Thiazolino 2-Pyridone Amide Inhibitors of Chlamydia trachomatis Infectivity
| Autor: | Olli Salin, Patrik Engström, Wael Bahnan, Åsa Gylfe, James A. D. Good, Fredrik Almqvist, Sven Bergström, Carlos Núñez-Otero, K. Syam Krishnan, Richard Svensson, Jim Silver, Per Artursson |
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| Rok vydání: | 2016 |
| Předmět: |
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 |
| Zdroj: | Journal of Medicinal Chemistry. 59:2094-2108 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.5b01759 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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