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

• 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; Cytotoxicity; 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; Parasites; Phthalazines - pharmacology; Superoxide Dismutase - antagonists & inhibitors; Superoxide Dismutase - metabolism; Vector-borne diseases
• ISSN: 0031-1820; 1469-8161; 1469-8161
• DOI: 10.1017/S0031182015000219

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.