Preparation and Evaluation of Potent Pentafluorosulfanyl‐Substituted Anti‐Tuberculosis Compounds

Abstract

Abstract 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 (SF 5 ) 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 n m . 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 n m for three compounds), which is often the most challenging to target. In general, the SF 5 ‐bearing compounds were very similar to their CF 3 counterparts, with the major differences observed being their in vitro ADME properties. Two SF 5 ‐bearing compounds were found to have greater protein binding than their corresponding CF 3 counterparts, but were also less metabolized in human microsomes, resulting in longer half‐lives.