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
J. Med. Chem. 59 (5) 2094-2108 [2016-03-10; online 2016-02-22]
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.
Uppsala Drug Optimization and Pharmaceutical Profiling (UDOPP)