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

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.

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

McConkey, G. A., Bedingfield, P. T., Burrell, D. R., Chambers, N. C., Cunningham, F., Prior, T. J., Fishwick, C. W., & 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
• 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
• 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.
• Contract Date: Jun 23, 2017