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Structural Simplification of Bedaquiline: the Discovery of 3‐(4‐(N,N‐Dimethylaminomethyl)phenyl)quinoline‐Derived Antitubercular Lead Compounds
Bedaquiline (BDQ) is a novel and highly potent last‐line antituberculosis drug that was approved by the US FDA in 2013. Owing to its stereo‐structural complexity, chemical synthesis and compound optimization are rather difficult and expensive. This study describes the structural simplification of be...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5298006/ https://www.ncbi.nlm.nih.gov/pubmed/27792278 http://dx.doi.org/10.1002/cmdc.201600441 |
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author | He, Chunxian Preiss, Laura Wang, Bin Fu, Lei Wen, Hui Zhang, Xiang Cui, Huaqing Meier, Thomas Yin, Dali |
author_facet | He, Chunxian Preiss, Laura Wang, Bin Fu, Lei Wen, Hui Zhang, Xiang Cui, Huaqing Meier, Thomas Yin, Dali |
author_sort | He, Chunxian |
collection | PubMed |
description | Bedaquiline (BDQ) is a novel and highly potent last‐line antituberculosis drug that was approved by the US FDA in 2013. Owing to its stereo‐structural complexity, chemical synthesis and compound optimization are rather difficult and expensive. This study describes the structural simplification of bedaquiline while preserving antitubercular activity. The compound's structure was split into fragments and reassembled in various combinations while replacing the two chiral carbon atoms with an achiral linkage instead. Four series of analogues were designed; these candidates retained their potent antitubercular activity at sub‐microgram per mL concentrations against both sensitive and multidrug‐resistant (MDR) Mycobacterium tuberculosis strains. Six out of the top nine MIC‐ranked candidates were found to inhibit mycobacterial ATP synthesis activity with IC(50) values between 20 and 40 μm, one had IC(50)>66 μm, and two showed no inhibition, despite their antitubercular activity. These results provide a basis for the development of chemically less complex, lower‐cost bedaquiline derivatives and describe the identification of two derivatives with antitubercular activity against non‐ATP synthase related targets. |
format | Online Article Text |
id | pubmed-5298006 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-52980062017-02-22 Structural Simplification of Bedaquiline: the Discovery of 3‐(4‐(N,N‐Dimethylaminomethyl)phenyl)quinoline‐Derived Antitubercular Lead Compounds He, Chunxian Preiss, Laura Wang, Bin Fu, Lei Wen, Hui Zhang, Xiang Cui, Huaqing Meier, Thomas Yin, Dali ChemMedChem Full Papers Bedaquiline (BDQ) is a novel and highly potent last‐line antituberculosis drug that was approved by the US FDA in 2013. Owing to its stereo‐structural complexity, chemical synthesis and compound optimization are rather difficult and expensive. This study describes the structural simplification of bedaquiline while preserving antitubercular activity. The compound's structure was split into fragments and reassembled in various combinations while replacing the two chiral carbon atoms with an achiral linkage instead. Four series of analogues were designed; these candidates retained their potent antitubercular activity at sub‐microgram per mL concentrations against both sensitive and multidrug‐resistant (MDR) Mycobacterium tuberculosis strains. Six out of the top nine MIC‐ranked candidates were found to inhibit mycobacterial ATP synthesis activity with IC(50) values between 20 and 40 μm, one had IC(50)>66 μm, and two showed no inhibition, despite their antitubercular activity. These results provide a basis for the development of chemically less complex, lower‐cost bedaquiline derivatives and describe the identification of two derivatives with antitubercular activity against non‐ATP synthase related targets. John Wiley and Sons Inc. 2016-10-28 2017-01-20 /pmc/articles/PMC5298006/ /pubmed/27792278 http://dx.doi.org/10.1002/cmdc.201600441 Text en © 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Full Papers He, Chunxian Preiss, Laura Wang, Bin Fu, Lei Wen, Hui Zhang, Xiang Cui, Huaqing Meier, Thomas Yin, Dali Structural Simplification of Bedaquiline: the Discovery of 3‐(4‐(N,N‐Dimethylaminomethyl)phenyl)quinoline‐Derived Antitubercular Lead Compounds |
title | Structural Simplification of Bedaquiline: the Discovery of 3‐(4‐(N,N‐Dimethylaminomethyl)phenyl)quinoline‐Derived Antitubercular Lead Compounds |
title_full | Structural Simplification of Bedaquiline: the Discovery of 3‐(4‐(N,N‐Dimethylaminomethyl)phenyl)quinoline‐Derived Antitubercular Lead Compounds |
title_fullStr | Structural Simplification of Bedaquiline: the Discovery of 3‐(4‐(N,N‐Dimethylaminomethyl)phenyl)quinoline‐Derived Antitubercular Lead Compounds |
title_full_unstemmed | Structural Simplification of Bedaquiline: the Discovery of 3‐(4‐(N,N‐Dimethylaminomethyl)phenyl)quinoline‐Derived Antitubercular Lead Compounds |
title_short | Structural Simplification of Bedaquiline: the Discovery of 3‐(4‐(N,N‐Dimethylaminomethyl)phenyl)quinoline‐Derived Antitubercular Lead Compounds |
title_sort | structural simplification of bedaquiline: the discovery of 3‐(4‐(n,n‐dimethylaminomethyl)phenyl)quinoline‐derived antitubercular lead compounds |
topic | Full Papers |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5298006/ https://www.ncbi.nlm.nih.gov/pubmed/27792278 http://dx.doi.org/10.1002/cmdc.201600441 |
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