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Evaluation of analogues of furan-amidines as inhibitors of NQO2


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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 furanamidine 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 ?M.


Russo. (2018). Evaluation of analogues of furan-amidines as inhibitors of NQO2. Bioorganic and Medicinal Chemistry Letters, 1292 - 1297.

Acceptance Date Mar 10, 2018
Publication Date May 1, 2018
Journal Bioorganic and Medicinal Chemistry Letters
Print ISSN 0960-894X
Publisher Elsevier
Pages 1292 - 1297
Keywords NQO2 inhibitors; Furan-amidines; IsosteresAnti-cancer; Malaria; SAR
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