umu.sePublications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Statistical molecular design, QSAR modeling, and scaffold hopping – Development of type III secretion inhibitors in Gram negative bacteria
Umeå University, Faculty of Science and Technology, Department of Chemistry. (Mikael Elofsson)
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 [en]
Statistical molecular design, QSAR, synthesis, type III secretion, virulence, scaffold hopping
National Category
Organic Chemistry
Research subject
läkemedelskemi
Identifiers
URN: urn:nbn:se:umu:diva-32506ISBN: 978-91-7264-976-7 (print)OAI: oai:DiVA.org:umu-32506DiVA: diva2:303829
Public defence
2010-04-16, KB3B1, Umeå Universitet, kemiska Institutionen, Linaeus v., KBC, 10:00 (Swedish)
Opponent
Supervisors
Available from: 2010-03-18 Created: 2010-03-15 Last updated: 2014-03-10Bibliographically approved
List of papers
1. Design, Synthesis, and Multivariate Quantitative Structure-Activity Relationship of Salicylanilides-Potent Inhibitors of Type III Secretion in Yersinia
Open this publication in new window or tab >>Design, Synthesis, and Multivariate Quantitative Structure-Activity Relationship of Salicylanilides-Potent Inhibitors of Type III Secretion in Yersinia
Show others...
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.

National Category
Other Basic Medicine
Identifiers
urn:nbn:se:umu:diva-18198 (URN)10.1021/jm070741b (DOI)17975903 (PubMedID)
Available from: 2007-11-29 Created: 2007-11-29 Last updated: 2017-12-14Bibliographically approved
2. Statistical molecular design of a focused salicylidene acylhydrazide library and multivariate QSAR of inhibition of type III secretion in the Gram-negative bacterium Yersinia
Open this publication in new window or tab >>Statistical molecular design of a focused salicylidene acylhydrazide library and multivariate QSAR of inhibition of type III secretion in the Gram-negative bacterium Yersinia
Show others...
2010 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 18, no 7, 2686-2703 p.Article in journal (Refereed) Published
Abstract [en]

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.

Keyword
Statistical molecular design, QSAR, Type III secretion, Bacterial virulence, Antibacterial, Yersinia, Chlamydia
National Category
Other Basic Medicine
Identifiers
urn:nbn:se:umu:diva-32591 (URN)10.1016/j.bmc.2010.02.022 (DOI)000276258700035 ()20219378 (PubMedID)
Available from: 2010-03-18 Created: 2010-03-18 Last updated: 2017-12-12Bibliographically approved
3. Synthesis of 2-(2-Aminopyrimidine)-2,2-difluoroethanols as Potential Bioisosters of Salicylidene Acylhydrazides
Open this publication in new window or tab >>Synthesis of 2-(2-Aminopyrimidine)-2,2-difluoroethanols as Potential Bioisosters of Salicylidene Acylhydrazides
Show others...
2010 (English)In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 15, no 6, 4207-12 p.Article in journal (Refereed) Published
Abstract [en]

Salicylidene acylhydrazides are inhibitors of type III secretion in several Gramnegative pathogens. To further develop the salicylidene acylhydrazides, scaffold hopping was applied to replace the core fragment of the compounds. The novel 2-(2-aminopyrimidine)-2,2-difluoroethanol scaffold was identified as a possible analog to thesalicylidene acylhydrazide core structure. The synthesis of a library of 2-(2-aminopyrimidine)-2,2-difluoro-ethanols is described in this paper.

Keyword
scaffold hopping, Reformatsky reaction, salicylidene acylhydrazide, type III secretion
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-34860 (URN)10.3390/molecules15064423 (DOI)000279207300043 ()
Available from: 2010-06-22 Created: 2010-06-22 Last updated: 2017-12-12Bibliographically approved
4. Synthesis of [4-(2-Hydroxyphenyl)thiazol-2-yl]methanones as Potential Bioisosteres of Salicylidene Acylhydrazides
Open this publication in new window or tab >>Synthesis of [4-(2-Hydroxyphenyl)thiazol-2-yl]methanones as Potential Bioisosteres of Salicylidene Acylhydrazides
2010 (English)In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 15, no 9, 6019-34 p.Article in journal (Refereed) Published
Abstract [en]

A focused library of [4-(2-hydroxyphenyl)thiazol-2-yl]methanones was prepared in a four-step synthesis with the aim to obtain potent inhibitors of type III secretion in Gram-negative bacteria. The compounds are potential bioisosteres of salicylidene acylhydrazides that are a known class of type III secretion inhibitors.

Keyword
Type III secretion, Suzuki coupling, Grignard addition
National Category
Other Basic Medicine
Identifiers
urn:nbn:se:umu:diva-32604 (URN)10.3390/molecules15096019 (DOI)000282221100013 ()
Available from: 2010-03-18 Created: 2010-03-18 Last updated: 2017-12-12Bibliographically approved

Open Access in DiVA

avhandling(511 kB)717 downloads
File information
File name FULLTEXT01.pdfFile size 511 kBChecksum SHA-512
bc561f8ff856c72c69e68ce73460aa95928d124bf0971ef8fd94580fa31a91fbfec101afb7a1b80b3a3db2bfc1625d5e6ad0a4de8cb963b022b7cd0ed44e99b4
Type fulltextMimetype application/pdf

Search in DiVA

By author/editor
Dahlgren, Markus
By organisation
Department of Chemistry
Organic Chemistry

Search outside of DiVA

GoogleGoogle Scholar
Total: 717 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

isbn
urn-nbn

Altmetric score

isbn
urn-nbn
Total: 412 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf