Design, synthesis and evaluation of peptidomimetics based on substituted bicyclic 2-pyridones -: Targeting virulence of uropathogenic E-coli
Design, synthesis and evaluation of peptidomimetics based on substituted bicyclic 2-pyridones -: Targeting virulence of uropathogenic E-coli
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DOI：
10.1016/j.bmc.2006.07.017
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发表时间：
2006-11-15
影响因子：
3.5
通讯作者：
Almqvist, Fredrik
中科院分区：
文献类型：
--
作者：
Aberg, Veronica;Sellstedt, Magnus;Almqvist, Fredrik
取代的双环 2-吡啶酮（称为毛菌杀剂）是二肽模拟物，可防止泌尿道致病性大肠杆菌中的菌毛组装。在这里，我们应用合理的设计来生产基于两种生物活性 2-吡啶酮的四类扩展肽模拟物。合成中的关键中间体是氨基功能化的2-吡啶酮支架，它可以通过温和的选择性硝化和随后的还原来获得。然后开发程序以进一步衍生化该氨基取代的核心，并合成了总共 24 个延伸的拟肽，并评估了产生菌毛的大肠杆菌中的分子伴侣亲和力和体内抗毒活性。在生成的化合物组中观察到对靶蛋白的亲和力增强，而与母体先导化合物相比，体内防止菌毛组装的能力显着降低。结果表明，类似物的有限体内效力要么与摄取/分布相关，要么是由于结合特异性的丧失。 (c) 2006 Elsevier Ltd. 保留所有权利。
Substituted bicyclic 2-pyridones, termed pilicides, are dipeptide mimetics that prevent pilus assembly in uropathogenic Escherichia coli. Here, we apply rational design to produce four classes of extended peptidomimetics based on two bioactive 2-pyridones. The key intermediate in the synthesis was an amino-functionalised 2-pyridone scaffold, which could be obtained via a mild and selective nitration and subsequent reduction. Procedures were then developed to further derivatize this amino-substituted core and a total of 24 extended peptidomimetics were synthesised and evaluated for chaperone affinity and in vivo antivirulence activity in P pili producing E coli. Enhanced affinities for the target protein were observed within the generated set of compounds, while the ability to prevent pilus assembly in vivo was significantly decreased compared to the parent lead compounds. The results suggest that the limited in vivo potencies of the analogues are either uptake/distribution related or due to loss in binding specificity. (c) 2006 Elsevier Ltd. All rights reserved.