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 and Sekibo, Doreen A.T. (2012) Design, synthesis and antibacterial activity of minor groove binders: the role of non-cationic tail groups. European Journal of Medicinal Chemistry, 56, 39-47. (doi:10.1016/j.ejmech.2012.08.013).

Abstract

The design and synthesis of a new class of minorgroove binder (MGBs) in which, the cationictailgroup has been replaced by a neutral, polar variant including cyanoguanidine, nitroalkene, and trifluoroacetamide groups. Antibacterialactivity (against Gram positive bacteria) was found for both the nitroalkene and trifluoroacetamide groups. For the case of the nitroalkene tailgroup, strong binding of a minorgroove binder containing this tailgroup was demonstrated by both DNA footprinting and melting temperature measurements, showing a correlation between DNA binding and antibacterialactivity. 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 cationictailgroups 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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Contributors

Author: Keith Fox

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