Substituted 2-imino-5-arylidenethiazolidin-4-one inhibitors of bacterial type III secretion

Abstract

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.

Figure 1

The lead structure emerging from our high-throughput screen for T3SS inhibitors

Figure 2. Inhibition of the secretion of the virulence protein SipA into the culture medium by S. typhimurium

Representative Western Blots of SipA secreted into culture medium from S. typhimurium grown in the presence of compound 1 (above) and 52 (below) at the concentrations (in μM) indicated above each blot. The results for 55a were comparable to those shown for 52. Secretion in the absence of compound but the presence of 5% DMSO is shown (‘0’) at the far left.

Scheme 1

Scheme 2

Scheme 3