Design and Synthesis of Some Newer Pyrimidine Hydroxamates as Histone Deacetylase Inhibitors

Author(s): Jagannath Behera, Barij N. Sinha, Abhishek Kumar.

Journal Name: Current Enzyme Inhibition

Volume 11 , Issue 2 , 2015

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Graphical Abstract:


Histone Deacetylases (HDACs) are a class of enzymes that has become one of the potential, promising and well established targets for the treatment of cancer. In the present work, a series of pyrimidine hydroxamates were designed and synthesized as novel HDAC inhibitors.The compounds possess diaryl pyrimidine as cap, piperazine as linker and hydroxamate at Zn2+ binding group. These were designed with an idea to substitute diaryl group in place of single aryl cap in continuation to our earlier reported compounds from our lab. First S-methylisothiuronium hydroiodide 1 was prepared, which is reacted with monoboc piperazine 2 to form tert-butyl 4-carbamimidoylpiperazine-1- carboxylate 3, further it is treated with different substituted Chalcones (4a-k) to form 2, 4, 6- tri substituted pyrimidine (5a-k). After addition of ethylchloroacetate, the compounds formed are then treated with hydroxylamine hydrochloride to give the final compounds (7a-k). The antiproliferative activities of the synthesized compounds were evaluated by MTT assay against human breast cancer cell lines MDA-MB-231. The compounds found active were later on tested for Histone Deacetylase (HDAC) inhibitory activity. The IC50 values of the best-performing compounds were found to be in-between 9 to 38 M. The results obtained suggest that in a few cases, the modifications carried out retained the selectivity towards HDAC with increased potency, which may be associated with variation in the aryl cap region along with an increase in linker length. Out of all synthesized compounds, 2-(4-(4, 6-bis (2-hydroxyphenyl) pyrimidin-2-yl) piperazin-1-yl)-N-hydroxyacetamide (T8) showed promising inhibitory activity (MDA-MB-231= 9 M) & (HDAC = 6M). Further ADMET results also demonstrated that these synthesized compounds exhibit good absorption, permeability and penetration abilities in the human body. The ability of the diaryl cap of the compounds to accommodate both the pocket of the HDAC (B & D) may be the reason for its enzyme inhibitory activity.

Keywords: Histone deacetylase, hydroxamates, pocket, pyrimidine.

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Article Details

Year: 2015
Page: [132 - 139]
Pages: 8
DOI: 10.2174/1573408011666150702190040
Price: $58

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