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Thiazolino 2-Pyridone Amide Inhibitors of Chlamydia trachomatis Infectivity
Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
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2016 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 59, no 5, 2094-2108 p.Article in journal (Refereed) Published
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Abstract [en]

The bacterial pathogen Chlamydia trachomatis is a global health burden currently treated with broad-spectrum antibiotics which disrupt commensal bacteria. We recently identified a compound through phenotypic screening that blocked infectivity of this intracellular pathogen without host cell toxicity (compound 1, KSK 120). Herein, we present the optimization of 1 to a class of thiazolino 2-pyridone amides that are highly efficacious (EC50 <= 100 nM) in attenuating infectivity across multiple serovars of C. trachomatis without host cell toxicity. The lead compound 21a exhibits reduced lipophilicity versus 1 and did not affect the growth or viability of representative commensal flora at 50 mu M. In microscopy studies, a highly active fluorescent analogue 37 localized inside the parasitiphorous inclusion, indicative of a specific targeting of bacterial components. In summary, we present a class of small molecules to enable the development of specific treatments for C. trachomatis.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2016. Vol. 59, no 5, 2094-2108 p.
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Microbiology in the medical area Biochemistry and Molecular Biology
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URN: urn:nbn:se:umu:diva-119066DOI: 10.1021/acs.jmedchem.5b01759ISI: 000372043400031PubMedID: 26849778OAI: oai:DiVA.org:umu-119066DiVA: diva2:921528
Available from: 2016-04-20 Created: 2016-04-11 Last updated: 2016-04-20Bibliographically approved

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Good, James A. D.Silver, JimNunez-Otero, CarlosBahnan, WaelKrishnan, K. SyamSalin, OlliGylfe, ÅsaBergström, SvenAlmqvist, Fredrik
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Department of ChemistryUmeå Centre for Microbial Research (UCMR)Molecular Infection Medicine Sweden (MIMS)Department of Molecular Biology (Faculty of Medicine)Department of Clinical Microbiology
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