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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...

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Autores principales: He, Chunxian, Preiss, Laura, Wang, Bin, Fu, Lei, Wen, Hui, Zhang, Xiang, Cui, Huaqing, Meier, Thomas, Yin, Dali
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2016
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.
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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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