Kline Toni, Felise Heather B, Barry Kathleen C, Jackson Stona R, Nguyen Hai V, Miller Samuel I
Departments of Genome Sciences, Microbiology, and Medicine, University of Washington, Seattle, Washington 98195, USA.
J Med Chem. 2008 Nov 27;51(22):7065-74. doi: 10.1021/jm8004515.
Diverse species of pathogenic Gram-negative bacteria use secretion systems to export a variety of protein toxins and virulence factors that help establish and maintain infection. Disruption of such secretion systems is a potentially effective therapeutic strategy. We developed a high-throughput screen and identified a tris-aryl substituted 2-imino-5-arylidenethiazolidin-4-one, compound 1, as an inhibitor of the type III secretion system. Expansion of this chemotype enabled us to define the essential pharmacophore for type III secretion inhibition by this structural class. A synthetic diversity set helped us identify N-3 as the most permissive locus and led to the design of a panel of novel N-3-dipeptide-modified congeners with improved activity and physiochemical properties. We now report on the synthesis of these compounds, including a novel solid phase approach to the rapid generation of the dipeptide-thiazolidinone hybrids, and their in vitro characterization as inhibitors of type III secretion in Salmonella enterica serovar Typhimurium.
多种致病性革兰氏阴性细菌利用分泌系统输出多种蛋白质毒素和毒力因子，这些有助于建立和维持感染。破坏此类分泌系统是一种潜在有效的治疗策略。我们开发了一种高通量筛选方法，并鉴定出一种三芳基取代的2-亚氨基-5-芳基亚甲基噻唑烷-4-酮（化合物1）作为III型分泌系统的抑制剂。对这种化学类型的扩展使我们能够确定该结构类别抑制III型分泌的必需药效基团。一个合成多样性集帮助我们确定N-3是最宽松的位点，并促成了一组具有改进活性和物理化学性质的新型N-3-二肽修饰类似物的设计。我们现在报告这些化合物的合成，包括一种快速生成二肽-噻唑烷酮杂化物的新型固相方法，以及它们作为鼠伤寒沙门氏菌III型分泌抑制剂的体外表征。
