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Design, Synthesis, and Multivariate Quantitative Structure-Activity Relationship of Salicylanilides-Potent Inhibitors of Type III Secretion in Yersinia
Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
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2007 (Engelska)Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 50, nr 24, s. 6177-6188Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
2007. Vol. 50, nr 24, s. 6177-6188
Nationell ämneskategori
Annan medicinsk grundvetenskap
Identifikatorer
URN: urn:nbn:se:umu:diva-18198DOI: 10.1021/jm070741bPubMedID: 17975903OAI: oai:DiVA.org:umu-18198DiVA, id: diva2:157871
Tillgänglig från: 2007-11-29 Skapad: 2007-11-29 Senast uppdaterad: 2018-06-09Bibliografiskt granskad
Ingår i avhandling
1. Statistical molecular design, QSAR modeling, and scaffold hopping – Development of type III secretion inhibitors in Gram negative bacteria
Öppna denna publikation i ny flik eller fönster >>Statistical molecular design, QSAR modeling, and scaffold hopping – Development of type III secretion inhibitors in Gram negative bacteria
2010 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Umeå: VMC-KBC, 2010. s. 65
Nyckelord
Statistical molecular design, QSAR, synthesis, type III secretion, virulence, scaffold hopping
Nationell ämneskategori
Organisk kemi
Forskningsämne
datorlingvistik
Identifikatorer
urn:nbn:se:umu:diva-32506 (URN)978-91-7264-976-7 (ISBN)
Disputation
2010-04-16, KB3B1, Umeå Universitet, kemiska Institutionen, Linaeus v., KBC, 10:00 (Svenska)
Opponent
Handledare
Tillgänglig från: 2010-03-18 Skapad: 2010-03-15 Senast uppdaterad: 2018-06-08Bibliografiskt granskad

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Dahlgren, MarkusKauppi, AnnaLinusson Jonsson, AnnaElofsson, Mikael

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