期刊
CHEMMEDCHEM
卷 18, 期 1, 页码 -出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.202200533
关键词
Bedaquiline; Drug-Resistant Tuberculosis; ATP Synthase Inhibitor; Pyridine; hERG Inhibition
The clinical use of bedaquiline has been limited due to safety concerns. Recent investigations have found that modification of the B- and C-ring units of bedaquiline can lead to the development of new compounds with potent anti-tubercular activity but improved safety. Concurrent modification of the A-, B-, and C-ring units in bedaquiline variants has been shown to result in compounds with relatively potent anti-tubercular activity and reduced safety issues.
To date, the clinical use of the anti-tubercular therapy bedaquiline has been somewhat limited due to safety concerns. Recent investigations determined that modification of the B- and C-ring units of bedaquiline delivered new diarylquinolines (for example TBAJ-587) with potent anti-tubercular activity yet an improved safety profile due to reduced affinity for the hERG channel. Building on our recent discovery that substitution of the quinoline motif (the A-ring subunit) for C5-aryl pyridine groups within bedaquiline analogues led to retention of anti-tubercular activity, we investigated the concurrent modification of A-, B- and C-ring units within bedaquiline variants. This led to the discovery that 4-trifluoromethoxyphenyl and 4-chlorophenyl pyridyl analogues of TBAJ-587 retained relatively potent anti-tubercular activity and for the 4-chlorophenyl derivative in particular, a significant reduction in hERG inhibition relative to bedaquiline was achieved, demonstrating that modifications of the A-, B- and C-ring units within the bedaquiline structure is a viable strategy for the design of effective, yet safer (and less lipophilic) anti-tubercular compounds.
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