Structure-activity relationships for analogs of the tuberculosis drug bedaquiline with the naphthalene unit replaced by bicyclic heterocycles

Abstract

Replacing the naphthalene C-unit of the anti-tuberculosis drug bedaquiline with a range of bicyclic heterocycles of widely differing lipophilicity gave analogs with a 4.5-fold range in clogP values. The biological results for these compounds indicate on average a lower clogP limit of about 5.0 in this series for retention of potent inhibitory activity (MIC₉₀s) against M.tb in culture. Some of the compounds also showed a significant reduction in inhibition of hERG channel potassium current compared with bedaquiline, but there was no common structural feature that distinguished these.

Keywords: Bedaquiline; Bedaquiline analogs; Drug development; Tuberculosis.

Graphical abstract

Fig. 1

Bedaquiline (1).

Scheme 1

Synthesis of the compounds of Table 1. Footnote for Scheme 1. (i) (a) HN(iPr)₂, n-BuLi, THF, −40 °C, 0.25 h; (b) A/B-unit, THF, −78 °C, 1.5 h; (c) Mannich base, THF, −78 °C, 4 h; (ii) Zn, Zn(CN)₂, Pd₂(dba)₃, P(o-tol)_3, DMF, 50 °C.

Scheme 2

Synthesis of the required A/B units. Footnote for Scheme 2. Y = Me (Ref. 8): Y = H; 3-F; 2-F, 3-OMe; 2,3-diOMe (Ref. 10): 3-aza, 2-OMe; 3-aza, 4,5-diOMe; 4-aza, 2,3-diOMe (Ref 11); Y = 2,3-O(CH₂)₂O– (route 2, yield 52%); 4-aza, 3,5-diOEt (route 2, yield 56%); 4-aza, 3-OMe, 5-OEt (route 2, yield 68%); 4-aza, 3-OMe, 5-OiPr (route 2, yield 78%) 4-aza, 3-OMe, 5-OnPr (route 2, yield 75%), 4-aza, 3-OEt, 5-OnPr (route 2, yield 78%) (this paper). (i) LiTMP, then AcOH; (ii) Et₃SiH, TFA, DCM, 20 °C; (iii) Cs₂CO₃, Pd(PPh₃)₄, PhMe/DMF, 110 °C (sealed tube), 5 h.

Scheme 3

Synthesis of Mannich base C/D units.