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In vitro leishmanicidal activity of pyrazole-containing polyamine macrocycles which inhibit the Fe-SOD enzyme of Leishmania infantum and Leishmania braziliensis species

Published online by Cambridge University Press:  17 March 2014

P. NAVARRO ,
M. SÁNCHEZ-MORENO ,
C. MARÍN ,
E. GARCÍA-ESPAÑA ,
I. RAMÍREZ-MACÍAS ,
F. OLMO ,
M. J. ROSALES ,
F. GÓMEZ-CONTRERAS ,
M. J. R. YUNTA  and
R. GUTIERREZ-SÁNCHEZ
P. NAVARRO*
Affiliation:
Instituto de Química Médica, Centro de Química Orgánica M. Lora-Tamayo, CSIC, E-28006 Madrid, Spain
M. SÁNCHEZ-MORENO
Affiliation:
Departamento de Parasitología, Facultad de Ciencias, Universidad de Granada, E-18071 Granada, Spain
C. MARÍN
Affiliation:
Departamento de Parasitología, Facultad de Ciencias, Universidad de Granada, E-18071 Granada, Spain
E. GARCÍA-ESPAÑA
Affiliation:
Departamento de Química Inorgánica, Instituto de Ciencia Molecular, Universidad de Valencia, E-46980 Paterna (Valencia), Spain
I. RAMÍREZ-MACÍAS
Affiliation:
Departamento de Parasitología, Facultad de Ciencias, Universidad de Granada, E-18071 Granada, Spain
F. OLMO
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
F. GÓMEZ-CONTRERAS
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
R. GUTIERREZ-SÁNCHEZ
Affiliation:
Departamento de Estadística. Facultad de Ciencias, Universidad de Granada, E-18071 Granada, Spain
*
*Corresponding author: Instituto de Química Médica, Centro de Química Orgánica M. Lora-Tamayo, CSIC, E-28006 Madrid, Spain. E-mail: fercon@ucm.es and iqmnt38@iqm.csic.es
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Summary

The in vitro leishmanicidal activity and cytotoxicity of pyrazole-containing macrocyclic polyamines 1–4 was assayed on Leishmania infantum and Leishmania braziliensis species. Compounds 1–4 were more active and less toxic than glucantime and both infection rates and ultrastructural alterations confirmed that 1 and 2 were highly leishmanicidal and induced extensive parasite cell damage. Modifications in the excretion products of parasites treated with 1–3 were also consistent with substantial cytoplasm alterations. Compound 2 was highlighted as a potent inhibitor of Fe-SOD in both species, whereas its effect on human CuZn-SOD was poor. Molecular modelling suggested that 2 could deactivate Fe-SOD due to a sterically favoured enhanced ability to interact with the H-bonding net that supports the enzyme`s antioxidant features.

Keywords

Leishmania braziliensisLeishmania infantumiron superoxide dismutaseleishmanicidal activitypyrazolepolyamine macrocycle
Type
Research Article
Information
Parasitology , Volume 141 , Issue 8 , July 2014 , pp. 1031 - 1043
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Copyright
Copyright © Cambridge University Press 2014 

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