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.

Highlights

  • Bedaquiline (TMC207, SirturoÒ, Janssen Pharmaceuticals; Fig. 1; 1) is an exciting new drug for the treatment of tuberculosis (TB). It exhibits a novel mechanism of action compared to other TB drugs namely inhibition of the ATP synthase1 of Mycobacterium tuberculosis (M.tb), the etiological agent of TB

  • Resistance to other TB drugs occurs primarily due to mutations in genes encoding their respective bacterial drug targets

  • We explore the effects of a variety of more hydrophilic bicyclic C units (Fig. 1) in place of the naphthalene unit of bedaquiline

Read more

Summary

Introduction

Bedaquiline (TMC207, SirturoÒ, Janssen Pharmaceuticals; Fig. 1; 1) is an exciting new drug for the treatment of tuberculosis (TB). In addition to being another way to lower the overall lipophilicity of analogs, a particular interest in exploring unit C structure is highlighted by a recent paper on the 1.7 Å resolution crystal structure of bedaquiline bound to the c subunit of the ATP synthase Fo of the mycobacterium M. phlei (84% sequence identity with M.tb). This shows the dimethylaminoethyl unit D making an H-bond to Glu in the ion-binding site of the enzyme, with the rest of the molecule demonstrating multiple hydrophobic contacts with the enzyme, including the naphthalene unit C with Tyr and Leu, but clashing with Tyr. Interest from a structural point of view, and in this paper, we prepare and evaluate a series of these, with the major focus on less lipophilic examples than naphthalene

Chemistry
Structure-activity relationships
Conclusions
Full Text
Paper version not known

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call

Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.