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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Activity of imidazole compounds on Leishmania (L.) infantum chagasi: reactive oxygen species induced by econazole

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Mesquita, Juliana Tonini [1] ; da Costa-Silva, Thais Alves [1] ; Treiger Borborema, Samanta Etel [1] ; Tempone, Andre Gustavo [1]
Total Authors: 4
[1] Adolfo Lutz Inst, Ctr Parasitol & Mycol, BR-01246900 Sao Paulo - Brazil
Total Affiliations: 1
Document type: Journal article
Source: Molecular and Cellular Biochemistry; v. 389, n. 1-2, p. 293-300, APR 2014.
Web of Science Citations: 18

Drug repositioning has been considered a promising approach to discover novel treatments against neglected diseases. Among the major protozoan diseases, leishmaniasis remains a public health threat with few therapeutic alternatives, affecting 12 million people in 98 countries. In this study, we report the in vitro antileishmanial activity of the imidazole drugs clotrimazole, and for the first time in literature, econazole and bifonazole and their potential action to affect the regulation of reactive oxygen species (ROS) of the parasites. The lethal action of the imidazoles was investigated using spectrofluorimetric techniques to detect ROS content, plasma membrane permeability, and mitochondrial membrane potential. The imidazoles showed activity against L. (L.) infantum chagasi promastigotes with IC50 values in a range of 2-8 mu M; econazole was also effective against Leishmania intracellular amastigotes, with an IC50 value of 11 mu M, a similar in vitro effectiveness to miltefosine. Leishmania promastigotes rapidly up-regulated the ROS release after incubation with the imidazoles, but econazole showed a marked increase in ROS content of approximately 1,900 % higher than untreated parasites. When using SYTOXA (R) Green as a fluorescent probe, the imidazoles demonstrated considerable interference in plasma membrane permeability at the early time of incubation; econazole resulted in the higher influx of SYTOXA (R) Green at 60 min. Despite cellular alterations, no depolarization could be observed to the mitochondrial membrane potential of Leishmania until 60 min. The lethal action of econazole involved strong permeabilization of plasma membrane of promastigotes, with an overloaded ROS content that contributed to the death of parasites. Affecting the ROS regulation of Leishmania via small molecules would be an interesting strategy for new drugs. (AU)

FAPESP's process: 12/18756-1 - Evaluation of novel alternative therapies with synthetic drugs using in vitro and experimental models of Leishmania (L.) infantum chagasi
Grantee:André Gustavo Tempone Cardoso
Support type: Regular Research Grants