Design, synthesis and evaluation of N-benzoylindazole derivatives and analogues as inhibitors of human neutrophil elastase
Design, synthesis and evaluation of N-benzoylindazole derivatives and analogues as inhibitors of human neutrophil elastase
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DOI：
10.1016/j.bmc.2011.06.036
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发表时间：
2011-08-01
影响因子：
3.5
通讯作者：
Vergelli, Claudia
中科院分区：
文献类型：
--
作者：
Crocetti, Letizia;Giovannoni, Maria Paola;Vergelli, Claudia
人中性粒细胞弹性酶（HNE）在肿瘤侵袭和炎症中起重要作用。合成了一系列n -苯甲酰林唑，并对其抑制HNE的能力进行了评价。我们发现这种支架适用于HNE抑制剂，并且位置1的苯甲酰片段对活性至关重要。最有效的化合物抑制HNE活性，IC50值在亚微摩尔范围内。此外，对接研究表明，结合位点内抑制剂的几何形状和Michaelis复合物形成的能量学是影响抑制剂生物活性的关键因素。因此，n -苯甲酰林唑衍生物及其类似物代表了新的结构模板，可用于进一步开发有效的HNE抑制剂。(C) 2011 Elsevier Ltd.版权所有。
Human neutrophil elastase (HNE) plays an important role in tumour invasion and inflammation. A series of N-benzoylindazoles was synthesized and evaluated for their ability to inhibit HNE. We found that this scaffold is appropriate for HNE inhibitors and that the benzoyl fragment at position 1 is essential for activity. The most active compounds inhibited HNE activity with IC50 values in the submicromolar range. Furthermore, docking studies indicated that the geometry of an inhibitor within the binding site and energetics of Michaelis complex formation were key factors influencing the inhibitor's biological activity. Thus, N-benzoylindazole derivatives and their analogs represent novel structural templates that can be utilized for further development of efficacious HNE inhibitors. (C) 2011 Elsevier Ltd. All rights reserved.