title: Design, synthesis, and multivariate quantitative structure-activity relationship of salicylanilides--potent inhibitors of type III secretion in Yersinia.
abstract: Analogues to the salicylanilide N-(4-Chlorophenyl)-2-acetoxy-3,5-diiodobenzamide, 1a, an inhibitor of type III secretion (T3S) in Yersinia, were selected, synthesized, and biologically evaluated in three cycles. First, a set of analogues with variations in the salicylic acid ring moiety was synthesized to probe possible structural variation. A basic structure-activity relationship was established and then used to cherry-pick compounds from a principal component analysis score plot of salicylanilides to generate a second set. A third set with increased likelihood of biological activity was designed using D-optimal onion design. A quantitative structure-activity relationship model using hierarchical partial least-square regression to latent structures (Hi-PLS) was computed using PLS score vectors of building blocks correlated to the % inhibition of T3S as a response. A PLS discriminant analysis (PLS-DA) model was derived using the same descriptor set as that for the Hi-PLS model. Both models were validated with an external test set.
authors.affiliation: Department of Chemistry, Umeå University, SE-901 87 Umeå, Sweden.
authors.forename: Markus K
authors.initials: MK
authors.lastname: Dahlgren
authors.forename: Anna M
authors.initials: AM
authors.lastname: Kauppi
authors.forename: Ing-Marie
authors.initials: IM
authors.lastname: Olsson
authors.forename: Anna
authors.initials: A
authors.lastname: Linusson
authors.forename: Mikael
authors.initials: M
authors.lastname: Elofsson
mesh_terms: D015195:Drug Design; D008958:Models, Molecular; D015999:Multivariate Analysis; D021281:Quantitative Structure-Activity Relationship; D012458:Salicylanilides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D037521:Virulence Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015011:Yersinia pseudotuberculosis / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism
chemical_list: D012458:Salicylanilides; D037521:Virulence Factors