Synthesis and evaluation of analogues of the tuberculosis drug bedaquiline containing heterocyclic B-ring units

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:27

Article

Choi, Peter J.¹  Sutherland, Hamish S.¹  Tong, Amy S. T.¹  Blaser, Adrian¹  Franzblau, Scott G.³  Cooper, Christopher B.⁴  Lotlikar, Manisha U.⁴  Upton, Anna M.⁴  Guillemont, Jerome⁵  Motte, Magali⁵  Queguiner, Laurence⁵  Andries, Koen⁶  Van den Broeck, Walter⁶  Denny, William A.^1,2  Palmer, Brian D.^1,2 

[1] Univ Auckland, Sch Med Sci, Auckland Canc Soc, Res Ctr, Private Bag 92019, Auckland 1142, New Zealand

[2] Univ Auckland, Maurice Wilkins Ctr, Private Bag 92019, Auckland 1142, New Zealand

[3] Univ Illinois, Inst TB Res, Coll Pharm, 833 South Wood St, Chicago, IL 60612 USA

[4] Global Alliance TB Drug Dev, 40 Wall St, New York, NY 10005 USA

[5] Janssen Pharmaceut, Med Chem Dept, Infect Dis, Campus Maigremont,BP315, F-27106 Val De Reuil, France

[6] Janssen Infect Dis BVBA, Beerse, Belgium

关键词: Bedaquiline;    Bedaquiline analogues;    Tuberculosis;    Drug development;   

DOI  :  10.1016/j.bmcl.2017.10.042

来源: Elsevier

【 摘 要 】

Analogues of bedaquiline where the phenyl B-unit was replaced with monocyclic heterocycles of widely differing lipophilicity (thiophenes, furans, pyridines) were synthesised and evaluated. While there was an expected broad positive correlation between lipophilicity and anti-TB activity, the 4-pyridyl derivatives appeared to have an additional contribution to antibacterial potency. The majority of the compounds were (desirably) more polar and had higher rates of clearance than bedaquiline, and showed acceptable oral bioavailability, but there was only limited (and unpredictable) improvement in their hERG liability. (C) 2017 The Authors. Published by Elsevier Ltd.

【 授权许可】

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