Thiazolino 2‑Pyridone Amide Inhibitors of Chlamydia trachomatis Infectivity

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.