title: Statistical molecular design of a focused salicylidene acylhydrazide library and multivariate QSAR of inhibition of type III secretion in the Gram-negative bacterium Yersinia.
abstract: 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.
authors.affiliation: Department of Chemistry, Umeå University, SE-901 87 Umeå, Sweden.
authors.forename: Markus K
authors.initials: MK
authors.lastname: Dahlgren
authors.forename: Caroline E
authors.initials: CE
authors.lastname: Zetterström
authors.forename: Sa
authors.initials: S
authors.lastname: Gylfe
authors.forename: Anna
authors.initials: A
authors.lastname: Linusson
authors.forename: Mikael
authors.initials: M
authors.lastname: Elofsson
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002460:Cell Line; D002690:Chlamydia Infections / Q000188:drug therapy / Q000382:microbiology; D002692:Chlamydia trachomatis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006367:HeLa Cells; D006801:Humans; D006834:Hydrazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D007202:Indicators and Reagents; D013058:Mass Spectrometry; D051379:Mice; D008968:Molecular Conformation; D021281:Quantitative Structure-Activity Relationship; D012459:Salicylates / Q000138:chemical synthesis* / Q000494:pharmacology*; D015011:Yersinia pseudotuberculosis / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D015012:Yersinia pseudotuberculosis Infections / Q000188:drug therapy / Q000382:microbiology
chemical_list: D000900:Anti-Bacterial Agents; D006834:Hydrazines; D007202:Indicators and Reagents; D012459:Salicylates