Structure-activity relationships for analogs of the tuberculosis drug bedaquiline with the naphthalene unit replaced by bicyclic heterocycles. Issue 8 (1st May 2018)

• Record Type: Journal Article
• Authors: Sutherland, Hamish S.; Tong, Amy S.T.; Choi, Peter J.; Conole, Daniel; Blaser, Adrian; Franzblau, Scott G.; Cooper, Christopher B.; Upton, Anna M.; Lotlikar, Manisha U.; Denny, William A.; Palmer, Brian D.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 26:Issue 8(2018)
• Page Start: 1797
• Page End: 1809
• Publication Date: 2018-05-01
• Subjects: UWQADRQFXJNEOZ-UHFFFAOYSA-N -- KWOVKARWDHUSIN-UHFFFAOYSA-N -- ZHGWZQOAJKLQEL-UHFFFAOYSA-N -- KMAVUSDAUUUVLI-UHFFFAOYSA-N -- SIMUFWJFAOUTGX-UHFFFAOYSA-N -- YJCQPBKHHGIVPY-UHFFFAOYSA-N -- GWCAFEYJDZYUAU-UHFFFAOYSA-N -- LQSGBWREJUGOBD-UHFFFAOYSA-N -- PDOISTVVCHXKAI-UHFFFAOYSA-N -- NQFUJHNXWVONOM-UHFFFAOYSA-N -- ZQLMDJFHNAGDCJ-UHFFFAOYSA-N -- XONDVIJLBVRHDS-UHFFFAOYSA-N -- PZBKKZYNHFPQNH-UHFFFAOYSA-N -- GCEFZBMTHKSWDC-UHFFFAOYSA-N -- MXGZQCMWICEFKR-UHFFFAOYSA-N -- VWVPYZZKLRQLEG-UHFFFAOYSA-N -- QOJZGRXSHLTFGO-UHFFFAOYSA-N -- WUYSXIPYZLKHFQ-UHFFFAOYSA-N -- JWWKSAPFDYUJSV-UHFFFAOYSA-N -- MLNOGGWNTISHCL-UHFFFAOYSA-N; Bedaquiline -- Bedaquiline analogs -- Tuberculosis -- Drug development; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2018.02.026
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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 (MIC90 s) 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.