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Thiazolino 2-Pyridone Amide Inhibitors of Chlamydia trachomatis Infectivity.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2016 Mar 10; Vol. 59 (5), pp. 2094-108. Date of Electronic Publication: 2016 Feb 22. - Publication Year :
- 2016
-
Abstract
- 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 μM. 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.
- Subjects :
- Anti-Bacterial Agents chemical synthesis
Anti-Bacterial Agents chemistry
Dose-Response Relationship, Drug
HeLa Cells
Humans
Microbial Sensitivity Tests
Microbial Viability drug effects
Molecular Structure
Pyridones chemical synthesis
Pyridones chemistry
Structure-Activity Relationship
Thiazoles chemical synthesis
Thiazoles chemistry
Tumor Cells, Cultured
Anti-Bacterial Agents pharmacology
Chlamydia Infections drug therapy
Chlamydia Infections microbiology
Chlamydia trachomatis drug effects
Chlamydia trachomatis physiology
Pyridones pharmacology
Thiazoles pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 59
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 26849778
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.5b01759