmann, B. (2006). Synthesis of chalcone analogues with increased antileishmanial activity. Bioorganic and Medicinal Chemistry 14, 1538–1545. doi: 10.1016/j.bmc.2005.10.005.CrossRefGoogle ScholarPubMed
Bogdan, C. (2001). Nitric oxide and immune response. Nature Immunology 2, 907–916. doi: 10.1038/ni1001-907.CrossRefGoogle Scholar
Bogdan, C. and Röllinghoff, M. (1998). The immune response to Leishmania: mechanisms of parasite control and evasion. International Journal for Parasitology 28, 121–134.CrossRefGoogle ScholarPubMed
Bruijn, M. H. L. and Barker, D. C. (1992). Diagnosis of New World Leishmaniasis: specific detection of species of the Leishmania braziliensis complex by amplification of kinetoplast DNA. Acta Tropica 52, 45–58. doi: 10.1016/0001-706X(92)90006-J.CrossRefGoogle ScholarPubMed
Campos, M. B., Gomes, C. M. C., De Souza, A. A. A., Laison, R., Corbett, C. E. P. and Silveira, F. T. (2008). In vitro infectivity of species of Leishmania (Viannia) responsible for American cutaneous leishmaniasis. Parasitology Research 103, 771–776. doi: 10.1007/s00436-008-1039-8.CrossRefGoogle ScholarPubMed
Carvalho, E. M., Barral, A., Costa, J. M., Bittencourt, A. and Marsden, P. (1994). Clinical and immunopathological aspects of disseminated cutaneous leishmaniasis. Acta Tropica 56, 315–325. doi: 10.1016/0001-706X(94)90103-1.CrossRefGoogle ScholarPubMed
Couper, K. N., Blount, D. G. and Riley, E. M. (2008). IL-10: The master regulator of immunity to infection. The Journal of Immunology 180, 5771–5777.CrossRefGoogle ScholarPubMed
Croft, S. L., Sundar, S. and Fairlamb, A. H. (2006). Drug resistance in leishmaniasis. Clinical Microbiology Reviews 19, 111–126. doi: 10.1128/CMR.19.1.111-126.2006.CrossRefGoogle ScholarPubMed
Decuypere, S., Rijal, S., Yardley, V., De Doncker, S., Laurent, T., Khanal, B., Chappuis, F. and Dujardin, J. C. (2005). Gene expression analysis of the mechanism of natural Sb (V) resistance in Leishmania donovani isolates from Nepal. Antimicrobial Agents and Chemotherapy 49, 4616–4621. doi: 10.1128/AAC.49.11.4616-4621.2005.CrossRefGoogle Scholar
Denton, H., McGregor, J. C. and Coombs, G. H. (2004). Reduction of antileishmanial pentavalent antimonial drugs by parasite-specific thiol-dependent redutase, TDR1. Biochemistry Journal 381, 405–412. doi: 10.1042/BJ20040283.CrossRefGoogle Scholar
De Paiva, Y. G., Souza, A. A., Lima-Junior, C. G., Silva, F. P. L., Filho, E. B. A., De Vasconcelos, C. C., De Abreu, F. C., Goulart, M. O. F. and Vasconcellos, M. L. A. A. (2012). Correlation between electrochemical and theoretical studies on the leishmanicidal activity of twelve Morita-Baylis-Hillman adducts. Journal of the Brazilian Chemical Society 23, 5, 894–904.CrossRefGoogle Scholar
De Souza, R. O. M. A., Pereira, V. L. P., Muzitano, M. F., Falcão, C. A. B., Rossi-Bergmann, B., Filho, E. B. A. and Vasconcellos, M. L. A. A. (2007). High selective leishmanicidal activity of 3-hydroxy-2methylene-3-(4-bromophenyl)propanenitrile and analogous compounds. European Journal of Medicinal Chemistry 42, 99–102. doi: 10.106/j.ejmech.2006.07.013.CrossRefGoogle ScholarPubMed
Diehl, S., Anguita, J., Hoffmeyer, A., Zapton, T., Ihle, J. N., Fikrig, E. and Rincón, M. (2000). Inhibition of Th1 differentiation by IL-6 is mediated by SOCS1. Immunity 13, 805–815.CrossRefGoogle ScholarPubMed
Dos Santos, R. A. N., Júnior, J. B., Rosa, S. I. G., Torquato, H. F., Bassi, C. L., Ribeiro, T. A. N., Júnior, P. T. S., Bessera, S. A. M. S., Fontes, C. J. F., Da Silva, L. E. and Piuvezam, M. R. (2011). Leishmanicidal effect of Spiranthera adoratissima (Rutacea) and its isolated alkaloid skimmianine occurs by nitric oxide dependent mechanism. Parasitology 138, 1224–1233. doi: 10.1017/S0031182011001168.CrossRefGoogle Scholar
Dube, A., Singh, N., Sundar, S. and Singh, N. (2005). Refractoriness to the treatment of sodium stibogluconate in Indian kala-azar field isolates persist in in vitro and in vivo experimental models. Parasitology Research 96, 216–223. doi: 10.1007/s00436-005-1339-1.CrossRefGoogle Scholar
Ephros, M., Bitnun, A., Shaked, P., Waldman, E. and Zilberstein, D. (1999). Stage-specific activity of pentavalent against Leishmania donovani axenic amastigotes. Antimicrobial Agents and Chemotherapy 43, 278–282.CrossRefGoogle ScholarPubMed
Frézard, F., Demicheli, C. and Ribeiro, R. R. (2009). Pentavalent antimonials: new perspectives for old drugs. Molecules 14, 2317–2336. doi: 10.3390/molecules14072317.CrossRefGoogle ScholarPubMed
Gantt, K. R., Goldman, T. L., Miller, M. A., McCormick, M. L., Miller, M. A., Jeronimo, S. M. B., Nascimento, E. T., Britigan, B. E. and Wilson, M. E. (2001). Oxidative response of human and murine macrophages during phagocytosis of Leishmania chagasi. Journal of Immunology 167, 893–901.CrossRefGoogle ScholarPubMed
Goto, H. and Lindoso, J. A. L. (2010). Current diagnosis and treatment of cutaneous and mucocutaneous leishmaniasis. Expert Review of Anti-infective Therapy 8, 4, 419–433. doi: 10.1586/eri.10.19.CrossRefGoogle ScholarPubMed
Goto, H. and Lindoso, J. A. L. (2012). Cutaneous and mucocutaneous leishmaniasis. Infectious Disease Clinics of North America 26, 293–307. doi: 10.1016/j.idc.2012.03.001.CrossRefGoogle ScholarPubMed
Gourbal, B., Sonuc, N., Bhattacharjee, H., Legare, D., Sundar, S., Oullette, M., Rosen, B. P. and Mukhopadhyay, R. (2004). Drug uptake and modulation of drug resistance in Leishmania by aquaglyceroporin*. The Journal of Biological Chemistry 279, 31013–31017. doi: 10.1074/jbc.M403959200.CrossRefGoogle ScholarPubMed
Green, L. C., Wagner, D. A., Glogowski, J., Skipper, P. L., Wishnok, J. S. and Tannenbaum, S. R. (1982). Analysis of nitrate, nitrite and [15N] nitrite in biological fluids. Analytical Biochemistry 126, 131–138.CrossRefGoogle ScholarPubMed
Hatzigeorgiou, D. E., He, S., Sobel, J., Grabstein, K. H., Hafner, A. and Ho, J. (1993). L. IL-6 down-modulates the cytokine-enhanced antileishmanial activity in human macrophages. The Journal of Immunology 151, 3682–3691.CrossRefGoogle ScholarPubMed
Liew, F. Y., Li, Y. and Millot, S. (1990). Tumour necrosis factor (TNF-α) in leishmaniasis. II TNF-α induced macrophage leishmanicidal activity is mediated by nitric oxide from L-arginine. Immunology 71, 556–559.Google ScholarPubMed
Oliveira, M. R., Tafuri, W. L., Afonso, L. C. C., Oliveira, M. A. P., Nicoli, J. R., Vieira, E. C., Scott, P., Melo, M. N. and Vieira, L. Q. (2005). Germ-free mice produce high levels of interferon-gamma in response to infection with Leishmania major but fail to heal lesions. Parasitology 131, 477–488. doi: 10.1017/S0031182005008073.CrossRefGoogle ScholarPubMed
Polonio, T. and Efferth, T. (2008). Leishmaniasis: Drug resistance and natural products (Review). International Journal of Molecular Medicine 22, 277–286. doi: 10.3892/ijmm_00000020.Google Scholar
Rincón, M., Anguita, J., Nakamura, T., Firkrig, E. and Flavell, R. A. (1997). IL-6 directs the differentiation of IL-4 producing CD4+T cells. The Journal of Experimental Medicine 185, 461–469. doi: 10.1084/jem.185.3.46.CrossRefGoogle ScholarPubMed
Sacks, D. and Noben-Trauth, N. (2002). The immunology of susceptibility and resistance to Leishmania major in mice. Nature Reviews Immunology 2, 845–858. doi: 10.1038/nri933.CrossRefGoogle ScholarPubMed
Santos, D. O., Coutinho, C. E. R., Madeira, M. F., Bottino, C. G., Vieira, R. T., Nascimento, S. B., Bernadino, A., Bourguignon, S. C., Corte-Real, S., Pinho, R. T., Rodrigues, C. R. and Castro, H. C. (2008). Leishmaniasis treatment – a challenge that remains: a review. Parasitology Research 103, 1–10. doi: 10.1007/s00436-008-0943-2.CrossRefGoogle ScholarPubMed
Silva, F. P. L., Assis, P. A. C., Junior, C. G., Andrade, N. G., Cunha, S. M. D., Oliveira, M. R. and Vasconcellos, M. L. A. A. (2011). Synthesis, evaluation against Leishmania amazonensis and cytotoxicity assays in macrophages of sixteen new congeners Morita–Baylis–Hillman adducts. European Journal of Medicinal Chemistry 46, 4295–4301. doi: 10.1016/j.ejmech.2011.06.036.CrossRefGoogle ScholarPubMed
Silveira, F. T., Müller, S. R., De Souza, A. A. A., Laison, R., Gomes, C. M. C., Laurenti, M. D. and Corbett, C. E. P. (2008). Revisão sobre a patogenia da leishmaniose tegumentar americana na Amazônia, com ênfase à doença causada por L. (V.) braziliensis e L. (L.) amazonensis. Revista Paraense de Medicina 22, 9–19.Google Scholar
Sundar, S. and Chackavarty, J. (2010). Antimony toxicity. International Journal of Environmental Research and Public Health 7, 4267–4277. doi: 10.3390/ijerph7124267.CrossRefGoogle ScholarPubMed
Tuon, F. F., Amato, V. S., Graf, M. E., Siqueira, A. M., Nicodemo, A. C. and Neto, V. A. (2008). Treatment of New World cutaneous leishmaniasis – a systematic review with a meta-analysis. International Journal of Dermatology 47, 109–124. doi: 10.1111/j.1365-4632.2008.03417.x.CrossRefGoogle ScholarPubMed
Vermeersch, M., Da Luz, R. I., Toté, K., Timmermans, J. P., Cos, P. and Maes, L. (2009). In vitro susceptibilities of Leishmania donovani promastigote and amastigote stages to antileishmanial reference drugs: practical relevance of stage-specific differences. Antimicrobial Agents and Chemotherapy 53, 3855–3859. doi: 10.1128/AAC.00548-09.CrossRefGoogle ScholarPubMed
Vieth, M., Will, A., Schröppel, K., Röllinghoff, M. and Gessner, A. (1994). Interleukin-10 inhibits antimicrobial activity against Leishmania major in murine macrophages. Scandinavian Journal of Immunology 40, 403–409. doi: 10.1111/j.1365-3083.1994.tb03481.x.CrossRefGoogle ScholarPubMed
Vila-del Sol, V., Díaz-Munöz, M. D. and Fresno, M. (2007). Requirement of tumor necrosis factor α and nuclear factor-ΚB in the induction by IFN-γ of inducible nitric oxide synthase in macrophages. Journal of Leukocyte Biology 31, 272–283. doi: 10.1189/jlb.0905529.CrossRefGoogle Scholar
Vouldoukis, I., Bécherel, P. A., Riveros-Moreno, V., Arock, M., Da Silva, O., Debré, P., Mazier, D. and Mossalayi, M. D. (1997). Interleukin-10 and interleukin-4 inhibit intracellular killing of Leishmania infantum and Leishmania major by human macrophages by decreasing nitric oxide generation. European Journal of Immunology 27, 860–865. doi: 10.1002/eji.1830270409.CrossRefGoogle ScholarPubMed
World Health Organization (2010). Control of the Leishmaniasis. WHO Technical Report Series No. 949. World Health Organization, Geneva, Switzerland.Google Scholar