Scorpiand-like azamacrocycles prevent the chronic establishment of Trypanosoma cruzi in a murine model
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- 作者：Francisco Olmo ; Clotilde Mar铆n ; M. Paz Clares ; Salvador Blasco ; M. Teresa Albelda ; Conxa Soriano ; Ram贸n Guti茅rrez-S谩nchez ; Francisco Arrebola-Vargas ; Enrique Garc铆a-Espa帽a ; Manuel S谩nchez-Moreno
- 关键词：Trypanosoma cruzi ; Synthetic aza-scorpiand ; Trypanocidal activity ; In vivo activity
- 刊名：European Journal of Medicinal Chemistry
- 出版年：December, 2013
- 年：2013
- 卷：70
- 期：Complete
- 页码：189-198
- 全文大小：1803 K
文摘
Chagas disease is today one of the most important neglected diseases for its upcoming expansion to non-endemic areas and has become a threat to blood recipients in many countries. In this study, the trypanocidal activity of ten derivatives of a family of aza-scorpiand like macrocycles is evaluated against Trypanosoma cruzi in聽vitro and in聽vivo murine model in which the acute and chronic phases of Chagas disease were analyzed. The compounds 4, 3 and 1 were found to be more active against the parasite and less toxic against Vero cells than the reference drug benznidazole, 4 being the most active compound, particularly in the chronic phase. While all these compounds showed a remarkable degree of inhibition of the Fe-SOD enzyme of the epimastigote forms of T.聽cruzi, they produced a negligible inhibition of human CuZn-SOD and Mn-SOD from Escherichia coli. The modifications observed by 1H NMR and the amounts of excreted catabolites by the parasites after treatment suggested that the mechanism of action could be based on interactions of the side chains of the compounds with enzymes of the parasite metabolism. The ultrastructural alterations observed in treated epimastigote forms confirmed that the compounds having the highest activity are those causing the largest cell damage. A complementary histopathological analysis confirmed that the compounds tested were significantly less toxic to mammals than the reference drug.