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Evaluation of analogues of furan-amidines as inhibitors of NQO2

Russo

Evaluation of analogues of furan-amidines as inhibitors of NQO2 Thumbnail


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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 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.

Acceptance Date Mar 10, 2018
Publication Date May 1, 2018
Publicly Available Date Mar 28, 2024
Journal Bioorganic and Medicinal Chemistry Letters
Print ISSN 0960-894X
Publisher Elsevier
Pages 1292 - 1297
DOI https://doi.org/10.1016/j.bmcl.2018.03.025
Keywords NQO2 inhibitors; Furan-amidines; IsosteresAnti-cancer; Malaria; SAR
Publisher URL https://www.sciencedirect.com/science/article/pii/S0960894X1830204X?via%3Dihub

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