Diarylquinolines 321 History

The diarylquinoline TMC207 (Fig. 14; 14a), first reported in 2005, is the first known antitubercular compound in the diarylquinoline class [164] (for additional details, see [165, 166]). Tibotec, a subsidiary of Johnson and Johnson, has reported the vast majority of research and development on TMC207, although recent efforts by Chattopadhyaya and coworkers have contributed new related compounds [167, 168]. TMC207 was one of the lead compounds discovered in a high-throughput screen for compounds with activity against Mycobacterium smegmatis (a nonpatho-genic rapid-growing mycobacterium), which were subsequently evaluated against MTb [164].

3.2.2 SAR of TMC207

Correct absolute and relative configuration of the two stereocenters of TMC207 (Fig. 14; 14a), which have been assigned by NMR and X-ray crystallographic analysis [169, 170], are required for activity [171, 172]. Sterically undemanding functional groups can be substituted for the bromine on the quinoline ring without significant loss of activity, although a bromine atom appears to be preferred. The naphthyl substituent can be replaced with other electron-poor aryl groups and still maintain good activity against MTb. Based on initial reports, the dimethyl-substituted tertiary amine appears to be required for activity, with the replacement of one methyl substituent with a proton or ethyl substituent resulting in a decrease in activity [171]. However, more recent reports suggest that the N-monodesmethyl

Relative and absolute stereochemistry essential at both stereocenters

Fig. 14 SAR of TMC207

Electron-deficient aromatic preferred

Hydrophobe preferred

Relative and absolute stereochemistry essential at both stereocenters

Electron-deficient aromatic preferred

Hydrophobe preferred

Improves physico-chemical properties metabolite of TMC207 produced by oxidation by CYP3A4, a cytochrome P450 that is potently induced by RIF, maintains significant antitubercular activity [173].

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