Structure-activity relationships for unit C pyridyl analogues of the tuberculosis drug bedaquiline

Bioorganic & Medicinal Chemistry
Adrian BlaserBrian D Palmer

Abstract

The ATP-synthase inhibitor bedaquiline is effective against drug-resistant tuberculosis but is extremely lipophilic (clogP 7.25) with a very long plasma half-life. Additionally, inhibition of potassium current through the cardiac hERG channel by bedaquiline, is associated with prolongation of the QT interval, necessitating cardiovascular monitoring. Analogues were prepared where the naphthalene C-unit was replaced with substituted pyridines to produce compounds with reduced lipophilicity, anticipating a reduction in half-life. While there was a direct correlation between in vitro inhibitory activity against M. tuberculosis (MIC90) and compound lipophilicity, potency only fell off sharply below a clogP of about 4.0, providing a useful lower bound for analogue design. The bulk of the compounds remained potent inhibitors of the hERG potassium channel, with notable exceptions where IC50 values were at least 5-fold higher than that of bedaquiline. Many of the compounds had desirably higher rates of clearance than bedaquiline, but this was associated with lower plasma exposures in mice, and similar or higher MICs resulted in lower AUC/MIC ratios than bedaquiline for most compounds. The two compounds with lower potency against hERG ex...Continue Reading

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Citations

Jul 25, 2019·Expert Opinion on Drug Safety·Karen Cohen, Gary Maartens
Nov 13, 2019·Antimicrobial Agents and Chemotherapy·Jickky Palmae SarathyThomas Dick
Jul 4, 2019·SLAS Discovery·Salvatore NesciAlessandra Pagliarani
Jan 23, 2020·Antimicrobial Agents and Chemotherapy·Jickky Palmae SarathyThomas Dick
Jul 31, 2019·Antimicrobial Agents and Chemotherapy·Jickky Palmae SarathyThomas Dick
Jan 16, 2020·Molecular Diversity·Amaravadhi HarikishoreGerhard Grüber
Apr 5, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Peter J ChoiWilliam A Denny
Dec 15, 2019·Antibiotics·Jickky Palmae SarathyThomas Dick
Jan 11, 2021·European Journal of Medicinal Chemistry·Milan UrbanLucie Brulíková
Dec 8, 2019·Bioorganic & Medicinal Chemistry·Hamish S SutherlandBrian 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

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