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

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 selectiv...

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Bibliographic Details
Published in:Parasitology 2015-07, Vol.142 (8), p.1115-1129
Main Authors: SÁNCHEZ-MORENO, M., GÓMEZ-CONTRERAS, F., NAVARRO, P., MARÍN, C., RAMÍREZ-MACÍAS, I., ROSALES, M. J., CAMPAYO, L., CANO, C., SANZ, A. M., YUNTA, M. J. R.
Format: Article
Language:English
Subjects:
Animals
Enzyme Inhibitors - pharmacology
Female
Humans
Imidazoles - pharmacology
Leishmania - drug effects
Leishmania - enzymology
Leishmania braziliensis
Leishmania braziliensis - drug effects
Leishmania braziliensis - enzymology
Leishmania donovani
Leishmania donovani - drug effects
Leishmania donovani - enzymology
Leishmania infantum
Leishmania infantum - drug effects
Leishmania infantum - enzymology
Leishmaniasis - drug therapy
Leishmaniasis - parasitology
Leishmaniasis, Visceral - drug therapy
Leishmaniasis, Visceral - parasitology
Macrophages
Mice, Inbred BALB C
Oxidation-Reduction
Phthalazines - pharmacology
Superoxide Dismutase - antagonists & inhibitors
Superoxide Dismutase - metabolism
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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.
ISSN:0031-1820
1469-8161
1469-8161
DOI:10.1017/S0031182015000219