4.7 Article

Statistical molecular design of a focused salicylidene acylhydrazide library and multivariate QSAR of inhibition of type III secretion in the Gram-negative bacterium Yersinia

期刊

BIOORGANIC & MEDICINAL CHEMISTRY
卷 18, 期 7, 页码 2686-2703

出版社

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2010.02.022

关键词

Statistical molecular design; QSAR; Type III secretion; Bacterial virulence; Antibacterial; Yersinia; Chlamydia

资金

  1. Swedish National Research Council
  2. Swedish Governmental Agency for Innovation Systems (VINNOVA)
  3. Carl Trygger foundation
  4. Creative Antibiotics

向作者/读者索取更多资源

A combined application of statistical molecular design (SMD), quantitative structure-activity relationship (QSAR) modeling and prediction of new active compounds was effectively used to develop salicylidene acylhydrazides as inhibitors of type III secretion (T3S) in the Gram-negative pathogen Yersinia pseudotuberculosis. SMD and subsequent synthesis furnished 50 salicylidene acylhydrazides in high purity. Based on data from biological evaluation in T3S linked assays 18 compounds were classified as active and 25 compounds showed a dose-dependent inhibition. The 25 compounds were used to compute two multivariate QSAR models and two multivariate discriminant analysis models were computed from both active and inactive compounds. Three of the models were used to predict 4416 virtual compounds in consensus and eight new compounds were selected as an external test set. Synthesis and biological evaluation of the test set in Y. pseudotuberculosis and the intracellular pathogen Chlamydia trachomatis validated the models. Y. pseudotuberculosis and C. trachomatis cell-based infection models showed that compounds identified in this study are selective and non-toxic inhibitors of T3S dependent virulence. (C) 2010 Elsevier Ltd. All rights reserved.

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