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.