Imidazopyridine Amides: Synthesis, Mycobacterium smegmatis CIII₂CIV₂ Supercomplex Binding, and In Vitro Antimycobacterial Activity

Q203 (telacebec)is an imidazopyridine amide (IPA) targeting therespiratory CIII2CIV2 supercomplex of the mycobacterialelectron transport chain (ETC). Aiming for a better understandingof the molecular mechanism of action of IPA, 27 analogues were preparedthrough a seven-step synthetic scheme. Oxygen consumption assay wasdesigned to test the inhibition of purified Mycobacteriumsmegmatis CIII2CIV2 by thesecompounds. The assay results generally supported structure-activityrelationship information obtained from the structure of M. smegmatis CIII2CIV2 boundto Q203. The IC50 of Q203 and compound 27 was99 +/- 32 and 441 +/- 138 nM, respectively. All IPAs includingQ203 showed no inhibition of mitochondrial ETC, proving their selectivityagainst mycobacteria. In vitro Mycobacterium tuberculosis growth inhibition and M. smegmatis CIII2CIV2 binding did not correlate perfectly.These observations suggest that further investigation into the mechanismsof resistance in different mycobacterial species is needed to understandthe lack of the correlation pattern between CIII2CIV2 inhibition and cellular activity.