Preparation and Evaluation of Potent PentafluorosulfanylSubstituted Anti-Tuberculosis Compounds
Moraski, Garrett C.
Boshoff, Helena I.
Tsang, Patricia Siu-Yee
Miller, Marvin J.
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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 <100â€…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 <10â€…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 inâ€…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.
Moraski, Garrett C. , Ryan Bristol, Natalie Seeger, Helena I. Boshoff, Patricia Siu-Yee Tsang, and Marvin J. Miller. "Preparation and Evaluation of Potent PentafluorosulfanylSubstituted Anti-Tuberculosis Compounds." ChemMedChem 12, no. 14 (July 2017): 1108-1115. DOI: 10.1002/cmdc.201700170.