格罗贝克-布莱克本-比纳梅衍生的咪唑并[1,2-a]吡啶-3-胺的抗菌活性。
Antibacterial activities of Groebke-Blackburn-Bienaymé-derived imidazo[1,2-a]pyridin-3-amines.
机构信息
Department of Medicinal Chemistry, University of Kansas, Multidisciplinary Research Building, Room 320D, 2030 Becker Drive, Lawrence, KS 66047, USA.
出版信息
Bioorg Med Chem. 2012 Oct 1;20(19):5850-63. doi: 10.1016/j.bmc.2012.07.052. Epub 2012 Aug 8.
Abstract
We sought to explore the imidazo[1,2-a]pyridin-3-amines for TLR7 (or 8)-modulatory activities. This chemotype, readily accessed via the Groebke-Blackburn-Bienaymé multi-component reaction, resulted in compounds that were TLR7/8-inactive, but exhibited bacteriostatic activity against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). To investigate the mechanism of antibacterial activity of this new chemotype, a resistant strain of S. aureus was generated by serially passaging the organism in escalating doses of the most active analogue. A comparison of minimum inhibitory concentrations (MICs) of known bacteriostatic agents in wild-type and resistant strains indicates a novel mechanism of action. Structure-activity relationship studies have led to the identification of positions on the scaffold for additional structural modifications that should allow for the introduction of probes designed to examine cognate binding partners and molecular targets, while not significantly compromising antibacterial potency.
摘要
我们试图探索咪唑并[1,2-a]吡啶-3-胺作为 TLR7（或 8）调节剂的活性。这种化学型可通过 Groebke-Blackburn-Bienaymé 多组分反应轻松获得，得到的化合物对 TLR7/8 无活性，但对革兰氏阳性菌（包括耐甲氧西林金黄色葡萄球菌（MRSA））具有抑菌活性。为了研究这种新型化学型的抗菌活性机制，通过在逐渐增加的最有效类似物剂量下对金黄色葡萄球菌进行连续传代，生成了一种耐药菌株。对野生型和耐药菌株的已知抑菌剂的最小抑菌浓度（MIC）进行比较，表明存在一种新的作用机制。构效关系研究确定了支架上的一些位置，可进行进一步的结构修饰，这应该允许引入设计用于检查同源结合伴侣和分子靶标的探针，而不会显著降低抗菌效力。
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