2. Academic Validation
  3. Imidazopyridine Amides: Synthesis, Mycobacterium smegmatis CIII2CIV2 Supercomplex Binding, and In Vitro Antimycobacterial Activity

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.
Rana Abdelaziz 1,  Justin M Di Trani 2,  Henok Sahile 3,  Lea Mann 1,  Adrian Richter 1,  Zhongle Liu 4,  Stephanie A Bueler 2,  Leah E Cowen 4,  John L Rubinstein 2 5 6,  Peter Imming 1
Affiliations

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.
PMID: 37273644 DOI: 10.1021/acsomega.3c02259
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.

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