Alnabulsi, Soraya, Hussein, Buthaina, Santina, Elham, Alsalahat, Izzeddin, Kadirvel, Manikandan, Magwaza, Rachael N., Bryce, Richard A., Schwalbe, Carl H., Baldwin, Alex ![]() |
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Abstract
Inhibitors of the enzyme NQO2 (NRH: quinone oxidoreductase 2) are of potential use in cancer chemotherapy and malaria. We have previously reported that non-symmetrical furan amidines are potent inhibitors of NQO2 and here novel analogues are evaluated. The furan ring has been changed to other heterocycles (imidazole, N-methylimidazole, oxazole, thiophene) and the amidine group has been replaced with imidate, reversed amidine, N-arylamide and amidoxime to probe NQO2 activity, improve solubility and decrease basicity of the lead furan amidine. All compounds were fully characterised spectroscopically and the structure of the unexpected product N-hydroxy-4-(5-methyl-4-phenylfuran-2-yl)benzamidine was established by X-ray crystallography. The analogues were evaluated for inhibition of NQO2, which showed lower activity than the lead furan amidine. The observed structure-activity relationship for the furan-amidine series with NQO2 was rationalized by preliminary molecular docking and binding mode analysis. In addition, the oxazole-amidine analogue inhibited the growth of Plasmodium falciparum with an IC50 value of 0.3 μM.
Item Type: | Article |
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Date Type: | Publication |
Status: | Published |
Schools: | Biosciences |
Publisher: | Elsevier |
ISSN: | 0960-894X |
Date of First Compliant Deposit: | 1 May 2018 |
Date of Acceptance: | 10 March 2018 |
Last Modified: | 28 Nov 2024 20:00 |
URI: | https://orca.cardiff.ac.uk/id/eprint/110008 |
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