Interconvertible geometric isomers of Plasmodium falciparum dihydroorotate dehydrogenase inhibitors exhibit multiple binding modes. Issue 16 (15th August 2017)

• Record Type: Journal Article
• Authors: 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.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 27:Issue 16(2017)
• Page Start: 3878
• Page End: 3882
• Publication Date: 2017-08-15
• Subjects: Dihydroorotate dehydrogenase -- DHODH -- Plasmodium falciparum -- Inhibitor; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2017.06.052
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Two new tricyclic β-aminoacrylate derivatives (2e and3e ) have been found to be inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase ( Pf DHODH) with Ki 0.037 and 0.15 μM respectively. 1 H and 13 C 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 Pf DHODH. This flexibility is favourable for inhibitors of this channel that require extensive positioning to reach their binding site.