2. Academic Validation
  3. Synthesis and evaluation of analogues of the tuberculosis drug bedaquiline containing heterocyclic B-ring units

Synthesis and evaluation of analogues of the tuberculosis drug bedaquiline containing heterocyclic B-ring units

  • Bioorg Med Chem Lett. 2017 Dec 1;27(23):5190-5196. doi: 10.1016/j.bmcl.2017.10.042.
Peter J Choi 1,  Hamish S Sutherland 1,  Amy S T Tong 1,  Adrian Blaser 1,  Scott G Franzblau 2,  Christopher B Cooper 3,  Manisha U Lotlikar 3,  Anna M Upton 3,  Jerome Guillemont 4,  Magali Motte 4,  Laurence Queguiner 4,  Koen Andries 5,  Walter Van den Broeck 5,  William A Denny 6,  Brian D Palmer 7
Affiliations

Affiliations

  • 1 Auckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
  • 2 Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA.
  • 3 Global Alliance for TB Drug Development, 40 Wall St, New York 10005, USA.
  • 4 Medicinal Chemistry Department (Infectious Diseases), Janssen Pharmaceuticals, Campus de Maigremont, BP315, 27106 Val de Reuil Cedex, France.
  • 5 Janssen Infectious Diseases BVBA, Beerse, Belgium.
  • 6 Auckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Maurice Wilkins Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. Electronic address: b.denny@auckland.ac.nz.
  • 7 Auckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Maurice Wilkins Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
PMID: 29107541 DOI: 10.1016/j.bmcl.2017.10.042
Abstract

Analogues of bedaquiline where the phenyl B-unit was replaced with monocyclic heterocycles of widely differing lipophilicity (thiophenes, furans, pyridines) were synthesised and evaluated. While there was an expected broad positive correlation between lipophilicity and anti-TB activity, the 4-pyridyl derivatives appeared to have an additional contribution to Antibacterial potency. The majority of the compounds were (desirably) more polar and had higher rates of clearance than bedaquiline, and showed acceptable oral bioavailability, but there was only limited (and unpredictable) improvement in their hERG liability.

Keywords

Bedaquiline; Bedaquiline analogues; Drug development; Tuberculosis.

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