5′-Trityl-Substituted Thymidine Derivatives as a Novel Class of Antileishmanial Agents: Leishmania infantum EndoG as a Potential Target

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 IC50 values in the low micromolar range. Among these, 3...

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Bibliographic Details
Published in:ChemMedChem 2013-07, Vol.8 (7), p.1161-1174
Main Authors: Casanova, Elena, Moreno, David, Gigante, Alba, Rico, Eva, Genes, Carlos Mario, Oliva, Cristina, Camarasa, María-José, Gago, Federico, Jiménez-Ruiz, Antonio, Pérez-Pérez, María-Jesús
Format: Article
Language:eng ; ger
Subjects:
amino acids
Antiparasitic Agents - chemical synthesis
Antiparasitic Agents - chemistry
Antiparasitic Agents - pharmacology
Apoptosis
Cell Death - drug effects
Cells
Dose-Response Relationship, Drug
Endodeoxyribonucleases - antagonists & inhibitors
Endodeoxyribonucleases - metabolism
endonucleases
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Humans
Jurkat Cells
leishmania
Leishmania infantum
Leishmania infantum - drug effects
Leishmania infantum - enzymology
Mitochondria - enzymology
Molecular Structure
Structure-Activity Relationship
thymidine
Thymidine - chemical synthesis
Thymidine - chemistry
Thymidine - pharmacology
trityl groups
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Summary: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 IC50 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. LiEndoG as drug target? Thymidine derivatives with a triphenylmethyl substituent at the 5′‐position exhibit significant activity against Leishmania infantum parasites. Characterization of cell death points toward the mitochondrial endonuclease G (LiEndoG) as a target.
ISSN:1860-7179
1860-7187
DOI:10.1002/cmdc.201300129