title: Thiazolino 2-Pyridone Amide Inhibitors of Chlamydia trachomatis Infectivity.
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.
authors: Department of Chemistry, Umeå University , 901 87 Umeå, Sweden.|Umeå Centre for Microbial Research, Umeå University , 901 87 Umeå, Sweden.
authors: James A D
authors: JA
authors: Good
authors: Umeå Centre for Microbial Research, Umeå University , 901 87 Umeå, Sweden.|Department of Molecular Biology, Umeå University , 901 87 Umeå, Sweden.|Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University , 901 87 Umeå, Sweden.
authors: Jim
authors: J
authors: Silver
authors: Department of Clinical Microbiology, Umeå University , 901 85 Umeå, Sweden.
authors: Carlos
authors: C
authors: Núñez-Otero
authors: Umeå Centre for Microbial Research, Umeå University , 901 87 Umeå, Sweden.|Department of Molecular Biology, Umeå University , 901 87 Umeå, Sweden.|Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University , 901 87 Umeå, Sweden.
authors: Wael
authors: W
authors: Bahnan
authors: Department of Chemistry, Umeå University , 901 87 Umeå, Sweden.|Umeå Centre for Microbial Research, Umeå University , 901 87 Umeå, Sweden.
authors: K Syam
authors: KS
authors: Krishnan
authors: Umeå Centre for Microbial Research, Umeå University , 901 87 Umeå, Sweden.|Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University , 901 87 Umeå, Sweden.|Department of Clinical Microbiology, Umeå University , 901 85 Umeå, Sweden.
authors: Olli
authors: O
authors: Salin
authors: Umeå Centre for Microbial Research, Umeå University , 901 87 Umeå, Sweden.|Department of Molecular Biology, Umeå University , 901 87 Umeå, Sweden.|Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University , 901 87 Umeå, Sweden.
authors: Patrik
authors: P
authors: Engström
authors: Department of Pharmacy, Uppsala University , SE-751 23 Uppsala, Sweden.|The Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Chemical Biology Consortium Sweden, Uppsala University , SE-751 23 Uppsala, Sweden.
authors: Richard
authors: R
authors: Svensson
authors: Department of Pharmacy, Uppsala University , SE-751 23 Uppsala, Sweden.|The Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Chemical Biology Consortium Sweden, Uppsala University , SE-751 23 Uppsala, Sweden.
authors: Per
authors: P
authors: Artursson
authors: Umeå Centre for Microbial Research, Umeå University , 901 87 Umeå, Sweden.|Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University , 901 87 Umeå, Sweden.|Department of Clinical Microbiology, Umeå University , 901 85 Umeå, Sweden.
authors: Åsa
authors: Å
authors: Gylfe
authors: Umeå Centre for Microbial Research, Umeå University , 901 87 Umeå, Sweden.|Department of Molecular Biology, Umeå University , 901 87 Umeå, Sweden.|Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University , 901 87 Umeå, Sweden.
authors: Sven
authors: S
authors: Bergström
authors: Department of Chemistry, Umeå University , 901 87 Umeå, Sweden.|Umeå Centre for Microbial Research, Umeå University , 901 87 Umeå, Sweden.
authors: Fredrik
authors: F
authors: Almqvist
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002690:Chlamydia Infections / Q000188:drug therapy* / Q000382:microbiology*; D002692:Chlamydia trachomatis / Q000187:drug effects* / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D006367:HeLa Cells; D006801:Humans; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D015394:Molecular Structure; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: C000609789:6-amino-8-cyclopropyl-7-(naphthalen-1-ylmethyl)-5-oxo-N-phenyl-2,3-dihydro-5H-(1,3)thiazolo(3,2-a)pyridine-3-carboxamide; D000900:Anti-Bacterial Agents; D011728:Pyridones; D013844:Thiazoles