Evaluation of analogues of furan-amidines as inhibitors of NQO2

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  • 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


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

Bibliographic note

© 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.


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

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