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5′‐Trityl‐Substituted Thymidine Derivatives as a Novel Class of Antileishmanial Agents: Leishmania infantum EndoG as a Potential Target
Author(s) -
Casanova Elena,
Moreno David,
Gigante Alba,
Rico Eva,
Genes Carlos Mario,
Oliva Cristina,
Camarasa MaríaJosé,
Gago Federico,
JiménezRuiz Antonio,
PérezPérez MaríaJesús
Publication year - 2013
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201300129
Subject(s) - amastigote , leishmania infantum , thymidine , axenic , intracellular , chemistry , leishmania , nuclease , programmed cell death , kinetoplast , in vitro , leishmaniasis , biochemistry , microbiology and biotechnology , dna , biology , pharmacology , apoptosis , visceral leishmaniasis , immunology , parasite hosting , genetics , world wide web , bacteria , computer science
Two series of 5′‐triphenylmethyl (trityl)‐substituted thymidine derivatives were synthesized and tested against Leishmania infantum axenic promastigotes and amastigotes. Several of these compounds show significant antileishmanial activity, with IC 50 values in the low micromolar range. Among these, 3′‐ O ‐(isoleucylisoleucyl)‐5′‐ O ‐(3,3,3‐triphenylpropanoyl)thymidine displays particularly good activity against intracellular amastigotes. Assays performed to characterize the nature of parasite cell death in the presence of the tritylthymidines indicated significant alterations in mitochondrial transmembrane potential, an increase in superoxide concentrations, and also significant decreases in DNA degradation during the cell death process. Results point to the mitochondrial nuclease LiEndoG as a target for the action of this family of compounds.