Design, synthesis, and multivariate quantitative structure-activity relationship of salicylanilides--potent inhibitors of type III secretion in Yersinia.
J Med Chem
; 50(24): 6177-88, 2007 Nov 29.
Article
em En
| MEDLINE
| ID: mdl-17975903
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.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Salicilanilidas
/
Yersinia pseudotuberculosis
/
Fatores de Virulência
Tipo de estudo:
Prognostic_studies
Idioma:
En
Ano de publicação:
2007
Tipo de documento:
Article