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

Hamish S Sutherland; Amy S T Tong; Peter J Choi; Daniel Conole; Adrian Blaser; Scott G Franzblau; Christopher B Cooper; Anna M Upton; Manisha U Lotlikar; William A Denny; Brian D Palmer

doi:10.1016/j.bmc.2018.02.026

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

Bioorg Med Chem. 2018 May 1;26(8):1797-1809. doi: 10.1016/j.bmc.2018.02.026. Epub 2018 Feb 20.

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, NY 10005, USA.
⁴ 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.
⁵ 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.

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.

Keywords: Bedaquiline; Bedaquiline analogs; Drug development; Tuberculosis.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Antitubercular Agents / chemical synthesis
Antitubercular Agents / chemistry
Antitubercular Agents / pharmacology*
Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis
Bridged Bicyclo Compounds, Heterocyclic / chemistry
Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
Cell Line, Tumor
Diarylquinolines / chemistry
Diarylquinolines / pharmacology*
Dose-Response Relationship, Drug
Humans
Microbial Sensitivity Tests
Molecular Structure
Mycobacterium tuberculosis / drug effects*
Naphthalenes / chemistry
Naphthalenes / pharmacology*
Structure-Activity Relationship

Substances

Antitubercular Agents
Bridged Bicyclo Compounds, Heterocyclic
Diarylquinolines
Naphthalenes
naphthalene
bedaquiline