Thiazolino 2-Pyridone Amide Inhibitors of Chlamydia trachomatis Infectivity

详细信息    查看全文

• 作者：James A. D. Good ; Jim Silver ; Carlos Núñez-Otero ; Wael Bahnan ; K. Syam Krishnan ; Olli Salin ; Patrik Engström ; Richard Svensson ; Per Artursson ; Åsa Gylfe ; Sven Bergström ; Fredrik Almqvist
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：March 10, 2016
• 年：2016
• 卷：59
• 期：5
• 页码：2094-2108
• 全文大小：620K
• ISSN：1520-4804

文摘

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.