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

Abstract

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.

Leishmania infantum EndoG Is an Endo/Exo-Nuclease Essential for Parasite Survival

“…We have recently identified several molecules able to reduce the activity of LiEndoG in vitro [10]. Among them, Lei49 behaves as one of the best inhibitors (Figure 5) and also as one of the compounds with better cytotoxic activity against L. infantum promastigotes (IC 50  = 4.33±0.05 µM) and amastigotes (IC 50  = 6.44±0.01 µM).…”

“…Parasite death was induced by addition of edelfosine (Calbiochem) or Lei49 (2-[(S)-2-Amino-3-methylbutanoyl-oxy]ethyl [(2R,3S,5R)-5-(thymin-1-yl)-2-(trityloximethyl)tetrahydrofuran-3-yl] succinate) to the culture medium [10]. Growth curves were plotted as the product of cell concentration versus time.…”

Antileishmanial drug discovery: comprehensive review of the last 10 years

“…Aer performing an assay of this compound, they concluded that mitochondrial nuclease LiEndoG (L. infantum endonuclease G) was a target for the action of this family of compounds. 156 In early 2000, it was reported that methionine aminopeptidase 2 (MetAP2) inhibitors such as fumagillin and TNP-470, arrest parasite growth in L. donovani parasites. 157 As a part of a collaboration between Pzer and WHO-TDR to discover new hits and leads to treat neglected tropical diseases, 158 Chen et al reported synthesis and SAR study of the 2-(2-pyridinyl)-pyrimidine scaffold as an antileishmanial agent.…”

Design, Synthesis of Biaryl Piperidine Derivatives and Their Evaluation as Potential Antileishmanial Agents against Leishmania donovani Strain Ag83

“…The seriousness of the disease prompted several research groups to work on the development of new antileishmanial agents and the class of scaffolds explored includes various quinolines, [10–13] chalcones, [14,15] nitroimidazole, [16] triazolopyrimidine, [17] pyrazolopyrimidine, [18,19] aminopyrazole, [20] triazine, [21,22] quinazoline, [23] thymidine, [24] triterpenoids, [25] and quinazolinone [26] . The isolation and synthesis of a new class of biaryl naphthylisoquinoline alkaloid ancistroealaine A ( 1a ) from Ancistrocladus ealaensis and other alkaloids ( 1b , 1c ), and their antileishmanial activity has generated interest in the development of new antileishmanial agents [27–29] .…”