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

• Published in: Parasitology Vol. 141; no. 8; pp. 1031 - 1043
• Main Authors: 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., GUTIERREZ-SÁNCHEZ, R.
• Format: Journal Article
• Language: English
• Published: Cambridge, UK Cambridge University Press 01.07.2014
• Subjects: Animals; Antiprotozoal Agents - chemistry; Antiprotozoal Agents - pharmacology; Cell Line; Cell Survival - drug effects; Cytotoxicity; Erythrocytes - drug effects; Female; Humans; Leishmania braziliensis; Leishmania braziliensis - drug effects; Leishmania braziliensis - enzymology; Leishmania braziliensis - ultrastructure; Leishmania infantum; Leishmania infantum - drug effects; Leishmania infantum - enzymology; Leishmania infantum - ultrastructure; Leishmaniasis - drug therapy; Leishmaniasis - parasitology; Macrocyclic Compounds - chemistry; Macrocyclic Compounds - pharmacology; Macrophages - drug effects; Mice, Inbred BALB C; Microscopy, Electron, Transmission; Models, Molecular; Parasites; Polyamines - chemistry; Polyamines - pharmacology; Protozoan Proteins - drug effects; Protozoan Proteins - metabolism; Pyrazoles - chemistry; Pyrazoles - pharmacology; Superoxide Dismutase - drug effects; Superoxide Dismutase - metabolism; Leishmania braziliensis; pyrazole; Leishmania infantum; leishmanicidal activity; polyamine macrocycle; iron superoxide dismutase
• ISSN: 0031-1820; 1469-8161; 1469-8161
• DOI: 10.1017/S0031182014000201

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.