Preparation and Evaluation of Potent PentafluorosulfanylSubstituted Anti-Tuberculosis Compounds


Garrett C. Moraski, Ryan Bristol, Natalie Seeger, Helena I. Boshoff, Patricia Siu-Yee Tsang, Marvin J. Miller




The global fight to stop tuberculosis (TB) remains a great challenge, particularly with the increase in drug-resistant strains and a lack of funding to support the development of new treatments. To bolster a precarious drug pipeline, we prepared a focused panel of eight pentafluorosulfanyl (SF5 ) compounds which were screened for their activity against Mycobacterium tuberculosis (Mtb) H37Rv in three different assay conditions and media. All eight compounds had sub-micromolar potency, and four displayed MICs <100?nm. Seven compounds were evaluated against non-replicating and mono-drug-resistant Mtb, and for their ability to inhibit Mtb within the macrophage. The greatest potency was observed against intracellular Mtb (MIC <10?nm for three compounds), which is often the most challenging to target. In general, the SF5 -bearing compounds were very similar to their CF3 counterparts, with the major differences observed being their in?vitro ADME properties. Two SF5 -bearing compounds were found to have greater protein binding than their corresponding CF3 counterparts, but were also less metabolized in human microsomes, resulting in longer half-lives.



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