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

Rana Abdelaziz; Justin M Di Trani; Henok Sahile; Lea Mann; Adrian Richter; Zhongle Liu; Stephanie A Bueler; Leah E Cowen; John L Rubinstein; Peter Imming

doi:10.1021/acsomega.3c02259

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

ACS Omega. 2023 May 18;8(21):19081-19098. doi: 10.1021/acsomega.3c02259. eCollection 2023 May 30.

Authors

Affiliations

¹ Institut Für Pharmazie, Martin-Luther-Universität Halle-Wittenberg, Halle (Saale) 06120, Germany.
² Molecular Medicine Program, The Hospital for Sick Children, Toronto M5G 0A4, Canada.
³ Departments of Medicine and Microbiology and Immunology, Life Sciences Institute, University of British Columbia, Vancouver V6T 1Z3, Canada.
⁴ Department of Molecular Genetics, The University of Toronto, Toronto M5G 0A4, Canada.
⁵ Department of Medical Biophysics, The University of Toronto, Toronto M5G 0A4, Canada.
⁶ Department of Biochemistry, The University of Toronto, Toronto M5G 0A4, Canada.

Abstract

Q203 (telacebec) is an imidazopyridine amide (IPA) targeting the respiratory CIII₂CIV₂ 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 CIII₂CIV₂ by these compounds. The assay results generally supported structure-activity relationship information obtained from the structure of M. smegmatis CIII₂CIV₂ bound to Q203. The IC₅₀ 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 CIII₂CIV₂ 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 CIII₂CIV₂ inhibition and cellular activity.