Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 59, Issue 5, Pages 2094-2108Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b01759
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Funding
- Swedish Research Council
- Knut and Alice Wallenberg Foundation
- Goran Gustafsson Foundation
- Swedish Foundation for Strategic Research
- Swedish Government Fund for Clinical Research ALF
- Scandinavian Society for Antimicrobial Chemotherapy Foundation
- J.C. Kempe Foundation
- Swedish Society of Medical Research (SSMF)
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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.
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