Department of Biochemistry, and ‡Department of Chemistry, Case Western Reserve University , Millis Science Center, Rm 216, 2074 Adelbert Road, Cleveland Ohio 44106, United States.
ACS Comb Sci. 2014 Feb 10;16(2):85-91. doi: 10.1021/co400142t. Epub 2014 Jan 9.
Antibiotic resistance coupled with decreased development of new antibiotics necessitates the search for novel antibacterial agents. Antivirulence agents offer an alternative to conventional antibiotics. In this work, we report on a family of small-molecule antivirulence agents against methicillin-resistant Staphylococcus aureus (MRSA), the most widespread bacterial pathogen. Structure-activity relationship studies led to the development of a concise synthesis of a 148-member biarylhydroxyketone library. An acylation bond-forming process afforded resorcinols (1) and aryloxy acetonitriles (2) as synthons. A Lewis-acid-activated Friedel-Crafts' acylation step involving a nitrile functionality of 2 by ZnCl2, followed by nucleophilic attack by 1 was executed to obtain biaryl hydroxyketones in excellent yields. A large number of products crystallized. This strategy affords a range of biarylhydroxyketones in a single step. This is the first collective synthetic study documenting access to this class of compounds through a single synthetic operation. In vitro efficacy of compounds in this library was evaluated by a rabbit erythrocyte hemolysis assay. The most efficacious compound, 4f-12, inhibits hemolysis by 98.1 ± 0.1% compared to control in the absence of the compound.
抗生素耐药性的出现加上新抗生素研发的减少，促使人们需要寻找新型抗菌药物。抗毒剂为传统抗生素提供了一种替代方法。在这项工作中，我们报告了一系列针对耐甲氧西林金黄色葡萄球菌（MRSA）的小分子抗毒剂，MRSA 是最广泛的细菌病原体。构效关系研究导致了一种简洁的 148 成员联苯羟基酮文库的合成。酰化键形成过程提供了邻苯二酚（1）和芳氧基乙腈（2）作为合成子。通过 ZnCl2 激活的路易斯酸Friedel-Crafts 酰化步骤，涉及 2 的腈官能团，然后由 1 进行亲核攻击，以优异的收率得到联苯羟基酮。大量产物结晶。这种策略可在一步中提供多种联苯羟基酮。这是首次通过单一合成操作来获取此类化合物的综合合成研究。通过兔血红细胞溶血试验评估了该文库中化合物的体外功效。最有效的化合物 4f-12 在没有化合物的情况下，与对照相比，抑制溶血的效果为 98.1±0.1%。
