Evaluation of analogues of furan-amidines as inhibitors of NQO2

S. Alnabulsi, B. Hussein, E. Santina, I. Alsalahat, M. Kadirvel, R.N. Magwaza, R.A. Bryce, Carl H Schwalbe, A.G. Baldwin, I. Russo, I.J. Stratford, S. Freeman

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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.
Original languageEnglish
JournalBioorganic and Medicinal Chemistry Letters
Early online date12 Mar 2018
Publication statusE-pub ahead of print - 12 Mar 2018

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© 2018, Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International

Funding: Jordan University of Science and Technology, Irbid, and Al-Zaytoonah University, Jordan.


  • NQO2 inhibitors; Furan-amidines; Isosteres; Anti-cancer; Malaria; SAR

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    Alnabulsi, S., Hussein, B., Santina, E., Alsalahat, I., Kadirvel, M., Magwaza, R. N., Bryce, R. A., Schwalbe, C. H., Baldwin, A. G., Russo, I., Stratford, I. J., & Freeman, S. (2018). Evaluation of analogues of furan-amidines as inhibitors of NQO2. Bioorganic and Medicinal Chemistry Letters. https://doi.org/10.1016/j.bmcl.2018.03.025