6-Cyano Analogues of Bedaquiline as Less Lipophilic and Potentially Safer Diarylquinolines for Tuberculosis

نویسندگان

  • Amy S. T. Tong
  • Peter J. Choi
  • Adrian Blaser
  • Hamish S. Sutherland
  • Sophia K. Y. Tsang
  • Jerome Guillemont
  • Magali Motte
  • Christopher B. Cooper
  • Koen Andries
  • Walter Van den Broeck
  • Scott G. Franzblau
  • Anna M. Upton
  • William A. Denny
  • Brian D. Palmer
  • Daniel Conole
چکیده

Bedaquiline (1) is a new drug for tuberculosis and the first of the diarylquinoline class. It demonstrates excellent efficacy against TB but induces phospholipidosis at high doses, has a long terminal elimination half-life (due to its high lipophilicity), and exhibits potent hERG channel inhibition, resulting in clinical QTc interval prolongation. A number of structural ring A analogues of bedaquiline have been prepared and evaluated for their anti-M.tb activity (MIC90), with a view to their possible application as less lipophilic second generation compounds. It was previously observed that a range of 6-substituted analogues of 1 demonstrated a positive correlation between potency (MIC90) toward M.tb and drug lipophilicity. Contrary to this trend, we discovered, by virtue of a clogP/M.tb score, that a 6-cyano (CN) substituent provides a substantial reduction in lipophilicity with only modest effects on MIC values, suggesting this substituent as a useful tool in the search for effective and safer analogues of 1.

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عنوان ژورنال:

دوره 8  شماره 

صفحات  -

تاریخ انتشار 2017