Inhibitors of type III secretion in Yersinia: design, synthesis and multivariate QSAR of 2-arylsulfonylamino-benzanilides

Bioorg Med Chem. 2007 Nov 15;15(22):6994-7011. doi: 10.1016/j.bmc.2007.07.047. Epub 2007 Aug 22.

Abstract

Compound 1, 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-5-chloro-N-(3,4-dichloro-phenyl)-benzamide, was identified as a putative type III secretion inhibitor in Yersinia, and the compound thus has a potential to be used to prevent or treat bacterial infections. A set of seven analogues was synthesized and evaluated in a type III secretion dependent reporter-gene assay with viable bacterial to give basic SAR. A second set of 19 compounds was obtained by statistical molecular design in the building block and product space and by subsequent synthesis. Evaluation in the reporter-gene assay showed that the compounds ranged from non-active to compounds more potent than 1. Based on the data multivariate QSAR models were established and the final Hi-PLS model showed good correlation between experimentally determined % inhibition and the calculated % inhibition of the reporter-gene signal.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anilides* / chemical synthesis
  • Anilides* / chemistry
  • Anilides* / pharmacology
  • Anti-Bacterial Agents* / chemical synthesis
  • Anti-Bacterial Agents* / chemistry
  • Anti-Bacterial Agents* / pharmacology
  • Bacterial Proteins / antagonists & inhibitors*
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Drug Design
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Multivariate Analysis
  • Quantitative Structure-Activity Relationship*
  • Stereoisomerism
  • Yersinia pseudotuberculosis / drug effects*
  • Yersinia pseudotuberculosis / growth & development
  • Yersinia pseudotuberculosis / metabolism

Substances

  • Anilides
  • Anti-Bacterial Agents
  • Bacterial Proteins
  • benzanilide