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.

我们试图探索咪唑并[1,2- a ]吡啶-3-胺的 TLR7（或 8）调节活性。这种化学型很容易通过 Groebke-Blackburn-Bienaymé 多组分反应获得，产生 TLR7/8 无活性的化合物，但对革兰氏阳性菌（包括耐甲氧西林金黄色葡萄球菌(MRSA)）表现出抑菌活性。为了研究这种新化学型的抗菌活性机制，通过以递增剂量的最具活性的类似物连续传代该生物体，产生了金黄色葡萄球菌的耐药菌株。已知抑菌剂在野生型和耐药菌株中的最低抑菌浓度 (MIC) 的比较表明了一种新的作用机制。结构-活性关系研究已经确定了支架上进行额外结构修饰的位置，这些修饰应允许引入旨在检查同源结合配偶体和分子靶标的探针，同时不会显着损害抗菌效力。