Design, Synthesis and Evaluation of Triazole-Pyrimidine Analogues as SecA Inhibitors.
Design, Synthesis and Evaluation of Triazole-Pyrimidine Analogues as SecA Inhibitors.
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DOI：
10.1002/cmdc.201500447
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发表时间：
2016-01-05
期刊：
影响因子：
3.4
通讯作者：
Wang B
中科院分区：
文献类型：
--
作者：
Cui J;Jin J;Chaudhary AS;Hsieh YH;Zhang H;Dai C;Damera K;Chen W;Tai PC;Wang B
SecA是细菌Sec-dependent分泌途径的关键组分，是新型抗菌药物开发的一个有吸引力的靶标。通过虚拟筛选和周围化学空间的实验探索相结合，我们鉴定了一种热门的双三唑SecA抑制剂SCA-21，并通过对核心支架的系统解剖研究了一系列类似物。这些类似物的评价使我们能够建立SecA抑制的初始SAR。该组中最好的化合物在低至亚μM浓度下具有SecA依赖性蛋白传导通道活性和蛋白易位活性的强效抑制活性。它们还具有针对与SecA和蛋白质易位抑制数据相关的各种细菌菌株的MIC值。这些化合物对具有不同水平外排泵的耐甲氧西林金黄色葡萄球菌菌株有效，表明能够消除SecA抑制剂的多重耐药性效应。来自药物亲和力响应靶稳定性和蛋白质下拉测定的研究的结果与SecA作为这些化合物的靶一致。
SecA, a key component of bacterial Sec-dependent secretion pathway, is an attractive target for novel antimicrobial development. Through a combination of virtual screening and experimental exploration of surrounding chemical space, we identified a hit bistriazole SecA inhibitor, SCA-21, and studied a series of analogs by systematic dissections of the core scaffold. Evaluation of these analogs allowed us to establish an initial SAR in SecA inhibition. The best compounds in this group have potent inhibition activity of SecA-dependent protein-conducting channel activity and protein translocation activity at low to sub-μM concentrations. They also have MIC values against various strains of bacteria that are correlated with the SecA and protein translocation inhibition data. These compounds are effective against methicillin-resistant Staplylococcus aureus strains with various levels of efflux pumps, indicating the ability to null the effect of multiple-drug resistance with SecA inhibitors. Results from studies of drug affinity responsive target stability and protein pull-down assays are consistent with SecA as a target for these compounds.