ABSTRACT
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.
Subject(s)
Enzyme Inhibitors/pharmacology , Imidazoles/pharmacology , Leishmania/drug effects , Leishmaniasis/drug therapy , Phthalazines/pharmacology , Superoxide Dismutase/antagonists & inhibitors , Animals , Female , Humans , Leishmania/enzymology , Leishmania braziliensis/drug effects , Leishmania braziliensis/enzymology , Leishmania donovani/drug effects , Leishmania donovani/enzymology , Leishmania infantum/drug effects , Leishmania infantum/enzymology , Leishmaniasis/parasitology , Leishmaniasis, Visceral/drug therapy , Leishmaniasis, Visceral/parasitology , Macrophages , Mice, Inbred BALB C , Oxidation-Reduction , Superoxide Dismutase/metabolismABSTRACT
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.
Subject(s)
Antiprotozoal Agents/pharmacology , Leishmania braziliensis/drug effects , Leishmania infantum/drug effects , Leishmaniasis/drug therapy , Pyrazoles/pharmacology , Superoxide Dismutase/drug effects , Animals , Antiprotozoal Agents/chemistry , Cell Line , Cell Survival/drug effects , Erythrocytes/drug effects , Female , Humans , Leishmania braziliensis/enzymology , Leishmania braziliensis/ultrastructure , Leishmania infantum/enzymology , Leishmania infantum/ultrastructure , 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 , Superoxide Dismutase/metabolismABSTRACT
Quantum-chemical computations using the Hückel method have been performed on quinoline derivatives that exhibit antibacterial activity against E. coli, in order to obtain quantitative structure-activity relationship and drug-receptor interaction data.
