Imidazopyridine Amides: Synthesis, Mycobacterium smegmatis CIII 2 CIV 2 Supercomplex Binding, and In Vitro Antimycobacterial Activity.

Q203 (telacebec) is an imidazopyridine amide (IPA) targeting the respiratory CIII 2 CIV 2 supercomplex of the mycobacterial electron transport chain (ETC). Aiming for a better understanding of the molecular mechanism of action of IPA, 27 analogues were prepared through a seven-step synthetic scheme. Oxygen consumption assay was designed to test the inhibition of purified Mycobacterium smegmatis CIII 2 CIV 2 by these compounds. The assay results generally supported structure-activity relationship information obtained from the structure of M. smegmatis CIII 2 CIV 2 bound to Q203. The IC 50 of Q203 and compound 27 was 99 ± 32 and 441 ± 138 nM, respectively. All IPAs including Q203 showed no inhibition of mitochondrial ETC, proving their selectivity against mycobacteria. In vitro Mycobacterium tuberculosis growth inhibition and M. smegmatis CIII 2 CIV 2 binding did not correlate perfectly. These observations suggest that further investigation into the mechanisms of resistance in different mycobacterial species is needed to understand the lack of the correlation pattern between CIII 2 CIV 2 inhibition and cellular activity.