3,5-Dialkoxypyridine analogues of bedaquiline are potent antituberculosis agents with minimal inhibition of the hERG channel

Bioorganic & Medicinal Chemistry
Hamish S SutherlandBrian D Palmer

Abstract

Bedaquiline is a new drug of the diarylquinoline class that has proven to be clinically 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 preclinical development.

References

Jan 11, 2007·Antimicrobial Agents and Chemotherapy·Sang Hyun ChoScott G Franzblau
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Citations

Nov 13, 2019·Antimicrobial Agents and Chemotherapy·Jickky Palmae SarathyThomas Dick
Jan 23, 2020·Antimicrobial Agents and Chemotherapy·Jickky Palmae SarathyThomas Dick
Jul 31, 2019·Antimicrobial Agents and Chemotherapy·Jickky Palmae SarathyThomas Dick
Apr 5, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Peter J ChoiWilliam A Denny
Sep 16, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Hollis D Showalter
Dec 15, 2019·Antibiotics·Jickky Palmae SarathyThomas Dick
Nov 20, 2019·Progress in Biophysics and Molecular Biology·Neelagandan KamariahGerhard Grüber
Jan 29, 2021·Frontiers in Cellular and Infection Microbiology·Erik J HasenoehrlMichael Berney
Apr 11, 2020·Translational Research : the Journal of Laboratory and Clinical Medicine·Gauri S Shetye SanghyunCho
Dec 8, 2019·Bioorganic & Medicinal Chemistry·Hamish S SutherlandBrian D Palmer
Apr 14, 2021·Future Medicinal Chemistry·William A Denny
Jul 23, 2021·International Journal of Infectious Diseases : IJID : Official Publication of the International Society for Infectious Diseases·Jinmeng LiXinjun Cai
Nov 17, 2020·ACS Omega·Sara Motamen, Ronald J Quinn
Nov 12, 2021·Molecular Diversity·Mushtaq Ahmad Wani, Devendra Kumar Dhaked

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Methods Mentioned

BETA
column chromatography

Software Mentioned

PhysChem Suite
ACD

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