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Evaluation of analogues of furan-amidines as inhibitors of NQO2

Alnabulsi, Soraya, Hussein, Buthaina, Santina, Elham, Alsalahat, Izzeddin, Kadirvel, Manikandan, Magwaza, Rachael N., Bryce, Richard A., Schwalbe, Carl H., Baldwin, Alex ORCID: https://orcid.org/0000-0002-7126-5220, Russo, Ilaria, Stratford, Ian J. and Freeman, Sally 2018. Evaluation of analogues of furan-amidines as inhibitors of NQO2. Biorganic and Medicinal Chemistry Letters 28 (8) , pp. 1292-1297. 10.1016/j.bmcl.2018.03.025

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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
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: 07 Nov 2023 02:39
URI: https://orca.cardiff.ac.uk/id/eprint/110008

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