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
Summary
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
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