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. 2017 Sep 22;8(10):1019-1024.
doi: 10.1021/acsmedchemlett.7b00196. eCollection 2017 Oct 12.

6-Cyano Analogues of Bedaquiline as Less Lipophilic and Potentially Safer Diarylquinolines for Tuberculosis

Amy S T Tong  1 , Peter J Choi  1 , Adrian Blaser  1 , Hamish S Sutherland  1 , Sophia K Y Tsang  1 , Jerome Guillemont  2 , Magali Motte  2 , Christopher B Cooper  3 , Koen Andries  4 , Walter Van den Broeck  4 , Scott G Franzblau  5 , Anna M Upton  3 , William A Denny  1 , Brian D Palmer  1 , Daniel Conole  1
Affiliations

6-Cyano Analogues of Bedaquiline as Less Lipophilic and Potentially Safer Diarylquinolines for Tuberculosis

Amy S T Tong et al. ACS Med Chem Lett. .

Abstract

Bedaquiline (1) is a new drug for tuberculosis and the first of the diarylquinoline class. 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. A number of structural ring A analogues of bedaquiline have been prepared and evaluated for their anti-M.tb activity (MIC90), with a view to their possible application as less lipophilic second generation compounds. It was previously observed that a range of 6-substituted analogues of 1 demonstrated a positive correlation between potency (MIC90) toward M.tb and drug lipophilicity. Contrary to this trend, we discovered, by virtue of a clogP/M.tb score, that a 6-cyano (CN) substituent provides a substantial reduction in lipophilicity with only modest effects on MIC values, suggesting this substituent as a useful tool in the search for effective and safer analogues of 1.

Keywords: ATP synthase; Bedaquiline; diarylquinoline; hERG; lipophilicity; tuberculosis.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Structure of bedaquiline (1).
Scheme 1
Scheme 1. Syntheses of a Representative Subset of Mannich Bases and Diarylquinoline Analogues
Reagents and conditions: (a) (i) HN(iOPr)2 or TMP, n-BuLi, THF, −40 °C, 0.25 h; (ii) 103–132, THF, −78 °C, 1.5 h; (iii) 133–139, THF, −78 °C, 4 h; (b) acetophenone, CH2O, Me2NH·HCl, c.HCl, EtOH, 90 °C, 18 h; (c) P(o-tol)3, Zn, Zn(CN)2, Pd2(dba)3, DMF, 50 °C, 5–18 h.
Figure 2
Figure 2
Mean lipophilicity/M.tb activity score of most suitable X substituents (cf. with X = Br).
See this image and copyright information in PMC

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