Abstract
A versatile method for the synthesis of chiral 1,4-disubstituted-1,2,3-triazole derivatives starting from easily accessible naturally occurring D-or L-amino acids as chiral synthons is described. The amino acids were converted into azido alcohols, followed by copper catalyzed [3+2] cycloaddition reactions between the azido alcohols and methyl propiolate and subsequent ester aminolysis with primary and secondary amines furnished the target compounds, which were obtained in excellent yields with no racemization. Docking of selected target compounds shows that the chiral 1,4-disubstituted-1,2,3-triazoles derivatives has the potential of mimicking the binding mode of known purine analogues.
Highlights
Introduction1,2,3-Triazoles are an important class of heterocycles due to their wide range of applications as synthetic intermediates and pharmaceuticals [1,2]
A versatile method for the synthesis of chiral 1,4-disubstituted-1,2,3-triazole derivatives starting from accessible naturally occurring D-or L-amino acids as chiral synthons is described
We wanted to investigate the possibility of the 1,2,3-triazole scaffold to be docked into proteins that are inhibited of these nucleoside analogues and to develop efficient synthesis protocols for the preparation of 1,4-disubstituted-1,2,3-triazoles
Summary
1,2,3-Triazoles are an important class of heterocycles due to their wide range of applications as synthetic intermediates and pharmaceuticals [1,2]. In our search for synthetic non-natural frameworks that could mimic nucleosides, we wanted to investigate the possibility of using 1,2,3-triazole moiety as a mimic of the imidazole part of the adenine system (Figure 1). Imidazole and triazole based nucleoside derivatives have been reported as potent enzyme inhibitors. Imidazole based derivatives have been reported as potent adenosine deaminase (ADA) inhibitors (Figure 1) [16,17,18,19]. Of ribavirin-5’-triphosphate (blue) 1 in the active site of the NS5MTaseDV in the dengue virus; (b) The docking shows that the NH2-groups of compound (R)-3 and ribavirin-5’monophosphate are almost superimposed and makes the same important interaction with the carbonyl functions of Leu and Leu in the protein; (c) Docked binding mode of (R)-3 (yellow) compared to x-ray structure (1v7a) of inhibitor 2 in the active site of the ADA enzyme; (d) The imidazole part of compound (R)-3 is almost superimposed over compound 2 and the phenyl ring points in (R)-3 in the same direction as the naphtyl ring in 2
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