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; p. 1031
• 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: England 01-07-2014
• Subjects: Animals; Antiprotozoal Agents - chemistry; Antiprotozoal Agents - pharmacology; Cell Line; Cell Survival - drug effects; Erythrocytes - drug effects; Female; Humans; Leishmania braziliensis - drug effects; Leishmania braziliensis - enzymology; Leishmania braziliensis - ultrastructure; 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; Polyamines - chemistry; Polyamines - pharmacology; Protozoan Proteins - drug effects; Protozoan Proteins - metabolism; Pyrazoles - chemistry; Pyrazoles - pharmacology; Superoxide Dismutase - drug effects; Superoxide Dismutase - metabolism
• ISSN: 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.