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

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

doi:10.1021/acsmedchemlett.7b00196

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.

Highlights

Novel drugs that can reduce the treatment time for tuberculosis (TB) are vital, in cases of multiand extensively drug resistant tuberculosis (MDR-TB and XDR-TB).[1]
New TB drugs are effective against drugresistant and drug-sensitive TB, well tolerated, suitable for once daily oral dosing, and compatible with antiretroviral therapies for individuals coinfected with HIV
Bedaquiline has a novel mechanism of action, through inhibition of the mycobacterial ATP synthase enzyme.[2]

Summary

ACS Medicinal Chemistry Letters

Letter contribute to bedaquiline’s long terminal elimination half-life,[9] which may lead to tissue overproportional accumulation at high doses or with daily dosing. Bedaquiline emerged from a whole-cell screen of 70,000 library compounds against the nonpathogenic M.smegmatis strain of TB,[11] where the racemic mixture (comprising four diastereomers) was shown to have useful activity against both M.smegmatis and M.tuberculosis (M.tb), with the R,S enantiomer being the most potent. The study evaluated eight analogues of 1 with differing substituents at the 6-position of the methoxyquinoline ring, including compounds 1, 2, 5, and 6 in Table 1 below (mostly as RS,SR diastereomer mixtures). In the present Letter, we expand the range of 6-substituents in this series, across a number of modified B and C ring scaffolds, seeking more polar alternatives to Br that provide analogues of bedaquiline with similar potency of M.tb inhibition. Comparison of Different 6-Quinoline Substituents on Modified B/C Scaffolds

CN Xe

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