Thiazolino 2-Pyridone Amide Inhibitors of Chlamydia trachomatis Infectivity
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) PublishedText
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.
Microbiology in the medical area Biochemistry and Molecular Biology
IdentifiersURN: urn:nbn:se:umu:diva-119066DOI: 10.1021/acs.jmedchem.5b01759ISI: 000372043400031PubMedID: 26849778OAI: oai:DiVA.org:umu-119066DiVA: diva2:921528