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 (SF5) 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 SF5-bearing compounds were very similar to their CF3 counterparts with the major differences observed being their in vitro ADME properties. SF5-bearing compounds 18 and 19 had greater protein binding than the corresponding CF3 compounds (1 and 5) but also were less metabolized in human microsomes resulting in longer half-lives.

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The front cover picture shows promising pentafluorosulfanyl (SF5) anti‐tuberculosis compounds 6‐chloro‐2‐ethyl‐N‐(3‐(pentafluoro‐λ6‐sulfaneyl)benzyl)imidazo[1,2‐a]pyridine‐3‐carboxamide (18) and 2,6‐dimethyl‐N‐(4‐(pentafluoro‐λ6‐sulfaneyl)benzyl)imidazo[2,1‐b]thiazole‐5‐carboxamide (19) ascending a mountain of in vitro assessments (including replicating, nonreplicating, and intracellular potency, toxicity, solubility, and ADME). These SF5‐bearing compounds were also compared with similar CF3‐bearing compounds 2,6‐dimethyl‐N‐(4‐(trifluoromethyl)benzyl)imidazo[1,2‐a]pyridine‐3‐carboxamide (1) and 2,6‐dimethyl‐N‐(4‐(trifluoromethyl)benzyl)imidazo[2,1‐b]thiazole‐5‐carboxamide (5). The overarching goal is to advance compounds within the next “mountains” of preclinical evaluation. Cover art created by Rebecca Rausch. More information can be found in the Full Paper by Garrett C. Moraski, Marvin J. Miller et al. on page 1108 in Issue 14, 2017 (DOI: 10.1002/cmdc.201700170).