Evaluation of analogues of furan-amidines as inhibitors of NQO2

S. Alnabulsi; B. Hussein; E. Santina; I. Alsalahat; M. Kadirvel; R.N. Magwaza; R.A. Bryce; Carl H Schwalbe; A.G. Baldwin; I. Russo; I.J. Stratford; S. Freeman

doi:10.1016/j.bmcl.2018.03.025

Evaluation of analogues of furan-amidines as inhibitors of NQO2

S. Alnabulsi, B. Hussein, E. Santina, I. Alsalahat, M. Kadirvel, R.N. Magwaza, R.A. Bryce, Carl H Schwalbe, A.G. Baldwin, I. Russo, I.J. Stratford, S. Freeman

Aston Pharmacy School

Research output: Contribution to journal › Article › peer-review

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 language	English
Pages (from-to)	1292-1297
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	28
Issue number	8
Early online date	12 Mar 2018
DOIs	https://doi.org/10.1016/j.bmcl.2018.03.025
Publication status	Published - 1 May 2018

Bibliographical note

© 2018, Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/.

Funding: Jordan University of Science and Technology, Irbid, and Al-Zaytoonah University, Jordan.

Keywords

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

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10.1016/j.bmcl.2018.03.025

Evaluation of analogues of furan-amidines as inhibitors of NQO2
© 2018, Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/.
Accepted author manuscript, 812 KBLicence: CC BY-NC-ND 3.0

Cite this

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title = "Evaluation of analogues of furan-amidines as inhibitors of NQO2",

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.",

keywords = "NQO2 inhibitors; Furan-amidines; Isosteres; Anti-cancer; Malaria; SAR",

author = "S. Alnabulsi and B. Hussein and E. Santina and I. Alsalahat and M. Kadirvel and R.N. Magwaza and R.A. Bryce and Schwalbe, {Carl H} and A.G. Baldwin and I. Russo and I.J. Stratford and S. Freeman",

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AU - Alnabulsi, S.

AU - Hussein, B.

AU - Santina, E.

AU - Alsalahat, I.

AU - Kadirvel, M.

AU - Magwaza, R.N.

AU - Bryce, R.A.

AU - Schwalbe, Carl H

AU - Baldwin, A.G.

AU - Russo, I.

AU - Stratford, I.J.

AU - Freeman, S.

N1 - © 2018, Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/. Funding: Jordan University of Science and Technology, Irbid, and Al-Zaytoonah University, Jordan.

PY - 2018/5/1

Y1 - 2018/5/1

N2 - 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.

AB - 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.

KW - NQO2 inhibitors; Furan-amidines; Isosteres; Anti-cancer; Malaria; SAR

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DO - 10.1016/j.bmcl.2018.03.025

M3 - Article

SN - 0960-894X

VL - 28

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EP - 1297

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 8

ER -

Evaluation of analogues of furan-amidines as inhibitors of NQO2

Abstract

Bibliographical note

Keywords

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