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Recent investigations determined that modification of the B\u2010 and C\u2010ring units of bedaquiline delivered new diarylquinolines (for example TBAJ\u2010587) with potent anti\u2010tubercular 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\u2010ring subunit) for C5\u2010aryl pyridine groups within bedaquiline analogues led to retention of anti\u2010tubercular activity, we investigated the concurrent modification of A\u2010, B\u2010 and C\u2010ring units within bedaquiline variants. This led to the discovery that 4\u2010trifluoromethoxyphenyl and 4\u2010chlorophenyl pyridyl analogues of TBAJ\u2010587 retained relatively potent anti\u2010tubercular activity and for the 4\u2010chlorophenyl derivative in particular, a significant reduction in hERG inhibition relative to bedaquiline was achieved, demonstrating that modifications of the A\u2010, B\u2010 and C\u2010ring units within the bedaquiline structure is a viable strategy for the design of effective, yet safer (and less lipophilic) anti\u2010tubercular compounds.<\/jats:p>","DOI":"10.1002\/cmdc.202200533","type":"journal-article","created":{"date-parts":[[2022,10,19]],"date-time":"2022-10-19T04:49:10Z","timestamp":1666154950000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Discovery of Anti\u2010tubercular Analogues of Bedaquiline with Modified A\u2010, B\u2010 and C\u2010Ring 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