Alnabulsi, S, Hussein, B, Santina, E, Alsalahat, I, Kadirvel, M, Magwaza, R, Bryce, R, Schwalbe, C, Baldwin, A, Russo, I ORCID: https://orcid.org/0000-0002-2269-7078, Stratford, I and Freeman, S (2018) Evaluation of analogues of furan-amidines as inhibitors of NQO2. Bioorganic and Medicinal Chemistry Letters, 28 (8). 1292 - 1297.

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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.

Item Type: Article
Additional Information: The final published version of this accepted manuscript is available online at https://www.sciencedirect.com/science/article/pii/S0960894X1830204X?via%3Dihub
Uncontrolled Keywords: NQO2 inhibitors; Furan-amidines; IsosteresAnti-cancer; Malaria; SAR
Subjects: Q Science > QH Natural history
Q Science > QH Natural history > QH301 Biology
Divisions: Faculty of Natural Sciences > School of Life Sciences
Depositing User: Symplectic
Date Deposited: 09 Apr 2019 10:36
Last Modified: 15 Apr 2019 15:18
URI: http://eprints.keele.ac.uk/id/eprint/6167

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