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Identification, Design and Biological Evaluation of Bisaryl Quinolones Targeting Plasmodium falciparum Type II NADH:Quinone Oxidoreductase (PfNDH2)

[Image: see text] A program was undertaken to identify hit compounds against NADH:ubiquinone oxidoreductase (PfNDH2), a dehydrogenase of the mitochondrial electron transport chain of the malaria parasite Plasmodium falciparum. PfNDH2 has only one known inhibitor, hydroxy-2-dodecyl-4-(1H)-quinolone (...

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Autores principales: Pidathala, Chandrakala, Amewu, Richard, Pacorel, Bénédicte, Nixon, Gemma L., Gibbons, Peter, Hong, W. David, Leung, Suet C., Berry, Neil G., Sharma, Raman, Stocks, Paul A., Srivastava, Abhishek, Shone, Alison E., Charoensutthivarakul, Sitthivut, Taylor, Lee, Berger, Olivier, Mbekeani, Alison, Hill, Alasdair, Fisher, Nicholas E., Warman, Ashley J., Biagini, Giancarlo A., Ward, Stephen A., O’Neill, Paul M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2012
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3297363/
https://www.ncbi.nlm.nih.gov/pubmed/22364416
http://dx.doi.org/10.1021/jm201179h
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author Pidathala, Chandrakala
Amewu, Richard
Pacorel, Bénédicte
Nixon, Gemma L.
Gibbons, Peter
Hong, W. David
Leung, Suet C.
Berry, Neil G.
Sharma, Raman
Stocks, Paul A.
Srivastava, Abhishek
Shone, Alison E.
Charoensutthivarakul, Sitthivut
Taylor, Lee
Berger, Olivier
Mbekeani, Alison
Hill, Alasdair
Fisher, Nicholas E.
Warman, Ashley J.
Biagini, Giancarlo A.
Ward, Stephen A.
O’Neill, Paul M.
author_facet Pidathala, Chandrakala
Amewu, Richard
Pacorel, Bénédicte
Nixon, Gemma L.
Gibbons, Peter
Hong, W. David
Leung, Suet C.
Berry, Neil G.
Sharma, Raman
Stocks, Paul A.
Srivastava, Abhishek
Shone, Alison E.
Charoensutthivarakul, Sitthivut
Taylor, Lee
Berger, Olivier
Mbekeani, Alison
Hill, Alasdair
Fisher, Nicholas E.
Warman, Ashley J.
Biagini, Giancarlo A.
Ward, Stephen A.
O’Neill, Paul M.
author_sort Pidathala, Chandrakala
collection PubMed
description [Image: see text] A program was undertaken to identify hit compounds against NADH:ubiquinone oxidoreductase (PfNDH2), a dehydrogenase of the mitochondrial electron transport chain of the malaria parasite Plasmodium falciparum. PfNDH2 has only one known inhibitor, hydroxy-2-dodecyl-4-(1H)-quinolone (HDQ), and this was used along with a range of chemoinformatics methods in the rational selection of 17 000 compounds for high-throughput screening. Twelve distinct chemotypes were identified and briefly examined leading to the selection of the quinolone core as the key target for structure–activity relationship (SAR) development. Extensive structural exploration led to the selection of 2-bisaryl 3-methyl quinolones as a series for further biological evaluation. The lead compound within this series 7-chloro-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(1H)-one (CK-2-68) has antimalarial activity against the 3D7 strain of P. falciparum of 36 nM, is selective for PfNDH2 over other respiratory enzymes (inhibitory IC(50) against PfNDH2 of 16 nM), and demonstrates low cytotoxicity and high metabolic stability in the presence of human liver microsomes. This lead compound and its phosphate pro-drug have potent in vivo antimalarial activity after oral administration, consistent with the target product profile of a drug for the treatment of uncomplicated malaria. Other quinolones presented (e.g., 6d, 6f, 14e) have the capacity to inhibit both PfNDH2 and P. falciparum cytochrome bc(1), and studies to determine the potential advantage of this dual-targeting effect are in progress.
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spelling pubmed-32973632012-03-08 Identification, Design and Biological Evaluation of Bisaryl Quinolones Targeting Plasmodium falciparum Type II NADH:Quinone Oxidoreductase (PfNDH2) Pidathala, Chandrakala Amewu, Richard Pacorel, Bénédicte Nixon, Gemma L. Gibbons, Peter Hong, W. David Leung, Suet C. Berry, Neil G. Sharma, Raman Stocks, Paul A. Srivastava, Abhishek Shone, Alison E. Charoensutthivarakul, Sitthivut Taylor, Lee Berger, Olivier Mbekeani, Alison Hill, Alasdair Fisher, Nicholas E. Warman, Ashley J. Biagini, Giancarlo A. Ward, Stephen A. O’Neill, Paul M. J Med Chem [Image: see text] A program was undertaken to identify hit compounds against NADH:ubiquinone oxidoreductase (PfNDH2), a dehydrogenase of the mitochondrial electron transport chain of the malaria parasite Plasmodium falciparum. PfNDH2 has only one known inhibitor, hydroxy-2-dodecyl-4-(1H)-quinolone (HDQ), and this was used along with a range of chemoinformatics methods in the rational selection of 17 000 compounds for high-throughput screening. Twelve distinct chemotypes were identified and briefly examined leading to the selection of the quinolone core as the key target for structure–activity relationship (SAR) development. Extensive structural exploration led to the selection of 2-bisaryl 3-methyl quinolones as a series for further biological evaluation. The lead compound within this series 7-chloro-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(1H)-one (CK-2-68) has antimalarial activity against the 3D7 strain of P. falciparum of 36 nM, is selective for PfNDH2 over other respiratory enzymes (inhibitory IC(50) against PfNDH2 of 16 nM), and demonstrates low cytotoxicity and high metabolic stability in the presence of human liver microsomes. This lead compound and its phosphate pro-drug have potent in vivo antimalarial activity after oral administration, consistent with the target product profile of a drug for the treatment of uncomplicated malaria. Other quinolones presented (e.g., 6d, 6f, 14e) have the capacity to inhibit both PfNDH2 and P. falciparum cytochrome bc(1), and studies to determine the potential advantage of this dual-targeting effect are in progress. American Chemical Society 2012-02-24 2012-03-08 /pmc/articles/PMC3297363/ /pubmed/22364416 http://dx.doi.org/10.1021/jm201179h Text en Copyright © 2012 American Chemical Society http://pubs.acs.org This is an open-access article distributed under the ACS AuthorChoice Terms & Conditions. Any use of this article, must conform to the terms of that license which are available at http://pubs.acs.org.
spellingShingle Pidathala, Chandrakala
Amewu, Richard
Pacorel, Bénédicte
Nixon, Gemma L.
Gibbons, Peter
Hong, W. David
Leung, Suet C.
Berry, Neil G.
Sharma, Raman
Stocks, Paul A.
Srivastava, Abhishek
Shone, Alison E.
Charoensutthivarakul, Sitthivut
Taylor, Lee
Berger, Olivier
Mbekeani, Alison
Hill, Alasdair
Fisher, Nicholas E.
Warman, Ashley J.
Biagini, Giancarlo A.
Ward, Stephen A.
O’Neill, Paul M.
Identification, Design and Biological Evaluation of Bisaryl Quinolones Targeting Plasmodium falciparum Type II NADH:Quinone Oxidoreductase (PfNDH2)
title Identification, Design and Biological Evaluation of Bisaryl Quinolones Targeting Plasmodium falciparum Type II NADH:Quinone Oxidoreductase (PfNDH2)
title_full Identification, Design and Biological Evaluation of Bisaryl Quinolones Targeting Plasmodium falciparum Type II NADH:Quinone Oxidoreductase (PfNDH2)
title_fullStr Identification, Design and Biological Evaluation of Bisaryl Quinolones Targeting Plasmodium falciparum Type II NADH:Quinone Oxidoreductase (PfNDH2)
title_full_unstemmed Identification, Design and Biological Evaluation of Bisaryl Quinolones Targeting Plasmodium falciparum Type II NADH:Quinone Oxidoreductase (PfNDH2)
title_short Identification, Design and Biological Evaluation of Bisaryl Quinolones Targeting Plasmodium falciparum Type II NADH:Quinone Oxidoreductase (PfNDH2)
title_sort identification, design and biological evaluation of bisaryl quinolones targeting plasmodium falciparum type ii nadh:quinone oxidoreductase (pfndh2)
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3297363/
https://www.ncbi.nlm.nih.gov/pubmed/22364416
http://dx.doi.org/10.1021/jm201179h
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