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

[Image: see text] 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-ste...

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Autores principales: Abdelaziz, Rana, Di Trani, Justin M, Sahile, Henok, Mann, Lea, Richter, Adrian, Liu, Zhongle, Bueler, Stephanie A., Cowen, Leah E., Rubinstein, John L., Imming, Peter
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2023
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10233671/
https://www.ncbi.nlm.nih.gov/pubmed/37273644
http://dx.doi.org/10.1021/acsomega.3c02259
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author Abdelaziz, Rana
Di Trani, Justin M
Sahile, Henok
Mann, Lea
Richter, Adrian
Liu, Zhongle
Bueler, Stephanie A.
Cowen, Leah E.
Rubinstein, John L.
Imming, Peter
author_facet Abdelaziz, Rana
Di Trani, Justin M
Sahile, Henok
Mann, Lea
Richter, Adrian
Liu, Zhongle
Bueler, Stephanie A.
Cowen, Leah E.
Rubinstein, John L.
Imming, Peter
author_sort Abdelaziz, Rana
collection PubMed
description [Image: see text] 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.
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spelling pubmed-102336712023-06-02 Imidazopyridine Amides: Synthesis, Mycobacterium smegmatis CIII(2)CIV(2) Supercomplex Binding, and In Vitro Antimycobacterial Activity Abdelaziz, Rana Di Trani, Justin M Sahile, Henok Mann, Lea Richter, Adrian Liu, Zhongle Bueler, Stephanie A. Cowen, Leah E. Rubinstein, John L. Imming, Peter ACS Omega [Image: see text] 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. American Chemical Society 2023-05-18 /pmc/articles/PMC10233671/ /pubmed/37273644 http://dx.doi.org/10.1021/acsomega.3c02259 Text en © 2023 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by-nc-nd/4.0/Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Abdelaziz, Rana
Di Trani, Justin M
Sahile, Henok
Mann, Lea
Richter, Adrian
Liu, Zhongle
Bueler, Stephanie A.
Cowen, Leah E.
Rubinstein, John L.
Imming, Peter
Imidazopyridine Amides: Synthesis, Mycobacterium smegmatis CIII(2)CIV(2) Supercomplex Binding, and In Vitro Antimycobacterial Activity
title Imidazopyridine Amides: Synthesis, Mycobacterium smegmatis CIII(2)CIV(2) Supercomplex Binding, and In Vitro Antimycobacterial Activity
title_full Imidazopyridine Amides: Synthesis, Mycobacterium smegmatis CIII(2)CIV(2) Supercomplex Binding, and In Vitro Antimycobacterial Activity
title_fullStr Imidazopyridine Amides: Synthesis, Mycobacterium smegmatis CIII(2)CIV(2) Supercomplex Binding, and In Vitro Antimycobacterial Activity
title_full_unstemmed Imidazopyridine Amides: Synthesis, Mycobacterium smegmatis CIII(2)CIV(2) Supercomplex Binding, and In Vitro Antimycobacterial Activity
title_short Imidazopyridine Amides: Synthesis, Mycobacterium smegmatis CIII(2)CIV(2) Supercomplex Binding, and In Vitro Antimycobacterial Activity
title_sort imidazopyridine amides: synthesis, mycobacterium smegmatis ciii(2)civ(2) supercomplex binding, and in vitro antimycobacterial activity
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10233671/
https://www.ncbi.nlm.nih.gov/pubmed/37273644
http://dx.doi.org/10.1021/acsomega.3c02259
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