Q203 (telacebec) is an imidazopyridine amide (IPA) targeting the respiratory CIIICIV 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 CIIICIV by these compounds. The assay results generally supported structure-activity relationship information obtained from the structure of CIIICIV bound to Q203. The IC of Q203 and compound 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 growth inhibition and CIIICIV 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 CIIICIV inhibition and cellular activity.
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| http://dx.doi.org/10.1021/acsomega.3c02259 | DOI Listing |
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