Synthesis of pyrimidines containing hydroxamic acid, 1,3,4-oxadiazole or 1,2,4-triazole moieties as potential HDAC inhibitors

Abstract

The histone deacetylases (HDACs) play an essential role in the transcriptional regulation of cells through deacetylation of nuclear histone proteins and are promising therapeutic targets for treatment of various diseases. Therefore, interest to the design and synthesis of novel HDAC inhibitors, among which hydroxamic acids occupy an important place, has been constantly increasing in recent years. Here, synthesis of pyrimidines with 1,3,4-oxadiazole or 1,2,4-triazole and hydroxamic acid moieties as potential HDAC inhibitors is described. The target compounds were obtained by sequential reactions of (O- and N-pyrimidinyl)alkanoates with hydrazine hydrate followed by cyclization reaction of the obtained hydrazides with potassium O-ethyl xanthate and alkylation of the synthesised oxadiazole(triazole)thiones with 2-chloro-N-hydroxyacetamide. One of 1,3,4-oxadiazole-2-thiones under the treatment with hydrazine hydrate underwent the recyclisation reaction to give the corresponding 4-amino-1,2,4-triazole. Investigation of the inhibitory activity of the synthesised compounds against HDAC4 and HDAC8 isoforms revealed that N-hydroxy-2-(5-(4-(6-(6-methyl-2-(methylthio)pyrimidin-4-yloxy) butyl)-1,3,4-oxadiazol-2-ylthio)acetamide exhibited a weak inhibitory activity against HDAC8 isoform (IC50 = 12.7 μM).