Herein, a high-yielding
cycloaddition reaction of β-ketoesters
and azides to provide 1,2,3-triazoles is described. The reactions
employing 2-unsubstituted β-ketoesters were found to provide
5-methyl-1,2,3-triazoles, whereas 2-alkyl-substituted β-ketoesters
provided 5-hydroxy-1,2,3-triazoles (shown to be relatively acidic)
in high yields and as single regioisomers. Several novel compounds
were reported and characterized including long-chain 5-hydroxy-1,2,3-triazoles
potentially bioisosteric to hydroxamic acids.
We have recently developed a new synthetic methodology that provided both
N
-aryl-5-hydroxytriazoles and
N
-pyridine-4-alkyl triazoles. A selection of these products was carried through virtual screening towards targets that are contemporary and validated for drug discovery and development. This study determined a number of potential structure target dyads of which
N
-pyridinium-4-carboxylic-5-alkyl triazole displayed the highest score specificity towards KAT2A. Binding affinity tests of abovementioned triazole and related analogs towards KAT2A confirmed the predictions of the
in-silico
assay. Finally, we have run
in vitro
inhibition assays of selected triazoles towards KAT2A; the ensemble of binding and inhibition assays delivered pyridyl-triazoles carboxylates as the prototype of a new class of inhibitors of KAT2A.
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