Thiazolino 2-Pyridone Amide Inhibitors of Chlamydia trachomatis Infectivity

J Med Chem. 2016 Mar 10;59(5):2094-108. doi: 10.1021/acs.jmedchem.5b01759.

James A D Good ¹ ², Jim Silver ² ³ ⁴, Carlos Núñez-Otero ⁵, Wael Bahnan ² ³ ⁴, K Syam Krishnan ¹ ², Olli Salin ² ⁴ ⁵, Patrik Engström ² ³ ⁴, Richard Svensson ⁶ ⁷, Per Artursson ⁶ ⁷, Åsa Gylfe ² ⁴ ⁵, Sven Bergström ² ³ ⁴, Fredrik Almqvist ¹ ²

Affiliations

1 Department of Chemistry, Umeå University , 901 87 Umeå, Sweden.
2 Umeå Centre for Microbial Research, Umeå University , 901 87 Umeå, Sweden.
3 Department of Molecular Biology, Umeå University , 901 87 Umeå, Sweden.
4 Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University , 901 87 Umeå, Sweden.
5 Department of Clinical Microbiology, Umeå University , 901 85 Umeå, Sweden.
6 Department of Pharmacy, Uppsala University , SE-751 23 Uppsala, Sweden.
7 The Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Chemical Biology Consortium Sweden, Uppsala University , SE-751 23 Uppsala, Sweden.

PMID: 26849778 DOI: 10.1021/acs.jmedchem.5b01759

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.

Name
Email *

	Sorry, but the email address you supplied was invalid.