Evaluation of analogues of furan-amidines as inhibitors of NQO2

Soraya Alnabulsi, Buthaina Hussein, Elham Santina, Izzeddin Alsalahat, Manikandan Kadirvel, Rachael N. Magwaza, Richard A. Bryce, Carl H. Schwalbe, Alex G. Baldwin, Ilaria Russo, Ian J. Stratford, Sally Freeman

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

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.

Original languageEnglish
Pages (from-to)1292-1297
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume28
Issue number8
DOIs
StatePublished - May 1 2018

Keywords

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

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