Bedaquiline (1) is the first FDA approved drug for the treatment of tuberculosis (TB) in 40 years and the first of the diarylaminoquinoline class. It has a novel mechanism of action through inhibition of the mycobacterial ATP synthase enzyme.1 It demonstrates excellent efficacy against TB, but induces phospholipidosis at high doses, has a long terminal elimination half-life (due to its high lipophilicity) and exhibits potent hERG channel inhibition, resulting in clinical QTc interval prolongation.2
A range analogues of 1 have been prepared to address these issues and evaluated for their anti- M.tb activity (MIC90) to examine their use as effective and safer second generation analogues of 1.
1. Koul, A.N.; Dendouga, K.; Vergauwen, B.; Molenberghs, B.; Vranckx, L.; Willebrords, R.; Ristic, Z.; Lill, H.; Dorange, I.; Guillemont, J.; Bald, D;, Andries, K. Diarylquinolines target subunit c of mycobacterial ATP synthase. Nat. Chem. Biol. 2007, 3, 323-324.
2. Kakkar, A.K.; Dahiya, N. Bedaquiline for the treatment of resistant tuberculosis: Promises and pitfalls. Tuberculosis 2014, 94 (4), 357-362.