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Thiazolino 2-Pyridone Amide Inhibitors of Chlamydia trachomatis Infectivity.

Authors :
Good JA
Silver J
Núñez-Otero C
Bahnan W
Krishnan KS
Salin O
Engström P
Svensson R
Artursson P
Gylfe Å
Bergström S
Almqvist F
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.

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