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Evaluation of analogues of furan-amidines as inhibitors of NQO2

Bioorganic & Medicinal Chemistry Letters, ISSN: 0960-894X, Vol: 28, Issue: 8, Page: 1292-1297
2018
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Article Description

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 IC 50 value of 0.3 μM.

Bibliographic Details

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

Elsevier BV

Biochemistry, Genetics and Molecular Biology; Pharmacology, Toxicology and Pharmaceutics; Chemistry

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