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Design, Synthesis, ...
Design, Synthesis, and X-ray Crystallographic Studies of alpha-Aryl Substituted Fosmidomycin Analogues as Inhibitors of Mycobacterium tuberculosis 1-Deoxy-D-xylulose 5-Phosphate Reductoisomerase
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- Andaloussi, Mounir (author)
- Uppsala universitet,Avdelningen för organisk farmaceutisk kemi
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- Henriksson, Lena M. (author)
- Uppsala universitet,Struktur- och molekylärbiologi
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- Wieckowska, Anna (author)
- Uppsala universitet,Avdelningen för organisk farmaceutisk kemi
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- Lindh, Martin, 1981- (author)
- Uppsala universitet,Avdelningen för organisk farmaceutisk kemi
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- Björkelid, Christofer (author)
- Uppsala universitet,Struktur- och molekylärbiologi
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- Larsson, Anna M. (author)
- Uppsala universitet,Struktur- och molekylärbiologi
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- Suresh, Surisetti (author)
- Uppsala universitet,Avdelningen för organisk farmaceutisk kemi
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Iyer, Harini (author)
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Srinivasa, Bachally R. (author)
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- Bergfors, Terese (author)
- Uppsala universitet,Struktur- och molekylärbiologi
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- Unge, Torsten (author)
- Uppsala universitet,Struktur- och molekylärbiologi
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- Mowbray, Sherry L. (author)
- Swedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Uppsala universitet,Struktur- och molekylärbiologi,Institutionen för molekylär biovetenskap,Department of Molecular Biosciences
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- Larhed, Mats (author)
- Uppsala universitet,Avdelningen för organisk farmaceutisk kemi
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- Jones, T. Alwyn (author)
- Uppsala universitet,Struktur- och molekylärbiologi
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- Karlén, Anders (author)
- Uppsala universitet,Avdelningen för organisk farmaceutisk kemi
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(creator_code:org_t)
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- American Chemical Society (ACS), 2011
- 2011
- English.
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In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 54:14, s. 4964-4976
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Abstract
Subject headings
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- The natural antibiotic fosmidomycin acts via inhibition of 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR), an essential enzyme in the non-mevalonate pathway of isoprenoid biosynthesis. Fosmidomycin is active on Mycobacterium tuberculosis DXR (MtDXR), but it lacks antibacterial activity probably because of poor uptake. alpha-Aryl substituted fosmidomycin analogues have more favorable physicochemical properties and are also more active in inhibiting malaria parasite growth. We have solved crystal structures of MtDXR in complex with 3,4-dichlorophenyl substituted fosmidomycin analogues; these show important differences compared to our previously described forsmidomycin-DXR complex. Our best inhibitor has an IC(50) = 0.15 mu M on MtDXR but still lacked activity in a mycobacterial growth assay (MIC > 32 mu g/mL). The combined results, however, provide insights into how DXR accommodates the new inhibitors and serve as an excellent starting point for the design of other novel and more potent inhibitors, particularly against pathogens where uptake is less of a problem, such as the malaria parasite.
Subject headings
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Andra medicinska och farmaceutiska grundvetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Other Basic Medicine (hsv//eng)
- LANTBRUKSVETENSKAPER -- Veterinärmedicin -- Medicinsk biovetenskap (hsv//swe)
- AGRICULTURAL SCIENCES -- Veterinary Science -- Medical Bioscience (hsv//eng)
Keyword
- Cell and molecular biology
- Cell- och molekylärbiologi
- Chemistry
- Kemi
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Andaloussi, Moun ...
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Henriksson, Lena ...
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Wieckowska, Anna
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Lindh, Martin, 1 ...
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Björkelid, Chris ...
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Larsson, Anna M.
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show more...
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Suresh, Surisett ...
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Iyer, Harini
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Srinivasa, Bacha ...
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Bergfors, Terese
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Unge, Torsten
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Mowbray, Sherry ...
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Larhed, Mats
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Jones, T. Alwyn
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Karlén, Anders
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show less...
- About the subject
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Biochemistry and ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Other Basic Medi ...
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- AGRICULTURAL SCIENCES
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AGRICULTURAL SCI ...
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and Veterinary Scien ...
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and Medical Bioscien ...
- Articles in the publication
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Journal of Medic ...
- By the university
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Uppsala University
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Swedish University of Agricultural Sciences