Design, synthesis and antibacterial activity of minor groove binders: The role of non-cationic tail groups

Abedawn I. Khalaf, Claire Bourdin, David Breen, Gavin Donoghue, Fraser J. Scott, Colin J. Suckling, Donna Macmillan, Carol Clements, Keith Fox, Doreen A.t. Sekibo

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

The design and synthesis of a new class of minor groove binder (MGBs) in which, the cationic tail group has been replaced by a neutral, polar variant including cyanoguanidine, nitroalkene, and trifluoroacetamide groups. Antibacterial activity (against Gram positive bacteria) was found for both the nitroalkene and trifluoroacetamide groups. For the case of the nitroalkene tail group, strong binding of a minor groove binder containing this tail group was demonstrated by both DNA footprinting and melting temperature measurements, showing a correlation between DNA binding and antibacterial activity. The compounds have also been evaluated for binding to the hERG ion channel to determine whether non-cationic but polar substituents might have an advantage compared with conventional cationic tail groups in avoiding hERG binding. In this series of compounds, it was found that whilst non-cationic compounds generally had lower affinity to the hERG ion channel, all of the compounds studied bound weakly to the hERG ion channel, probably associated with the hydrophobic head groups.
LanguageEnglish
Pages39-47
JournalEuropean Journal of Medicinal Chemistry
Volume56
DOIs
Publication statusPublished - 1 Oct 2012
Externally publishedYes

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Ion Channels
Binders
DNA Footprinting
Nucleic Acid Denaturation
DNA
Gram-Positive Bacteria
Temperature measurement
Melting point
Bacteria
Head
Temperature
trifluoroacetamide

Cite this

Khalaf, Abedawn I. ; Bourdin, Claire ; Breen, David ; Donoghue, Gavin ; Scott, Fraser J. ; Suckling, Colin J. ; Macmillan, Donna ; Clements, Carol ; Fox, Keith ; Sekibo, Doreen A.t. / Design, synthesis and antibacterial activity of minor groove binders : The role of non-cationic tail groups. In: European Journal of Medicinal Chemistry. 2012 ; Vol. 56. pp. 39-47.
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abstract = "The design and synthesis of a new class of minor groove binder (MGBs) in which, the cationic tail group has been replaced by a neutral, polar variant including cyanoguanidine, nitroalkene, and trifluoroacetamide groups. Antibacterial activity (against Gram positive bacteria) was found for both the nitroalkene and trifluoroacetamide groups. For the case of the nitroalkene tail group, strong binding of a minor groove binder containing this tail group was demonstrated by both DNA footprinting and melting temperature measurements, showing a correlation between DNA binding and antibacterial activity. The compounds have also been evaluated for binding to the hERG ion channel to determine whether non-cationic but polar substituents might have an advantage compared with conventional cationic tail groups in avoiding hERG binding. In this series of compounds, it was found that whilst non-cationic compounds generally had lower affinity to the hERG ion channel, all of the compounds studied bound weakly to the hERG ion channel, probably associated with the hydrophobic head groups.",
author = "Khalaf, {Abedawn I.} and Claire Bourdin and David Breen and Gavin Donoghue and Scott, {Fraser J.} and Suckling, {Colin J.} and Donna Macmillan and Carol Clements and Keith Fox and Sekibo, {Doreen A.t.}",
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Khalaf, AI, Bourdin, C, Breen, D, Donoghue, G, Scott, FJ, Suckling, CJ, Macmillan, D, Clements, C, Fox, K & Sekibo, DAT 2012, 'Design, synthesis and antibacterial activity of minor groove binders: The role of non-cationic tail groups', European Journal of Medicinal Chemistry, vol. 56, pp. 39-47. https://doi.org/10.1016/j.ejmech.2012.08.013

Design, synthesis and antibacterial activity of minor groove binders : The role of non-cationic tail groups. / Khalaf, Abedawn I.; Bourdin, Claire; Breen, David; Donoghue, Gavin; Scott, Fraser J.; Suckling, Colin J.; Macmillan, Donna; Clements, Carol; Fox, Keith; Sekibo, Doreen A.t.

In: European Journal of Medicinal Chemistry, Vol. 56, 01.10.2012, p. 39-47.

Research output: Contribution to journalArticle

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T2 - European Journal of Medicinal Chemistry

AU - Khalaf, Abedawn I.

AU - Bourdin, Claire

AU - Breen, David

AU - Donoghue, Gavin

AU - Scott, Fraser J.

AU - Suckling, Colin J.

AU - Macmillan, Donna

AU - Clements, Carol

AU - Fox, Keith

AU - Sekibo, Doreen A.t.

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AB - The design and synthesis of a new class of minor groove binder (MGBs) in which, the cationic tail group has been replaced by a neutral, polar variant including cyanoguanidine, nitroalkene, and trifluoroacetamide groups. Antibacterial activity (against Gram positive bacteria) was found for both the nitroalkene and trifluoroacetamide groups. For the case of the nitroalkene tail group, strong binding of a minor groove binder containing this tail group was demonstrated by both DNA footprinting and melting temperature measurements, showing a correlation between DNA binding and antibacterial activity. The compounds have also been evaluated for binding to the hERG ion channel to determine whether non-cationic but polar substituents might have an advantage compared with conventional cationic tail groups in avoiding hERG binding. In this series of compounds, it was found that whilst non-cationic compounds generally had lower affinity to the hERG ion channel, all of the compounds studied bound weakly to the hERG ion channel, probably associated with the hydrophobic head groups.

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