3,5-Dialkoxypyridine analogues of bedaquiline are potent antituberculosis agents with minimal inhibition of the hERG channel was written by Sutherland, Hamish S.;Tong, Amy S. T.;Choi, Peter J.;Blaser, Adrian;Conole, Daniel;Franzblau, Scott G.;Lotlikar, Manisha U.;Cooper, Christopher B.;Upton, Anna M.;Denny, William A.;Palmer, Brian D.. And the article was included in Bioorganic & Medicinal Chemistry in 2019.Electric Literature of C6H7NO2 This article mentions the following:
Bedaquiline is a new drug of the diarylquinoline class that has proven to be clin. effective against drug-resistant tuberculosis, but has a cardiac liability (prolongation of the QT interval) due to its potent inhibition of the cardiac potassium channel protein hERG. Bedaquiline is highly lipophilic and has an extremely long terminal half-life, so has the potential for more-than-desired accumulation in tissues during the relatively long treatment durations required to cure TB. The present work is part of a program that seeks to identify a diarylquinoline that is as potent as bedaquiline against Mycobacterium tuberculosis, with lower lipophilicity, higher clearance, and lower risk for QT prolongation. Previous work led to the identification of compounds with greatly-reduced lipophilicity compounds that retain good anti-tubercular activity in vitro and in mouse models of TB, but has not addressed the hERG blockade. We now present compounds where the C-unit naphthalene is replaced by a 3,5-dialkoxy-4-pyridyl, demonstrate more potent in vitro and in vivo anti-tubercular activity, with greatly attenuated hERG blockade. Two examples of this series are in preclin. development. In the experiment, the researchers used many compounds, for example, 5-Hydroxy-2-methoxylpyridine (cas: 51834-97-0Electric Literature of C6H7NO2).
5-Hydroxy-2-methoxylpyridine (cas: 51834-97-0) belongs to pyridine derivatives. Pyridine has a dipole moment and a weaker resonant stabilization than benzene (resonance energy 117 kJ璺痬ol閳? in pyridine vs. 150 kJ璺痬ol閳? in benzene). Reduced pyridines, namely tetrahydropyridines, dihydropyridines and piperidines, are found in numerous natural and synthetic compounds. The synthesis and reactivity of these compounds have often been driven by the fact many of these compounds have interesting and unique pharmacological properties. Electric Literature of C6H7NO2