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. 2017 Jul 20;12(14):1108-1115.
doi: 10.1002/cmdc.201700170. Epub 2017 Jun 27.

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

Garrett C Moraski  1 , Ryan Bristol  1 , Natalie Seeger  1 , Helena I Boshoff  2 , Patricia Siu-Yee Tsang  2 , Marvin J Miller  3
Affiliations

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

Garrett C Moraski et al. ChemMedChem. .

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 (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.

Keywords: Mycobacterium tuberculosis; drug resistance; imidazo[1,2-a]pyridines; imidazo[2,1-b]thiazoles; pentafluorosulfanyl.

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Figures

Figure 1
Figure 1
Previously published imidazo[1,2-a]pyridine-3-carboxamides (1 – 4) and imidazo[2,1-b]thaizole-5-carboxamides (5 – 6).
Figure 2
Figure 2
Trifluoromethyl (CF3) and trifluoromethoxy (OCF3) substituted TB clinical candidates (pretomanid, PTBZ169, BTZ043, and TBA354) and approved drug (delamanid).
Figure 3
Figure 3
Eight pentafluorosulfanyl (SF5) compounds (13 – 20) prepared for biological evaluation.
Scheme 1
Scheme 1
Syntheses of pentafluorosulfanyl compounds of Makrush structures 11 and 12. Reagents and conditions: a) EDC-HCl (1.1 equiv), 9 or 10 (1 equiv), DMAP (1.1 equiv), CH3CN, 12 h.
See this image and copyright information in PMC

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