title: Antimicrobial lexitropsins containing amide, amidine, and alkene linking groups.
abstract: The synthesis and properties of 80 short minor groove binders related to distamycin and the thiazotropsins are described. The design of the compounds was principally predicated upon increased affinity arising from hydrophobic interactions between minor groove binders and DNA. The introduction of hydrophobic aromatic head groups, including quinolyl and benzoyl derivatives, and of alkenes as linkers led to several strongly active antibacterial compounds with MIC for Staphylococcus aureus, both methicillin-sensitive and -resistant strains, in the range of 0.1-5 microg mL-1, which is comparable to many established antibacterial agents. Antifungal activity was also found in the range of 20-50 microg mL-1 MIC against Aspergillus niger and Candida albicans, again comparable with established antifungal drugs. A quinoline derivative was found to protect mice against S. aureus infection for a period of up to six days after a single intraperitoneal dose of 40 mg kg-1.
authors.affiliation: WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow, Scotland, U.K.
authors.forename: Nahoum G
authors.initials: NG
authors.lastname: Anthony
authors.forename: David
authors.initials: D
authors.lastname: Breen
authors.forename: Joanna
authors.initials: J
authors.lastname: Clarke
authors.forename: Gavin
authors.initials: G
authors.lastname: Donoghue
authors.forename: Allan J
authors.initials: AJ
authors.lastname: Drummond
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Ellis
authors.forename: Curtis G
authors.initials: CG
authors.lastname: Gemmell
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Helesbeux
authors.forename: Iain S
authors.initials: IS
authors.lastname: Hunter
authors.forename: Abedawn I
authors.initials: AI
authors.lastname: Khalaf
authors.forename: Simon P
authors.initials: SP
authors.lastname: Mackay
authors.forename: John A
authors.initials: JA
authors.lastname: Parkinson
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Suckling
authors.forename: Roger D
authors.initials: RD
authors.lastname: Waigh
mesh_terms: D000475:Alkenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000578:Amidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001234:Aspergillus niger / Q000187:drug effects; D002176:Candida albicans / Q000187:drug effects; D002460:Cell Line; D013293:Enterococcus faecalis / Q000187:drug effects; D057927:Hydrophobic and Hydrophilic Interactions; D007364:Intercalating Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D016106:Methicillin Resistance; D051379:Mice; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D019907:Mycobacterium fortuitum / Q000187:drug effects; D009429:Netropsin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013203:Staphylococcal Infections / Q000188:drug therapy; D013211:Staphylococcus aureus / Q000187:drug effects / Q000302:isolation & purification; D013237:Stereoisomerism
chemical_list: D000475:Alkenes; D000577:Amides; D000578:Amidines; D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D007364:Intercalating Agents; C053654:lexitropsin; D009429:Netropsin