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Interconvertible geometric isomers of Plasmodium falciparum dihydroorotate dehydrogenase inhibitors exhibit multiple binding modes

Fishwick, Colin W. G.; McConkey, Glenn A.; Bedingfield, Paul T.P.; Burrell, David R.; Chambers, Nicholas C.; Cunningham, Fraser; Prior, Timothy J.; Fishwick, Colin W.G.; Boa, Andrew N.

Authors

Colin W. G. Fishwick

Glenn A. McConkey

Paul T.P. Bedingfield

David R. Burrell

Nicholas C. Chambers

Fraser Cunningham

Colin W.G. Fishwick



Abstract

Two new tricyclic β-aminoacrylate derivatives (2e and 3e) have been found to be inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) with Ki 0.037 and 0.15 μM respectively. 1H and 13C NMR spectroscopic data show that these compounds undergo ready cis-trans isomerisation at room temperature in polar solvents. In silico docking studies indicate that for both molecules there is neither conformation nor double bond configuration which bind preferentially to PfDHODH. This flexibility is favourable for inhibitors of this channel that require extensive positioning to reach their binding site.

Citation

Boa, A. N., McConkey, G. A., Bedingfield, P. T., Burrell, D. R., Chambers, N. C., Cunningham, F., …Boa, A. N. (2017). Interconvertible geometric isomers of Plasmodium falciparum dihydroorotate dehydrogenase inhibitors exhibit multiple binding modes. Bioorganic and Medicinal Chemistry Letters, 27(16), 3878-3882. https://doi.org/10.1016/j.bmcl.2017.06.052

Journal Article Type Article
Acceptance Date Jun 17, 2017
Online Publication Date Jun 21, 2017
Publication Date Aug 15, 2017
Deposit Date Jun 23, 2017
Publicly Available Date Jun 25, 2018
Journal Bioorganic and medicinal chemistry letters
Print ISSN 0960-894X
Electronic ISSN 1464-3405
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 27
Issue 16
Pages 3878-3882
DOI https://doi.org/10.1016/j.bmcl.2017.06.052
Keywords Dihydroorotate dehydrogenase; DHODH; Plasmodium falciparum; Inhibitor
Public URL https://hull-repository.worktribe.com/output/452754
Publisher URL https://www.sciencedirect.com/science/article/abs/pii/S0960894X17306467?via%3Dihub
Copyright Statement ©2018, Elsevier. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/
Additional Information This is the accepted manuscript of an article published in Bioorganic and medicinal chemistry letters, 2017. The version of record is available at the DOI link in this record.

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Publisher Licence URL
https://creativecommons.org/licenses/by-nc-nd/4.0/

Copyright Statement
©2018, Elsevier. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/





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