title: Design, synthesis and antibacterial activity of minor groove binders: the role of non-cationic tail groups.
abstract: The design and synthesis of a new class of minor groove binder (MGBs) in which, the cationic tail group has been replaced by a neutral, polar variant including cyanoguanidine, nitroalkene, and trifluoroacetamide groups.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.
authors.affiliation: WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow, G1 1XL, UK. abedawn.khalaf@strath.ac.uk
authors.forename: Abedawn I
authors.initials: AI
authors.lastname: Khalaf
authors.forename: Claire
authors.initials: C
authors.lastname: Bourdin
authors.forename: David
authors.initials: D
authors.lastname: Breen
authors.forename: Gavin
authors.initials: G
authors.lastname: Donoghue
authors.forename: Fraser J
authors.initials: FJ
authors.lastname: Scott
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Suckling
authors.forename: Donna
authors.initials: D
authors.lastname: Macmillan
authors.forename: Carol
authors.initials: C
authors.lastname: Clements
authors.forename: Keith
authors.initials: K
authors.lastname: Fox
authors.forename: Doreen A T
authors.initials: DA
authors.lastname: Sekibo
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000475:Alkenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D015195:Drug Design; D005463:Fluoroacetates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D006146:Guanidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000737:chemistry; D000071230:Transcriptional Regulator ERG
chemical_list: D000081:Acetamides; D000475:Alkenes; D000900:Anti-Bacterial Agents; C072312:ERG protein, human; D005463:Fluoroacetates; D006146:Guanidines; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; C030688:trifluoroacetamide; C004711:dicyandiamido