Hostname: page-component-78c5997874-g7gxr Total loading time: 0 Render date: 2024-11-19T13:19:56.517Z Has data issue: false hasContentIssue false
  • English
  • Français

In vitro antileishmanial activity and iron superoxide dismutase inhibition of arylamine Mannich base derivatives

Published online by Cambridge University Press:  09 August 2017

ALVARO MARTIN-MONTES ,
MERY SANTIVAÑEZ-VELIZ ,
ELSA MORENO-VIGURI ,
RUBÉN MARTÍN-ESCOLANO ,
CARMEN JIMÉNEZ-MONTES ,
CATALINA LOPEZ-GONZALEZ ,
CLOTILDE MARÍN ,
CARMEN SANMARTÍN ,
RAMÓN GUTIÉRREZ SÁNCHEZ  and
MANUEL SÁNCHEZ-MORENO
...Show all authors
ALVARO MARTIN-MONTES
Affiliation:
Departamento de Parasitología, Instituto de Investigación Biosanitaria (ibs.GRANADA), Hospitales Universitarios De Granada/Universidad de Granada, Granada, Spain
MERY SANTIVAÑEZ-VELIZ
Affiliation:
Universidad de Navarra, Instituto de Salud Tropical, Campus Universitario, 31008 Pamplona, Spain Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia y Nutrición, Universidad de Navarra, Campus Universitario, 31008 Pamplona, Spain
ELSA MORENO-VIGURI
Affiliation:
Universidad de Navarra, Instituto de Salud Tropical, Campus Universitario, 31008 Pamplona, Spain Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia y Nutrición, Universidad de Navarra, Campus Universitario, 31008 Pamplona, Spain
RUBÉN MARTÍN-ESCOLANO
Affiliation:
Departamento de Parasitología, Instituto de Investigación Biosanitaria (ibs.GRANADA), Hospitales Universitarios De Granada/Universidad de Granada, Granada, Spain
CARMEN JIMÉNEZ-MONTES
Affiliation:
Departamento de Parasitología, Instituto de Investigación Biosanitaria (ibs.GRANADA), Hospitales Universitarios De Granada/Universidad de Granada, Granada, Spain
CATALINA LOPEZ-GONZALEZ
Affiliation:
Departamento de Parasitología, Instituto de Investigación Biosanitaria (ibs.GRANADA), Hospitales Universitarios De Granada/Universidad de Granada, Granada, Spain
CLOTILDE MARÍN
Affiliation:
Departamento de Parasitología, Instituto de Investigación Biosanitaria (ibs.GRANADA), Hospitales Universitarios De Granada/Universidad de Granada, Granada, Spain
CARMEN SANMARTÍN
Affiliation:
Universidad de Navarra, Instituto de Salud Tropical, Campus Universitario, 31008 Pamplona, Spain Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia y Nutrición, Universidad de Navarra, Campus Universitario, 31008 Pamplona, Spain
RAMÓN GUTIÉRREZ SÁNCHEZ
Affiliation:
Department of Statistics, University of Granada, Severo Ochoa s/n, 18071 Granada, Spain
MANUEL SÁNCHEZ-MORENO*
Affiliation:
Departamento de Parasitología, Instituto de Investigación Biosanitaria (ibs.GRANADA), Hospitales Universitarios De Granada/Universidad de Granada, Granada, Spain
SILVIA PÉREZ-SILANES*
Affiliation:
Universidad de Navarra, Instituto de Salud Tropical, Campus Universitario, 31008 Pamplona, Spain Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia y Nutrición, Universidad de Navarra, Campus Universitario, 31008 Pamplona, Spain
*
*Corresponding authors: Facultad de Farmacia y Nutrición, Departamento de Química Orgánica y Farmacéutica, Universidad de Navarra, Campus Universitario, 31008 Pamplona, Spain. E-mail: [email protected] and Facultad de Ciencias, Departamento de Parasitología, Universidad de Granada, 18071 Granada, Spain. E-mail: [email protected]
*Corresponding authors: Facultad de Farmacia y Nutrición, Departamento de Química Orgánica y Farmacéutica, Universidad de Navarra, Campus Universitario, 31008 Pamplona, Spain. E-mail: [email protected] and Facultad de Ciencias, Departamento de Parasitología, Universidad de Granada, 18071 Granada, Spain. E-mail: [email protected]
Get access Rights & Permissions [Opens in a new window]

Summary

Leishmaniasis is one of the world's most neglected diseases, and it has a worldwide prevalence of 12 million. There are no effective human vaccines for its prevention, and treatment is hampered by outdated drugs. Therefore, research aiming at the development of new therapeutic tools to fight leishmaniasis remains a crucial goal today. With this purpose in mind, we present 20 arylaminoketone derivatives with a very interesting in vitro and in vivo efficacy against Trypanosoma cruzi that have now been studied against promastigote and amastigote forms of Leishmania infantum, Leishmania donovani and Leishmania braziliensis strains. Six out of the 20 Mannich base-type derivatives showed Selectivity Index between 39 and 2337 times higher in the amastigote form than the reference drug glucantime. These six derivatives affected the parasite infectivity rates; the result was lower parasite infectivity rates than glucantime tested at an IC25 dose. In addition, these derivatives were substantially more active against the three Leishmania species tested than glucantime. The mechanism of action of these compounds has been studied, showing a greater alteration in glucose catabolism and leading to greater levels of iron superoxide dismutase inhibition. These molecules could be potential candidates for leishmaniasis chemotherapy.

Keywords

Leishmania infantumLeishmania donovaniLeishmania braziliensisiron superoxide dismutasearylamine derivativesMannich base derivatives
Type
Research Article
Information
Parasitology , Volume 144 , Issue 13 , November 2017 , pp. 1783 - 1790
Check for updates
Copyright
Copyright © Cambridge University Press 2017 

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

Arun, M. I., Balakrishna, K. and Sridhar, K. (2010). Synthesis, characterization and biological activities of some new benzo[b]thiophene derivatives. European Journal of Medicinal Chemistry 45, 825–830.Google Scholar
Beyer, W. F. and Fridovich, I. (1987). Assaying for superoxide dismutase activity: some large consequences of minor changes in conditions. Analytical Biochemistry 161, 559–566.CrossRefGoogle ScholarPubMed
Bodyl, A. and Mackiewicz, P. (2008). Were class C iron-containing superoxide dismutases of trypanosomatid parasites initially imported into a complex plastid? A hypothesis based on analyses of their N-terminal targeting signals. Parasitology 135, 1101–1110.CrossRefGoogle Scholar
Bradford, M. M. (1976). A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Analytical Biochemistry 72, 248–254.CrossRefGoogle ScholarPubMed
Coimbra, E. S., Antinarelli, L. M., Silva, N. P., Souza, I. O., Meinel, R. S., Rocha, M. N., Soares, R. P. and da Silva, A. D. (2016). Quinoline derivatives: synthesis, leishmanicidal activity and involvement of mitochondrial oxidative stress as mechanism of action. Chemico-Biological Interactions 25, 50–57.CrossRefGoogle Scholar
Félix, M. B., de Souza, E. R., de Lima, M., Frade, D. K., de Serafim, V. L., Rodrigues, K. A., Néris, P. L., Ribeiro, F. F., Scotti, L., Scotti, M. T., de Aquino, T. M., Mendonça, F. J. Jr. and de Oliveira, M. R. (2016). Preliminary antifungal and cytotoxic evaluation of synthetic cycloalkyl[b]thiophene derivatives with PLS-DA analysis. Bioorganic and Medicinal Chemistry 24, 3972–3977.CrossRefGoogle Scholar
Fernandes, I. A., de Almeida, L., Ferreira, P. E., Marques, M. J., Rocha, R. P., Coelho, L. F., Carvalho, D. T. and Viegas, C. (2015). Synthesis and biological evaluation of novel piperidine-benzodioxole derivatives designed as potential leishmanicidal drug candidates. Bioorganic and Medicinal Chemistry Letters 25, 3346–3349.CrossRefGoogle ScholarPubMed
Fernandez-Becerra, C., Sánchez-Moreno, M., Osuna, A. and Opperdoes, F. R. (1997). Comparative aspects of energy metabolism in plant trypanosomatids. Journal of Eukaryotic Microbiology 44, 523–529.CrossRefGoogle Scholar
Ginger, M. (2005). Trypanosomatid biology and euglenozoan evolution: new insights and shifting paradigms revealed through genome sequencing. Protist 156, 377–392.CrossRefGoogle ScholarPubMed
González, P., Marín, C., Rodríguez-González, I., Hitos, A. B., Rosales, M. J., Reina, M., Díaz, J. G., González-Coloma, A. and Sánchez-Moreno, M. (2005). In vitro activity of C20-diterpenoid alkaloid derivatives in promastigotes and intracellular amastigotes of Leishmania infantum . International Journal of Antimicrobial Agents 25, 136–141.CrossRefGoogle ScholarPubMed
Hunter, W. N., Alphey, M. S., Bond, C. S. and Schuttelkopf, A. W. (2003). Targeting metabolic pathways in microbial pathogens: oxidative stress and anti-folate drug resistance in trypanosomatids. Biochemical Society transactions 31, 607–610.CrossRefGoogle ScholarPubMed
Issa, M. I. F., Mohamed, A. A. R., El-Batran, S., Abd El-Salam, O. M. E. and El-Shenawy, S. M. (2009). Synthesis and pharmacological evaluation of 2-substituted benzo[b]thiophenes as anti-inflammatory and analgesic agents. European Journal of Medicinal Chemistry 44, 1718–1725.Google Scholar
Kirkinezos, I. G. and Moraes, C. T. (2001). Reactive oxygen species and mitochondrial diseases. Seminars in Cell & Developmental Biology 12, 449–457.CrossRefGoogle ScholarPubMed
Lee, B., Bauer, H., Melchers, J., Ruppert, T., Rattray, L., Yardley, V., Davioud-Charvet, E. and Krauth-Siegel, R. L. (2005). Irreversible inactivation of trypanothione reductase by unsaturated Mannich bases: a divinyl ketone as key intermediate. Journal of Medicinal Chemistry 48, 7400–7410.CrossRefGoogle ScholarPubMed
Mahal, K., Ahmad, A., Schmitt, F., Lockhauserbäumer, J., Starz, K., Pradhan, R., Padhye, S., Sarkar, F. H., Koko, W. S., Schobert, R., Ersfeld, K. and Biersack, B. (2017). Improved anticancer and antiparasitic activity of new lawsone Mannich bases. European Journal of Medicinal Chemistry 126, 421–431.CrossRefGoogle ScholarPubMed
Manzano, J. I., Cochet, F., Boucherle, B., Gomez-Perez, V., Boumendjel, A., Gamarro, F., Peuchmaur, M. (2016). Arylthiosemicarbazones as antileishmanial agents. European Journal of Medicinal Chemistry 123, 161–170.CrossRefGoogle ScholarPubMed
Marín, C., Ramírez-Macías, I., López-Céspedes, A., Olmo, F., Villegas, N., Díaz, J. G. M., Rosales, J., Gutiérrez-Sánchez, R. and Sánchez-Moreno, M. (2011). In vitro and in vivo trypanocidal activity of flavonoids from Delphinium staphisagria against Chagas disease. Journal of Natural Products 74, 744–750.CrossRefGoogle ScholarPubMed
Menezes, J. P., Guedes, C. E., Petersen, A. L., Fraga, D. B. and Veras, P. S. (2015). Advances in development of new treatment for leishmaniasis. Biomed Research International 2015, 815023.CrossRefGoogle ScholarPubMed
Menna-Barreto, R. F. and de Castro, S. L. (2014). The double-edged sword in pathogenic trypanosomatids: the pivotal role of mitochondria in oxidative stress and bioenergetics. Biomedical Research International 2014, 614014.CrossRefGoogle ScholarPubMed
Moreno-Viguri, E.; Jiménez-Montes, C.; Martín-Escolano, R.; Santivañez-Veliz, M., Martin-Montes, A., Azqueta, A.; Jimenez-Lopez, M.; Zamora Ledesma, S.; Cirauqui, N.; López de Ceráin, A.; Marín, C.; Sánchez-Moreno, M. and Pérez-Silanes, S. (2016). In vitro and in vivo anti-Trypanosoma cruzi activity of new arylamine Mannich base-type derivatives. Journal of Medicinal Chemistry 59, 10929–10945.CrossRefGoogle ScholarPubMed
Mori-Yasumoto, K., Izumoto, R., Fuchino, H., Ooi, T., Agatsuma, Y., Kusumi, T., Satake, M., Sekita, S. (2012). Leishmanicidal activities and cytotoxicities of bisnaphthoquinone analogues and naphthol derivatives from Burman Diospyros burmanica. Bioorganic & Medicinal Chemistry 20, 5215–5219.CrossRefGoogle ScholarPubMed
Nwaka, S. and Hudson, A. (2006). Innovative lead discovery strategies for tropical diseases. Nature Reviews Drug Discovery 5, 941–955.CrossRefGoogle ScholarPubMed
Parise-Filho, R., Pasqualoto, K. F., Magri, F. M., Ferreira, A. K., da Silva, B. A., Damião, M. C., Tavares, M. T., Azevedo, R. A., Auada, A. V., Polli, M. C. and Brandt, C. A. (2012). Dillapiole as antileishmanial agent: discovery, cytotoxic activity and preliminary SAR studies of dillapiole analogues. Archiv der Pharmazie 345, 934–944.CrossRefGoogle ScholarPubMed
Piacenza, L., Zago, M. P., Peluffo, G., Alvarez, M. N., Basombrio, M. A. and Radi, R. (2009). Enzymes of the antioxidant network as novel determiners of Trypanosoma cruzi virulence. International Journal for Parasitology 39, 1455–1464.CrossRefGoogle ScholarPubMed
Puterová, Z., Krutosiková, A. (2010). Substituted 2-aminothiophenes: synthesis, properties and applications. In Heterocyclic Compounds: Synthesis, Properties and Applications (ed. Nylund, K. and Johansson, P.), pp. 1–46. Nova Science Publishers, USA.Google Scholar
Sanchez-Moreno, M., Sanz, A. M., Gomez-Contreras, F., Navarro, P., Marin, C., Ramirez-Macias, I., Rosales, M. J., Olmo, F., Garcia-Aranda, I., Campayo, L., Cano, C., Arrebola, F. and Yunta, M. J. (2011). In vivo trypanosomicidal activity of imidazole- or pyrazole-based benzo[g]phthalazine derivatives against acute and chronic phases of Chagas disease. Journal of Medicinal Chemistry 54, 970–979.CrossRefGoogle ScholarPubMed
Sánchez-Moreno, M., Gómez-Contreras, F., Navarro, P., Marín, C., Ramírez-Macías, I., Olmo, F., Sanz, A. M., Campayo, L., Cano, C. and Yunta, M. J. R. (2012). In vitro leishmanicidal activity of imidazole- or pyrazole-based benzo[g]phthalazine derivatives against Leishmania infantum and Leishmania braziliensis species. Journal of Antimicrobial Chemotherapy 67, 387–397.CrossRefGoogle ScholarPubMed
Sanchez-Moreno, M., Gomez-Contreras, F., Navarro, P., Marin, C., Ramirez-Macias, I., Rosales, M. J., Campayo, L., Cano, C., Sanz, A. M. and Yunta, M. J. (2015). Imidazole-containing phthalazine derivatives inhibit Fe-SOD performance in Leishmania species and are active in vitro against visceral and mucosal leishmaniasis. Parasitology 142, 1115–1129.CrossRefGoogle ScholarPubMed
Sanz, A. M., Gomez-Contreras, F., Navarro, P., Sanchez-Moreno, M., Boutaleb-Charki, S., Campuzano, J., Pardo, M.; Osuna, A., Cano, C., Yunta, M. J. and Campayo, L. (2008). Efficient inhibition of iron superoxide dismutase and of Trypanosoma cruzi growth by benzo[g]phthalazine derivatives functionalized with one or two imidazole rings. Journal of Medicinal Chemistry 51, 1962–1966.CrossRefGoogle ScholarPubMed
Singh, K., Garg, G. and Ali, V. (2016). Current therapeutics, their problems and thiol metabolism as potential drug targets in leishmaniasis. Current Drug Metabolism 17, 897–919.CrossRefGoogle ScholarPubMed
Turrens, J. F. (2004). Oxidative stress and antioxidant defenses: a target for the treatment of diseases caused by parasitic protozoa. Molecular Aspects of Medicine 25, 211–220.CrossRefGoogle ScholarPubMed
Uliana, S. R., Trinconi, C. T. and Coelho, A. C. (2017). Chemotherapy of leishmaniasis: present challenges. Parasitology. 20, 1–17.Google Scholar
Wenzel, I. N., Wong, P. E., Maes, L., Müller, T. J., Krauth-Siegel, R. L., Barrett, M. P., Davioud-Charvet, E. (2009). Unsaturated Mannich bases active against multidrug-resistant Trypanosoma brucei brucei strains. ChemMedChem 4, 339–351.CrossRefGoogle ScholarPubMed
World Health Organization (2016) Leishmaniasis in high-burden countries: an epidemiological update based on data reported in 2014. Weekly Epidemiological Record No. 22, 91, 285–296.Google Scholar
Supplementary material: File

Martin-Montes supplementary material

Supplementary Figure

Download Martin-Montes supplementary material(File)
File 111.3 KB