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Design, Synthesis, and Multivariate Quantitative Structure-Activity Relationship of Salicylanilides-Potent Inhibitors of Type III Secretion in Yersinia
Umeå University, Faculty of Science and Technology, Chemistry.
Umeå University, Faculty of Science and Technology, Chemistry.
Umeå University, Faculty of Science and Technology, Chemistry.
Umeå University, Faculty of Science and Technology, Chemistry.
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2007 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 50, no 24, 6177-6188 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2007. Vol. 50, no 24, 6177-6188 p.
National Category
Other Basic Medicine
Identifiers
URN: urn:nbn:se:umu:diva-18198DOI: 10.1021/jm070741bPubMedID: 17975903OAI: oai:DiVA.org:umu-18198DiVA: diva2:157871
Available from: 2007-11-29 Created: 2007-11-29 Last updated: 2010-03-18Bibliographically approved
In thesis
1. Statistical molecular design, QSAR modeling, and scaffold hopping – Development of type III secretion inhibitors in Gram negative bacteria
Open this publication in new window or tab >>Statistical molecular design, QSAR modeling, and scaffold hopping – Development of type III secretion inhibitors in Gram negative bacteria
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Type III secretion is a virulence system utilized by several clinically important Gram-negative pathogens. Computational methods have been used to develop two classes of type III secretion inhibitors, the salicylidene acylhydrazides and the acetylated salicylanilides. For these classes of compounds, quantitative structure-activity relationship models have been constructed with data from focused libraries obtained by statistical molecular design. The models have been validated and shown to provide useful predictions of untested compounds belonging to these classes. Scaffold hopping of the salicylidene acylhydrazides have resulted in a number of synthetic targets that might mimic the scaffold of the compounds. The synthesis of two libraries of analogs to two of these scaffolds and the biological evaluation of them is presented.

Place, publisher, year, edition, pages
Umeå: VMC-KBC, 2010. 65 p.
Keyword
Statistical molecular design, QSAR, synthesis, type III secretion, virulence, scaffold hopping
National Category
Organic Chemistry
Research subject
läkemedelskemi
Identifiers
urn:nbn:se:umu:diva-32506 (URN)978-91-7264-976-7 (ISBN)
Public defence
2010-04-16, KB3B1, Umeå Universitet, kemiska Institutionen, Linaeus v., KBC, 10:00 (Swedish)
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Available from: 2010-03-18 Created: 2010-03-15 Last updated: 2014-03-10Bibliographically approved

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Dahlgren, MarkusKauppi, AnnaLinusson Jonsson, AnnaElofsson, Mikael

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