Discovery of Anti-tubercular Analogues of Bedaquiline with Modified A-, B-and C-Ring Subunits




Barbaro, L., Nagalingam, G., Triccas, J. A., Tan, L., West, N. P., Priebbenow, D. L., & Baell, J. B.



To date, the clinical use of the anti-tubercular therapy bedaqui-line has been somewhat limited due to safety concerns. Recent investigations determined that modification of the Band 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-, Band C-ring units within bedaquiline variants. This led to the discovery that 4-trifluoromethoxyphenyl and 4-chlorophen-yl 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-, Band 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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