Preparation and Evaluation of Potent Pentafluorosulfanyl Substituted Anti-Tuberculosis Compounds

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 have prepared a focused panel of eight pentafluorosulfanyl (SF ₅) compounds ( 13 – 20) 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 ( 13, 15, 16, and 19) displayed MICs <100 nM. Seven compounds ( 13 – 19) 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 13, 15, and 17), 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. SF ₅-bearing compounds 18 and 19 had greater protein binding than the corresponding CF ₃ compounds ( 1 and 5) but also were less metabolized in human microsomes resulting in longer half-lives.

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A focused set of pentafluorosulfanyl (SF ₅) compounds were prepared and evaluated against Mycobacterium tuberculosis (Mtb) H37Rv in multiple assays. Overall the compounds demonstrated great potency against replicating Mtb particularly within the macrophage. However, in other evaluations (non-replicating Mtb, drug-resistant Mtb, MBC, and toxicity) these compounds began to show differences between each other.