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Hit Identification and Hit Expansion in Antituberculosis Drug Discovery: Design and Synthesis of Glutamine Synthetase and 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.
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 [en]
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: urn:nbn:se:uu:diva-155428ISBN: 978-91-554-8151-3 (print)OAI: oai:DiVA.org:uu-155428DiVA: diva2:439452
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
List of papers
1. Evaluation of the amino acid binding site of Mycobacterium tuberculosis glutamine synthetase for drug discovery
Open this publication in new window or tab >>Evaluation of the amino acid binding site of Mycobacterium tuberculosis glutamine synthetase for drug discovery
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2008 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 16, no 10, 5501-5513 p.Article in journal (Refereed) Published
Abstract [en]

A combination of a literature survey, structure-based virtual screening and synthesis of a small library was performed to identify hits to the potential antimycobacterial drug target, glutamine synthetase. The best inhibitor identified from the literature survey was (2S,5R)-2,6-diamino-5-hydroxyhexanoic acid (4, IC(50) of 610+/-15microM). In the virtual screening 46,400 compounds were docked and subjected to a pharmacophore search. Of these compounds, 29 were purchased and tested in a biological assay, allowing three novel inhibitors containing an aromatic scaffold to be identified. Based on one of the hits from the virtual screening a small library of 15 analogues was synthesized producing four compounds that inhibited glutamine synthetase.

Keyword
virtual screening, glutamine synthetase, gamma-glutamyl, ammonia ligase
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-102946 (URN)10.1016/j.bmc.2008.04.015 (DOI)000256052400015 ()18462943 (PubMedID)
Available from: 2009-05-13 Created: 2009-05-13 Last updated: 2017-12-13Bibliographically approved
2. Microwave-enhanced alpha-arylation of a protected glycine in water: evaluation of 3-phenylglycine derivatives as inhibitors of the tuberculosis enzyme, glutamine synthetase
Open this publication in new window or tab >>Microwave-enhanced alpha-arylation of a protected glycine in water: evaluation of 3-phenylglycine derivatives as inhibitors of the tuberculosis enzyme, glutamine synthetase
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2007 (English)In: Combinatorial chemistry & high throughput screening, ISSN 1386-2073, E-ISSN 1875-5402, Vol. 10, no 9, 783-789 p.Article in journal (Refereed) Published
Abstract [en]

A microwave-enhanced, palladium-catalyzed protocol for the alpha-arylation of a protected glycine in neat water is described. This reaction proceeds rapidly, under non-inert conditions, to afford a range of phenylglycine derivatives in moderate to good yields. Based on this arylation, a number of aryl L-methionine-SR-sulfoximine (MSO) analogues were prepared and evaluated for their Mycobacterium tuberculosis glutamine synthetase (TB-GS) inhibitory activity.

Keyword
arylation, glutamine synthetase, microwave, palladium, tuberculosis, water
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-16614 (URN)10.2174/138620707783018478 (DOI)000253584600005 ()18478959 (PubMedID)
Available from: 2008-06-05 Created: 2008-06-05 Last updated: 2017-12-08Bibliographically approved
3. Functionalized 3-amino-imidazo[1,2-a]pyridines: A novel class of drug-like Mycobacterium tuberculosis glutamine synthetase inhibitors
Open this publication in new window or tab >>Functionalized 3-amino-imidazo[1,2-a]pyridines: A novel class of drug-like Mycobacterium tuberculosis glutamine synthetase inhibitors
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2009 (English)In: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 19, no 16, 4790-4793 p.Article in journal (Refereed) Published
Abstract [en]

3-Amino-imidazo[1,2-a]pyridines have been identified as a novel class of Mycobacterium tuberculosis glutamine synthetase inhibitors. Moreover, these compounds represent the first drug-like inhibitors of this enzyme. A series of compounds exploring structural diversity in the pyridine and phenyl rings have been synthesized and biologically evaluated. Compound 4n was found to be the most potent inhibitor (IC50 = 0.38 ± 0.02 μM). This compound was significantly more potent than the known inhibitors, L-methionine-SR-sulfoximine and phosphinothricin.

Keyword
Mycobacterium tuberculosis, Glutamine synthetase inhibitors, Microwave, 3-Aminoimidazo[1, 2-a]pyridine
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-100360 (URN)10.1016/j.bmcl.2009.06.045 (DOI)000268358800057 ()19560924 (PubMedID)
Available from: 2009-03-31 Created: 2009-03-31 Last updated: 2017-12-13Bibliographically approved
4. Synthesis, biological evaluation and X-ray crystallographic studies of imidazo[1,2-a]-pyridine based Mycobacterium tuberculosis glutamine synthetase inhibitors
Open this publication in new window or tab >>Synthesis, biological evaluation and X-ray crystallographic studies of imidazo[1,2-a]-pyridine based Mycobacterium tuberculosis glutamine synthetase inhibitors
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2012 (English)In: MedChemComm, ISSN 2040-2503, E-ISSN 2040-2511, Vol. 3, no 5, 620-626 p.Article in journal (Refereed) Published
Abstract [en]

Based on an imidazo[1,2-a]pyridine hit from a high-throughput screen directed at the M. tuberculosis enzyme glutamine synthetase, a hit expansion was performed by synthesizing a series of analogs. A set of 16 molecules was first synthesized according to a statistical molecular design approach. One potent inhibitor was identified (IC50 = 3.0 µM), which led to the synthesis of 17 additional imidazo[1,2-a]pyridines in a follow-up study. Among these, several inhibitors were identified showing single digit micromolar potency. An X-ray structure of one of these revealed the binding mode of this class of inhibitors in the ATP-binding site, and allowed us to rationalize some of the structure-activity relationships observed.

National Category
Medicinal Chemistry Medical and Health Sciences
Research subject
Chemistry with specialization in Organic Chemistry; Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-100359 (URN)10.1039/c2md00310d (DOI)000304387300013 ()
Available from: 2009-03-31 Created: 2009-03-31 Last updated: 2017-12-13Bibliographically approved
5. 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
Open this publication in new window or tab >>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
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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.

National Category
Natural Sciences
Research subject
Chemistry with specialization in Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-158249 (URN)10.1021/jo201715x (DOI)000296206400040 ()21936546 (PubMedID)
Available from: 2011-09-05 Created: 2011-09-05 Last updated: 2017-12-08Bibliographically approved

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