2. Academic Validation
  3. Variations in the C-unit of bedaquiline provides analogues with improved biology and pharmacology

Variations in the C-unit of bedaquiline provides analogues with improved biology and pharmacology

  • Bioorg Med Chem. 2020 Jan 1;28(1):115213. doi: 10.1016/j.bmc.2019.115213.
Hamish S Sutherland 1,  Amy S T Tong 1,  Peter J Choi 1,  Adrian Blaser 1,  Scott G Franzblau 2,  Christopher B Cooper 3,  Anna M Upton 3,  Manisha Lotlikar 3,  William A Denny 4,  Brian D Palmer 5
Affiliations

Affiliations

  • 1 Auckland Cancer Society Research Centre, School of Medical Sciences, and Maurice Wilkins Centre, 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, NY 10005, USA.
  • 4 Auckland Cancer Society Research Centre, School of Medical Sciences, and Maurice Wilkins Centre, 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: [email protected].
  • 5 Auckland Cancer Society Research Centre, School of Medical Sciences, and Maurice Wilkins Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Maurice Wilkins Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
PMID: 31810890 DOI: 10.1016/j.bmc.2019.115213
Abstract

Analogues of the anti-tuberculosis drug bedaquiline, bearing a 3,5-dimethoxy-4-pyridyl C-unit, retain high anti-bacterial potency yet exert less inhibition of the hERG Potassium Channel, in vitro, than the parent compound. Two of these analogues (TBAJ-587 and TBAJ-876) are now in preclinical development. The present study further explores structure-activity relationships across a range of related 3,5-disubstituted-4-pyridyl C-unit bedaquiline analogues of greatly varying lipophilicity (clogP from 8.16 to 1.89). This broader class shows similar properties to the 3,5-dimethoxy-4-pyridyl series, being substantially more potent in vitro and equally active in an in vivo (mouse) model than bedaquiline, while retaining a lower cardiovascular risk profile through greatly attenuated hERG inhibition.

Keywords

CFU, colony-forming units; HPLC, high-peformance liquid chromatography; LDA, lithium diisopropylamide; LORA, low oxygen recovery assay; LiTMP, lithium tetramethylpiperidide; M.tb, Mycobacterium tuberculosis; MABA, microplate alamar blue assay; MIC(90), minimum concentration for 90% inhibition; TB, tuberculosis; hERG, the alpha subunit of a K+ channel that contributes to the electrical activity of the heart.

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