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Imidazole-containing phthalazine derivatives inhibit Fe-SOD performance in Leishmania species and are active in vitro against visceral and mucosal leishmaniasis

Published online by Cambridge University Press:  31 March 2015

M. SÁNCHEZ-MORENO ,
F. GÓMEZ-CONTRERAS ,
P. NAVARRO ,
C. MARÍN ,
I. RAMÍREZ-MACÍAS ,
M. J. ROSALES ,
L. CAMPAYO ,
C. CANO ,
A. M. SANZ  and
M. J. R. YUNTA
M. SÁNCHEZ-MORENO*
Affiliation:
Departamento de Parasitología, Facultad de Ciencias, Universidad de Granada, E-18071 Granada, Spain
F. GÓMEZ-CONTRERAS*
Affiliation:
Departamento de Química Orgánica, Facultad de Química, Universidad Complutense, E-28040 Madrid, Spain
P. NAVARRO
Affiliation:
Instituto de Química Médica, Centro de Química Orgánica M. Lora-Tamayo, CSIC, E-28006 Madrid, Spain
C. MARÍN
Affiliation:
Departamento de Parasitología, Facultad de Ciencias, Universidad de Granada, E-18071 Granada, Spain
I. RAMÍREZ-MACÍAS
Affiliation:
Departamento de Parasitología, Facultad de Ciencias, Universidad de Granada, E-18071 Granada, Spain
M. J. ROSALES
Affiliation:
Departamento de Parasitología, Facultad de Ciencias, Universidad de Granada, E-18071 Granada, Spain
L. CAMPAYO
Affiliation:
Departamento de Química Orgánica, Facultad de Química, Universidad Complutense, E-28040 Madrid, Spain
C. CANO
Affiliation:
Departamento de Química Orgánica, Facultad de Química, Universidad Complutense, E-28040 Madrid, Spain
A. M. SANZ
Affiliation:
Departamento de Química Orgánica, Facultad de Química, Universidad Complutense, E-28040 Madrid, Spain
M. J. R. YUNTA
Affiliation:
Departamento de Química Orgánica, Facultad de Química, Universidad Complutense, E-28040 Madrid, Spain
*
* Corresponding authors: Departamento de Parasitología, Facultad de Ciencias, Universidad de Granada, E-18071 Granada, Spain. Email: [email protected] and Departamento de Química Orgánica, Facultad de Química, Universidad Complutense, E-28040 Madrid, Spain. Email: [email protected]
* Corresponding authors: Departamento de Parasitología, Facultad de Ciencias, Universidad de Granada, E-18071 Granada, Spain. Email: [email protected] and Departamento de Química Orgánica, Facultad de Química, Universidad Complutense, E-28040 Madrid, Spain. Email: [email protected]
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Summary

The in vitro leishmanicidal activity of a series of imidazole-containing phthalazine derivatives 1–4 was tested on Leishmania infantum, Leishmania braziliensis and Leishmania donovani parasites, and their cytotoxicity on J774·2 macrophage cells was also measured. All compounds tested showed selectivity indexes higher than that of the reference drug glucantime for the three Leishmania species, and the less bulky monoalkylamino substituted derivatives 2 and 4 were clearly more effective than their bisalkylamino substituted counterparts 1 and 3. Both infection rate measures and ultrastructural alterations studies confirmed that 2 and 4 were highly leishmanicidal and induced extensive parasite cell damage. Modifications to the excretion products of parasites treated with 2 and 4 were also consistent with substantial cytoplasmic alterations. On the other hand, the most active compounds 2 and 4 were potent inhibitors of iron superoxide dismutase enzyme (Fe-SOD) in the three species considered, whereas their impact on human CuZn-SOD was low. Molecular modelling suggests that 2 and 4 could deactivate Fe-SOD due to a sterically favoured enhanced ability to interact with the H-bonding net that supports the antioxidant features of the enzyme.

Keywords

Leishmania infantumLeishmania donovaniLeishmania braziliensisiron superoxide dismutaseimidazolephthalazine derivatives
Type
Research Article
Information
Parasitology , Volume 142 , Issue 8 , July 2015 , pp. 1115 - 1129
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Copyright
Copyright © Cambridge University Press 2015 

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References

REFERENCES

Abreu, I. A. and Cabelli, D. E. (2010). Figure 2 in superoxide dismutases: a review of the metal-associated mechanistic variations. Biochimica et Biophysica Acta 1804, 263–274.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.Google Scholar
Blasco, S., Verdejo, B., Clarés, M. P., Castillo, C. E., Algarra, A. G., Latorre, J., Máñez, M. A., Basallote, M. G., Soriano, C. and García-España, E. (2010). Hydrogen and copper ion induced molecular reorganizations in two new scorpiand-like ligands appended with pyridine rings. Inorganic Chemistry. 49, 7016–7027.Google 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
Bringaud, F., Riviere, L. and Coustou, V. (2006). Energy metabolism of trypanosomatids: adaptation to available carbon sources. Molecular and Biochemical Parasitology 149, 1–9.Google Scholar
Case, D. A., Cheatham, T. E., Darden, T., Gohlke, H., Luo, R., Merz, K. M., Onufriev, A., Simmerling, C., Wang, B. and Woods, R. J. (2005). The Amber biomolecular simulation programs. Journal of Computational Chemistry 26, 1668–1688.CrossRefGoogle ScholarPubMed
Cazzulo, J. J. (1992). Aerobic fermentation of glucose by trypanosomatids. FASEB Journal 6, 3153–3161.CrossRefGoogle ScholarPubMed
Chappuis, F., Sundar, S., Hailu, A., Ghalib, H., Rijal, S., Peeling, R. W., Alvar, J. and Boelaert, M. (2007). Visceral leishmaniasis: what are the needs for diagnosis, treatment and control? Nature Reviews Microbiology 5, 873–882.Google Scholar
Cornell, W.D., Cieplak, P., Bayly, C. I., Gould, I. R., Merz, K. M. Jr, Ferguson, D. M., Spellmeyer, D. C., Fox, T., Caldwell, J. W. and Kollman, P. A. (1995). A Second Generation Force Field for the Simulation of Proteins, Nucleic Acids, and Organic Molecules. J. Am. Chem. Soc. 117, 5179–5197.Google Scholar
Croft, S. L., Sundar, S. and Fairlamb, A. H. (2006). Drug resistance in Leishmaniasis. Clinical Microbiology Reviews 19, 111–126.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.Google Scholar
Flohé, L. (2009). In search of trypanocidal drugs. In Antiparasitic and antibacterial drug discovery (ed. Selzer, P. M.), pp. 211–227. Wiley CH Verlag GmbH & Co KGaA, Weinheim.Google Scholar
Freitas-Junior, L. H., Chatelain, E., Kim, H. A. and Siqueira-Neto, J. L. (2012). Visceral leishmaniasis treatment: what do we have, what do we need and how to deliver it? International Journal for Parasitology Drugs and Drug Resistance 2, 11–19.Google Scholar
Ginger, M. (2005). Trypanosomatid biology and euglenozoan evolution: new insights and shifting paradigms revealed through genome sequencing. Protist 156, 377–392.Google Scholar
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 Antimicrobial Agents 25, 136–141.Google Scholar
Han, W. G., Lovell, T. and Noodleman, L. (2002). Coupled redox potentials in manganese and iron superoxide dismutases from reaction kinetics and density functional/electrostatics calculations. Inorganic Chemistry 41, 20–218.CrossRefGoogle ScholarPubMed
Kirkinezos, I. G. and Moraes, C. T. (2001). Reactive oxygen species and mitochondrial diseases. Cell and Developmental Biology 12, 449–457.Google ScholarPubMed
Lamarque, L., Navarro, P., Miranda, C., Arán, V. J., Ochoa, C., Escartí, F., García-España, E., Latorre, J., Luis, S. V. and Miravet, J. F. (2001). Dopamine interaction in the absence and in the presence of Cu(II) ions with macrocyclic and macrobicyclic polyamines containing pyrazole units. Crystal structures of [Cu2(L1)(H2O)2](ClO4)4 and [Cu2(H−1L3)](ClO4). Journal of the American Chemical Society 123, 10560–10570.Google Scholar
Loiseau, P. M., Cojean, S. and Schrével, J. (2011). Sitamaquine as a putative antileishmanial drug candidate: from the mechanism of action to the risk of drug resistance. Parasite 18, 115–119.Google Scholar
Longoni, S. S., Sánchez-Moreno, M., López, J. E. and Marín, C. (2013). Leishmania infantum secreted iron superoxide dismutase purification and its application to the diagnosis of canine Leishmaniasis. Comparative Immunology, Microbiology and Infectious Disease 36, 499–506.Google Scholar
Lukes, J., Mauricio, I. L., Schönian, G., Dujardin, J. C., Soteriadou, K., Dedet, J. P., Kuhls, K., Tintaya, K. W. Q., Jirků, M., Chocholová, E., Haralambous, C., Pratlong, F., Oborník, M., Horák, A., Ayala, F. J. and Miles, M. A. (2007). Evolutionary and geographical history of the Leishmania donovani complex with a revision of current taxonomy. PNAS 104, 9375–9380.CrossRefGoogle ScholarPubMed
Manta, B., Comini, M., Medeiros, A., Hugo, M., Trujillo, M. and Radi, R. (2013). Trypanothione: a unique bis-glutathionyl derivative in trypanosomatids. Biochimica et Biophysica Acta 1830, 3199–3216.Google Scholar
Marín, C., Ramírez-Macías, I., López-Céspedes, A., Olmo, F., Villegas, N., Díaz, J. G., Rosales, M. 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
Marín, C., Clares, M. P., Ramírez-Macías, I., Blasco, S., Olmo, F., Soriano, C., Verdejo, B., Rosales, M. J., Gómez-Herrera, D., García-España, E. and Sánchez-Moreno, M. (2013). In vitro activity of scorpiand-like azamacrocycle derivatives in promastigotes and intracellular amastigotes of Leishmania infantum and Leishmania braziliensis . European Journal of Medicinal Chemistry 62, 466–477.Google Scholar
Michels, P. A. M., Bringaud, F., Herman, M. and Hannaert, V. (2006). Metabolic functions of glycosomes in trypanosomatids. Biochimica et Biophysica Acta 1763, 1463–1477.Google Scholar
Miller, A. F. (2004). Superoxide dismutases: active sites that save, but a protein that kills. Current Opinion in Chemical Biology 8, 162–168.Google Scholar
Miller, A. F., Sorkin, D. L. and Padmakumar, K. (2005). Anion binding properties of reduced and oxidized iron-containing superoxide dismutase reveal no requirement for tyrosine 34. Biochemistry 44, 5969–5981.CrossRefGoogle ScholarPubMed
Miranda, C., Escartí, F., Lamarque, L., Yunta, M. J. R., Navarro, P., García-España, E. and Jimeno, M. L. (2004). New 1H-pyrazolecontaining polyamine receptors able to complex L-glutamate in water at physiological pH values. Journal of the American Chemical Society 126, 823–833.Google Scholar
Muñoz, I. G., Morán, J. F., Becana, M. and Montoya, G. (2005). The crystal structure of an eukaryotic iron superoxide dismutase suggests intersubunit cooperation during catalysis. Protein Science 14, 387–394.CrossRefGoogle ScholarPubMed
Navarro, P., Sánchez-Moreno, M., Marín, C., García-España, E., Ramírez-Macías, I., Olmo, F., Rosales, M. J., Gómez-Contreras, F., Yunta, M. J. R. and Gutiérrez-Sánchez, R. (2014). In vitro leishmanicidal activity of pyrazole-containing polyamine macrocycles which inhibit the Fe-SOD enzyme of L. infantum and L. braziliensis species. Parasitology 141, 1031–1043.Google Scholar
Nwaka, S., Besson, D., Ramirez, B., Maes, L., Matheeussen, A., Bickle, Q., Mansour, N. R., Yousif, F., Townson, S., Gokool, S., Cho-Ngwa, F., Samje, M., Misra-Bhattacharya, S., Murthy, P. K., Fakorede, F., Paris, J. M., Yeates, C., Ridley, R., Van Voorhis, W. C. and Geary, T. (2011). Integrated dataset of screening hits against multiple neglected disease pathogens. PLoS Neglected Tropical Diseases 5, 658, e1412.Google Scholar
Olmo, F., Marín, C., Clares, M. P., Blasco, S., Albelda, M. T., Soriano, C., Gutiérrez-Sánchez, R., Arrebola-Vargas, F., García-España, E. and Sánchez-Moreno, M. (2013). Scorpiand-like azamacrocycles prevent the chronic establishment of Trypanosoma cruzi in a murine model. European Journal of Medicinal Chemistry 70, 189–198.CrossRefGoogle ScholarPubMed
Ouellette, M., Drummelsmith, J. and Papadopoulou, B. (2004). Leishmaniasis: drugs in the clinic, resistance and new developments. Drug Resistance Update 7, 257–266.CrossRefGoogle ScholarPubMed
Reviriego, F., Navarro, P., García-España, E., Abelda, M. T., Frías, J. C., Domenech, A., Yunta, M. J. R., Costa, R. and Ortí, E. (2008). Diazatetraester 1H-pyrazole crowns as fluorescent chemosensors for AMPH, METH, MDMA (ecstasy), and dopamine. Organic Letters 10, 5099–5102.Google Scholar
Rodríguez-Ciria, M., Sanz, A. M., Yunta, M. J. R., Gómez-Contreras, F., Navarro, P., Sanchez–Moreno, M., Boutaleb-Charki, S., Osuna, A., Castiñeiras, A., Pardo, M., Cano, C. and Campayo, L. (2007). 1,4-Bis(alkylamino)benzo[g]phthalazines able to form complexes of Cu(II) which as free ligands behave as SOD inhibitors and show efficient in vitro activity against Trypanosoma cruzi . Bioorganic Medicinal Chemistry 15, 2081–2091.CrossRefGoogle Scholar
Ryan, K. J., Ray, C. G., Ahmad, N., Lawrence Drew, W. and Plorde, J. J. (2010). Sherris Medical Microbiology: an Introduction to Infectious Diseases, 5th Edn. McGraw Hill, New York.Google Scholar
Sánchez-Moreno, M., Sanz, A. M., Gómez-Contreras, F., Navarro, P., Marín, C., Ramírez-Macías, I., Rosales, M. J., Olmo, F., García-Aranda, I., Campayo, L., Cano, C., Arrebola, F. and Yunta, M. J. R. (2011). In vivo trypanosomicidal activity of imidazole- or pyrazole-based benzo[g]phthalazine derivatives against acute and chronic phases of Chagas disease. Journal Medicinal Chemistry 54, 970–979.Google Scholar
Sánchez-Moreno, M., Marín, C., Navarro, P., Lamarque, L., García-España, E., Miranda, C., Huertas, O., Olmo, F., Gómez-Contreras, F., Pitarch, J. and Arrebola, F. (2012 a). In vitro and in vivo trypanosomicidal activity of pyrazole-containing macrocyclic and macrobicyclic polyamines: their action on acute and chronic phases of Chagas disease. Journal Medicinal Chemistry 55, 4231–4243.Google Scholar
Sánchez-Moreno, M., Gómez-Contreras, F., Navarro, P., Marín, C., Olmo, F., Yunta, M. J. R., Sanz, A. M., Rosales, M. J., Cano, C. and Campayo, L. (2012 b). Phthalazine derivatives containing imidazole rings behave as Fe-SOD inhibitors and show remarkable anti-T. cruzi activity in immunodeficient-mouse mode of infection. Journal Medicinal Chemistry 55, 9900–9913.Google Scholar
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 c). In vitro leishmanicidal activity of imidazole- or pyrazole-based benzo[g]phthalazine derivatives against L. infantum and L. braziliensis species. Journal Antimicrobial Chemotherapy 67, 387–397.Google Scholar
Seifert, K. (2011). Structures, targets and recent approaches in anti-leishmanial drug: discovery and development. Open Medicinal Chemistry Journal 5, 31–39.Google Scholar
Turrens, J. F. (1999). More differences in energy metabolism between trypanosomatidae. Parasitology Today 15, 346–348.Google Scholar
Turrens, J. F. (2004). Oxidative stress and antioxidant defences: a target for the treatment of diseases caused by parasitic protozoa. Molecular Aspects of Medicine 25, 211–220.Google Scholar
Von der Malsburg, K., Müller, J. M., Bohnert, M., Oeljeklaus, S., Kwiatkowska, P., Becker, T., Loniewska-Lwowska, A., Wiese, S., Rao, S., Milenkovic, D., Hutu, D. P., Zerbes, R. M., Schulze-Specking, A., Meyer, H. E., Martinou, J. C., Rospert, S., Rehling, P., Meisinger, C., Veenhuis, M., Warscheid, B., van der Klei, I. J., Pfanner, N., Chacinska, A. and van der Laan, M. (2011). Dual role of mitofilin in mitochondrial membrane organization and protein biogenesis. Developmental Cell 21, 694–707.Google Scholar
Yikilmaz, E., Xie, J., Brunold, T. C. and Miller, A. F. (2002). Hydrogen bond mediated tuning of the redox potential of the non-heme Fe site of superoxide dismutase. Journal of the American Chemical Society 124, 3482–3483.Google Scholar
Yikilmaz, E., Rodgers, D. W. and Miller, A. F. (2006). The crucial importance of chemistry in the structure-function link: manipulating hydrogen bonding in iron-containing superoxide dismutase. Biochemistry 45, 1151–1161.CrossRefGoogle ScholarPubMed