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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, 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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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: 20 Oct 2019 06:50

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