Evaluation of analogues of furan-amidines as inhibitors of NQO2


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.

Publication DOI: https://doi.org/10.1016/j.bmcl.2018.03.025
Divisions: College of Health & Life Sciences > Aston Pharmacy School
Additional Information: © 2018, Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/. Funding: Jordan University of Science and Technology, Irbid, and Al-Zaytoonah University, Jordan.
Uncontrolled Keywords: NQO2 inhibitors; Furan-amidines; Isosteres; Anti-cancer; Malaria; SAR
Publication ISSN: 1464-3405
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Related URLs: https://www.sci ... 960894X1830204X (Publisher URL)
PURE Output Type: Article
Published Date: 2018-05-01
Published Online Date: 2018-03-12
Accepted Date: 2018-03-10
Authors: Alnabulsi, S.
Hussein, B.
Santina, E.
Alsalahat, I.
Kadirvel, M.
Magwaza, R.N.
Bryce, R.A.
Schwalbe, Carl H
Baldwin, A.G.
Russo, I.
Stratford, I.J.
Freeman, S.

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