Skip to main content Accessibility help

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



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 There are no effective human vaccines for its prevention, and treatment is hampered by outdated drugs.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.


Corresponding author

*Corresponding authors: Facultad de Farmacia y Nutrición, Departamento de Química Orgánica y Farmacéutica, Universidad de Navarra, Campus Universitario, 31008 Pamplona, Spain. E-mail: and Facultad de Ciencias, Departamento de Parasitología, Universidad de Granada, 18071 Granada, Spain. E-mail:


Hide All
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, 825830.
Beyer, W. F. and Fridovich, I. (1987). Assaying for superoxide dismutase activity: some large consequences of minor changes in conditions. Analytical Biochemistry 161, 559566.
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, 11011110.
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, 248254.
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, 5057.
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, 39723977.
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, 33463349.
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, 523529.
Ginger, M. (2005). Trypanosomatid biology and euglenozoan evolution: new insights and shifting paradigms revealed through genome sequencing. Protist 156, 377392.
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, 136141.
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, 607610.
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, 17181725.
Kirkinezos, I. G. and Moraes, C. T. (2001). Reactive oxygen species and mitochondrial diseases. Seminars in Cell & Developmental Biology 12, 449457.
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, 74007410.
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, 421431.
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, 161170.
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, 744750.
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.
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.
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, 1092910945.
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, 52155219.
Nwaka, S. and Hudson, A. (2006). Innovative lead discovery strategies for tropical diseases. Nature Reviews Drug Discovery 5, 941955.
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, 934944.
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, 14551464.
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. 146. Nova Science Publishers, USA.
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, 970979.
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, 387397.
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, 11151129.
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, 19621966.
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, 897919.
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, 211220.
Uliana, S. R., Trinconi, C. T. and Coelho, A. C. (2017). Chemotherapy of leishmaniasis: present challenges. Parasitology. 20, 117.
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, 339351.
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.


Type Description Title
Supplementary materials

Martin-Montes supplementary material
Supplementary Figure

 Word (111 KB)
111 KB

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



Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed