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Synthesis of Functionalized Cinnamaldehyde Derivatives by an Oxidative Heck Reaction and Their Use as Starting Materials for Preparation of Mycobacterium tuberculosis 1-Deoxy-D-xylulose-5-phosphate Reductoisomerase Inhibitors
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
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2011 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 76, no 21, 8986-8998 p.Article in journal (Refereed) Published
Abstract [en]

Cinnamaldehyde derivatives were synthesized in good to excellent yields in one step by a mild and selective, base-free palladium(II)-catalyzed oxidative Heck reaction starting from acrolein and various arylboronic acids. Prepared α,β-unsaturated aldehydes were used for synthesis of novel α-aryl substituted fosmidomycin analogues, which were evaluated for their inhibition of Mycobacterium tuberculosis 1-deoxy-d-xylulose 5-phosphate reductoisomerase. IC(50) values between 0.8 and 27.3 μM were measured. The best compound showed activity comparable to that of the most potent previously reported α-aryl substituted fosmidomycin-class inhibitor.

Place, publisher, year, edition, pages
2011. Vol. 76, no 21, 8986-8998 p.
National Category
Natural Sciences
Research subject
Chemistry with specialization in Organic Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-158249DOI: 10.1021/jo201715xISI: 000296206400040PubMedID: 21936546OAI: oai:DiVA.org:uu-158249DiVA: diva2:438680
Available from: 2011-09-05 Created: 2011-09-05 Last updated: 2017-12-08Bibliographically approved
In thesis
1. Hit Identification and Hit Expansion in Antituberculosis Drug Discovery: Design and Synthesis of Glutamine Synthetase and 1-Deoxy-D-Xylulose-5-Phosphate Reductoisomerase Inhibitors
Open this publication in new window or tab >>Hit Identification and Hit Expansion in Antituberculosis Drug Discovery: Design and Synthesis of Glutamine Synthetase and 1-Deoxy-D-Xylulose-5-Phosphate Reductoisomerase Inhibitors
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Since the discovery of Mycobacterium tuberculosis (Mtb) as the bacterial agent causing tuberculosis, the permanent eradication of this disease has proven challenging. Although a number of drugs exist for the treatment of tuberculosis, 1.7 million people still die every year from this infection. The current treatment regimen involves lengthy combination therapy with four different drugs in an effort to combat the development of resistance. However, multidrug-resistant and extensively drug-resistant strains are emerging in all parts of the world. Therefore, new drugs effective in the treatment of tuberculosis are much-needed.

The work presented in this thesis was focused on the early stages of drug discovery by applying different hit identification and hit expansion strategies in the exploration of two new potential drug targets, glutamine synthetase (GS) and 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR).

A literature survey was first carried out to identify new Mtb GS inhibitors from compounds known to inhibit GS in other species. Three compounds, structurally unrelated to the typical amino acid derivatives of previously known GS inhibitors, were then discovered by virtual screening and found to be Mtb GS inhibitors, exhibiting activities in the millimolar range. Imidazo[1,2-a]pyridine analogues were also investigated as Mtb GS inhibitors. The chemical functionality, size requirements and position of the substituents in the imidazo[1,2-a]pyridine hit were investigated, and a chemical library was designed based on a focused hierarchical design of experiments approach. The X-ray structure of one of the inhibitors in complex with Mtb GS provided additional insight into the structure–activity relationships of this class of compounds.

Finally, new α-arylated fosmidomycin analogues were synthesized as inhibitors of Mtb DXR, exhibiting IC50 values down to 0.8 µM. This work shows that a wide variety of aryl groups are tolerated by the enzyme. Cinnamaldehydes are important synthetic intermediates in the synthesis of fosmidomycin analogues. These were prepared by an oxidative Heck reaction from acrolein and various arylboronic acids. Electron-rich, electron-poor, heterocyclic and sterically hindered boronic acids could be employed, furnishing cinnamaldehydes in 43–92% yield.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2011. 86 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 148
Keyword
Tuberculosis, Glutamine synthetase, Imidazo[1, 2-a]pyridine analogues, Focused hierarchical design of experiments, DXR, Fosmidomycin analogues, 1-Deoxy-D-xylulose-5-phosphate reductoisomerase, Cinnamaldehydes, Oxidative Heck reaction
National Category
Medicinal Chemistry
Research subject
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-155428 (URN)978-91-554-8151-3 (ISBN)
Public defence
2011-10-21, B22, Husargatan 3, SE-751 23, Uppsala, 09:15 (Swedish)
Opponent
Supervisors
Available from: 2011-09-30 Created: 2011-06-22 Last updated: 2011-11-03Bibliographically approved

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Nordqvist, AnneliBjörkelid, ChristoferJansson, Anna M.Mowbray, Sherry L.Karlén, AndersLarhed, Mats

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