LAUSR

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.