In Vitro and in Vivo Trypanosomicidal Activity of Pyrazole-Containing Macrocyclic and Macrobicyclic Polyamines: Their Action on Acute and Chronic Phases of Chagas Disease

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• 作者：Manuel S谩nchez-Moreno ; Clotilde Mar铆n ; Pilar Navarro ; Laurent Lamarque ; Enrique Garc铆a-Espa帽a ; Carlos Miranda ; Oscar Huertas ; Francisco Olmo ; Fernando G贸mez-Contreras ; Javier Pitarch ; Francisco Arrebola
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：May 10, 2012
• 年：2012
• 卷：55
• 期：9
• 页码：4231-4243
• 全文大小：470K
• 年卷期：v.55,no.9(May 10, 2012)
• ISSN：1520-4804

文摘

The in vitro and in vivo anti-Trypanosoma cruzi activity of the pyrazole-containing macrobicyclic polyamine 1 and N-methyl- and N-benzyl-substituted monocyclic polyamines 2 and 3 was studied. Activity against both the acute and chronic phases of Chagas disease was considered. The compounds were more active against the parasite and less toxic against Vero cells than the reference drug benznidazole, but 1 and 2 were especially effective, where cryptand 1 was the most active, particularly in the chronic phase. The activity results found for these compounds were complemented and discussed by considering their inhibitory effect on the iron superoxide dismutase enzyme of the parasite, the nature of the metabolites excreted after treatment, and the ultrastructural alterations produced. A complementary histopathological analysis confirmed that the compounds tested were significantly less toxic to mammals than the reference drug and that 1 and 2 exhibited lower levels of damage than 3.