Evaluation of analogues of furan-amidines as inhibitors of NQO2

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

doi:10.1016/j.bmcl.2018.03.025

Evaluation of analogues of furan-amidines as inhibitors of NQO2

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

^*Corresponding author for this work

Chemical Engineering

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

11 Citations (Scopus)

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

Funding Information:
SA thanks the Jordan University of Science and Technology, Irbid, BH thanks Al-Zaytoonah University, Jordan and RM thanks National Research Foundation (NRF) and Aspen Pharmacare (South Africa) for their sponsorship. Elena Bichenkova and Fariba Fanimarvasti are thanked for their assistance. Mass spectra were recorded at the School of Chemistry, University of Manchester. Peter Horton provided the X-ray diffraction data from the National Crystallography Service, University of Southampton.

Publisher Copyright:
© 2018

Keywords

Anti-cancer
Furan-amidines
Isosteres
Malaria
NQO2 inhibitors
SAR

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bmcl.2018.03.025

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

author = "Soraya Alnabulsi and Buthaina Hussein and Elham Santina and Izzeddin Alsalahat and Manikandan Kadirvel and Magwaza, {Rachael N.} and Bryce, {Richard A.} and Schwalbe, {Carl H.} and Baldwin, {Alex G.} and Ilaria Russo and Stratford, {Ian J.} and Sally Freeman",

note = "Funding Information: SA thanks the Jordan University of Science and Technology, Irbid, BH thanks Al-Zaytoonah University, Jordan and RM thanks National Research Foundation (NRF) and Aspen Pharmacare (South Africa) for their sponsorship. Elena Bichenkova and Fariba Fanimarvasti are thanked for their assistance. Mass spectra were recorded at the School of Chemistry, University of Manchester. Peter Horton provided the X-ray diffraction data from the National Crystallography Service, University of Southampton. Publisher Copyright: {\textcopyright} 2018",

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doi = "10.1016/j.bmcl.2018.03.025",

language = "English",

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AU - Alnabulsi, Soraya

AU - Hussein, Buthaina

AU - Santina, Elham

AU - Alsalahat, Izzeddin

AU - Kadirvel, Manikandan

AU - Magwaza, Rachael N.

AU - Bryce, Richard A.

AU - Schwalbe, Carl H.

AU - Baldwin, Alex G.

AU - Russo, Ilaria

AU - Stratford, Ian J.

AU - Freeman, Sally

N1 - Funding Information: SA thanks the Jordan University of Science and Technology, Irbid, BH thanks Al-Zaytoonah University, Jordan and RM thanks National Research Foundation (NRF) and Aspen Pharmacare (South Africa) for their sponsorship. Elena Bichenkova and Fariba Fanimarvasti are thanked for their assistance. Mass spectra were recorded at the School of Chemistry, University of Manchester. Peter Horton provided the X-ray diffraction data from the National Crystallography Service, University of Southampton. Publisher Copyright: © 2018

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.

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KW - Isosteres

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KW - NQO2 inhibitors

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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

ASJC Scopus subject areas

UN SDGs

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