Structure-activity relationships for analogs of the tuberculosis drug bedaquiline with the naphthalene unit replaced by bicyclic heterocycles

Bioorganic & Medicinal Chemistry
Hamish S SutherlandBrian D Palmer

Abstract

Replacing the naphthalene C-unit of the anti-tuberculosis drug bedaquiline with a range of bicyclic heterocycles of widely differing lipophilicity gave analogs with a 4.5-fold range in clogP values. The biological results for these compounds indicate on average a lower clogP limit of about 5.0 in this series for retention of potent inhibitory activity (MIC90s) against M.tb in culture. Some of the compounds also showed a significant reduction in inhibition of hERG channel potassium current compared with bedaquiline, but there was no common structural feature that distinguished these.

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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
Dec 15, 2019·Antibiotics·Jickky Palmae SarathyThomas Dick
Jan 16, 2020·Molecular Diversity·Amaravadhi HarikishoreGerhard Grüber
Mar 14, 2019·Current Opinion in Pulmonary Medicine·Simon F K LeeMarc Lipman
Jul 14, 2020·Frontiers in Chemistry·Rogelio Jiménez-JuárezBlanca Estela García-Pérez
Jul 19, 2018·Frontiers in Microbiology·Diana MachadoMarco Pieroni
Jan 18, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Ying LinFan Yang
Aug 21, 2020·Communications Biology·Min LuoDavid M Mueller
Apr 5, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Peter J ChoiWilliam A Denny
Nov 20, 2019·Progress in Biophysics and Molecular Biology·Neelagandan KamariahGerhard Grüber
Feb 23, 2019·Bioorganic & Medicinal Chemistry·Adrian BlaserBrian D Palmer
May 26, 2020·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Andrés-Felipe Villamizar-MogotocoroVladimir V Kouznetsov
Apr 14, 2021·Future Medicinal Chemistry·William A Denny
May 1, 2021·Pharmaceutics·Filia StephanieUsman Sumo Friend Tambunan

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Methods Mentioned

BETA
column chromatography
NMR

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