1,3-Diphenylureido hydroxamate as a promising scaffold for generation of potent antimalarial histone deacetylase inhibitors.
1,3-Diphenylureido hydroxamate as a promising scaffold for generation of potent antimalarial histone deacetylase inhibitors.
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DOI：
10.1038/s41598-023-47959-z
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发表时间：
2023-11-29
影响因子：
4.6
通讯作者：
中科院分区：
文献类型：
--
作者：
我们报告了一系列1，3-二苯基脲氧肟酸HDAC抑制剂对敏感和耐药恶性疟原虫菌株的评价。化合物8a-d显示出有效的抗疟原虫活性，表明苯基间隔基允许相对于肉桂基和二氢肉桂基接头改善的效力。在体外，机制研究证明了PfHDAC 1在重组水平上的靶向活性，这与乙酰化组蛋白水平的细胞定量一致。化合物6c、7 c和8 c在表型测定和PfHDAC 1酶抑制中被鉴定为最具活性。化合物8 c作为一种显著的抑制剂脱颖而出，显示出令人印象深刻的85% PfHDAC 1抑制，在Pf 3D 7的表型筛选中IC 50值为0.74 μM，对多重耐药PfDd 2寄生虫的IC 50值为0.8 μM。尽管其对PfHDAC 1的有效抑制，但8 c对人HDAC 1的活性仍然最低，显示出显著的选择性。计算机模拟研究表明，苯基接头在允许异羟肟酸酯与PfHDAC 1有效相互作用的系列中具有理想的长度，并且该化合物系列可以与HsHDAC 1结合。总之，这些结果突出了二苯基脲类异羟肟酸盐作为产生有效的抗疟HDAC抑制剂的特权支架的潜力，其具有比人HDAC更高的选择性。
We report a series of 1,3-diphenylureido hydroxamate HDAC inhibitors evaluated against sensitive and drug-resistant P. falciparum strains. Compounds 8a–d show potent antiplasmodial activity, indicating that a phenyl spacer allows improved potency relative to cinnamyl and di-hydrocinnamyl linkers. In vitro, mechanistic studies demonstrated target activity for PfHDAC1 on a recombinant level, which agreed with cell quantification of the acetylated histone levels. Compounds 6c, 7c, and 8c, identified as the most active in phenotypic assays and PfHDAC1 enzymatic inhibition. Compound 8c stands out as a remarkable inhibitor, displaying an impressive 85% inhibition of PfHDAC1, with an IC50 value of 0.74 µM in the phenotypic screening on Pf3D7 and 0.8 µM against multidrug-resistant PfDd2 parasites. Despite its potent inhibition of PfHDAC1, 8c remains the least active on human HDAC1, displaying remarkable selectivity. In silico studies suggest that the phenyl linker has an ideal length in the series for permitting effective interactions of the hydroxamate with PfHDAC1 and that this compound series could bind as well as in HsHDAC1. Taken together, these results highlight the potential of diphenylurea hydroxamates as a privileged scaffold for the generation of potent antimalarial HDAC inhibitors with improved selectivity over human HDACs.
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