Department of Pharmacology & Molecular Sciences, 725 North Wolfe Street, Baltimore, MD 21205, USA.
Bioorg Med Chem. 2012 Jul 15;20(14):4507-13. doi: 10.1016/j.bmc.2012.05.022. Epub 2012 May 17.
Our previous target validation studies established that inhibition of methionine aminopeptidases (MtMetAP, type 1a and 1c) from Mycobacterium tuberculosis (Mtb) is an effective approach to suppress Mtb growth in culture. A novel class of MtMetAP1c inhibitors comprising of N'-hydroxy-N-(4H,5H-naphtho[1,2-d]thiazol-2-yl)methanimidamide (4c) was uncovered through a high-throughput screen (HTS). A systematic structure-activity relationship study (SAR) yielded variants of the hit, 4b, 4h, and 4k, bearing modified A- and B-rings as potent inhibitors of both MtMetAPs. Except methanimidamide 4h that showed a moderate Mtb inhibition, a desirable minimum inhibitory concentration (MIC) was not obtained with the current set of MtMetAP inhibitors. However, the SAR data generated thus far may prove valuable for further tuning of this class of inhibitors as effective anti-tuberculosis agents.
我们之前的靶标验证研究表明，抑制结核分枝杆菌（Mtb）中的蛋氨酸氨肽酶（MtMetAP，1a 型和 1c 型）是抑制 Mtb 在培养中生长的有效方法。通过高通量筛选（HTS）发现了一类新型的 MtMetAP1c 抑制剂，包括 N'-羟基-N-（4H，5H-萘并[1,2-d]噻唑-2-基）甲脒（4c）。通过系统的构效关系研究（SAR），得到了具有修饰的 A 环和 B 环的化合物 4b、4h 和 4k 的变体，它们是 MtMetAPs 的有效抑制剂。除了甲脒 4h 对 Mtb 具有中等抑制作用外，当前的 MtMetAP 抑制剂系列没有获得理想的最小抑菌浓度（MIC）。然而，迄今为止产生的 SAR 数据可能对进一步调整这类抑制剂作为有效的抗结核药物具有重要价值。
