Preparation and Evaluation of Potent Pentafluorosulfanyl‐Substituted Anti‐Tuberculosis Compounds
Year: 2017
Type: article
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.
Source: ChemMedChem
Authors: Garrett C. Moraski, Ryan Bristol, Natalie Seeger, Helena I. Boshoff, Patricia Siu‐Yee Tsang, Marvin J. Miller
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Design, Syntheses and Studies of Novel Antituberculosis Agents, G1719725309, G1889142286, G2625630894, G280512946, G2909499646, G3311445712, G3902111948, G4937329612, G5523047586, MRI: Acquisition of a cryoprobe- and autosampler-equipped AVANCE III 500 MHz solution NMR, Acquisition of a Quadrupole Time-of-Flight Mass Spectrometer, G6401591588, G7633065944, Design, Syntheses and Studies of Novel Antituberculosis Agents
OpenAlex ID: W2729029554