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
2016. Vol. 59, no 5, 2094-2108 p.
IdentifiersURN: urn:nbn:se:uu:diva-283770DOI: 10.1021/acs.jmedchem.5b01759ISI: 000372043400031PubMedID: 26849778OAI: oai:DiVA.org:uu-283770DiVA: diva2:919665
FunderSwedish Research CouncilKnut and Alice Wallenberg FoundationGöran Gustafsson Foundation for promotion of scientific research at Uppala University and Royal Institute of TechnologySwedish Foundation for Strategic Research The Kempe FoundationsSwedish Society for Medical Research (SSMF)