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Thiazolino 2-Pyridone Amide Inhibitors of Chlamydia trachomatis Infectivity
- Source :
- Journal of Medicinal Chemistry. 59:2094-2108
- Publication Year :
- 2016
- Publisher :
- American Chemical Society (ACS), 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 :
- Serotype
Pyridones
medicine.drug_class
Phenotypic screening
Antibiotics
Chlamydia trachomatis
Microbial Sensitivity Tests
010402 general chemistry
medicine.disease_cause
01 natural sciences
Microbiology
Structure-Activity Relationship
Drug Discovery
Tumor Cells, Cultured
medicine
Humans
Pathogen
Infectivity
Microbial Viability
Dose-Response Relationship, Drug
Molecular Structure
010405 organic chemistry
Chemistry
Chlamydia Infections
Small molecule
Virology
Anti-Bacterial Agents
0104 chemical sciences
Thiazoles
Toxicity
Molecular Medicine
HeLa Cells
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 59
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....2f62725a446ad67d1430ec5dc5033545