title: The antibacterial activity of 4,4'-bipyridinium amphiphiles with conventional, bicephalic and gemini architectures.
abstract: Dialkyl 4,4'-bipyridinium compounds are widely employed for their useful redox properties, and are commonly known as viologens due to their intense coloration upon reduction. Despite their prevalence and amphiphilic nature, the antibacterial activity of these compounds remains largely unreported. We have thus prepared a series of mono- and bis-alkylated analogs of 4,4'-bipyridine to investigate structure-activity relationships in their inhibition of a battery of Gram positive and Gram negative bacteria. The prepared cationic compounds were conventional (one cationic head, one non-polar tail), bicephalic (two heads, one tail), or gemini (two heads, two tails) in their amphiphilic structure. Additionally, an isomeric series of six bis-alkylated compounds ranging from symmetric (PQ-11,11) to highly asymmetric (PQ-20,2) were prepared. Four themes of bioactivity emerged: (1) the most bioactive compounds were gemini in structure; (2) 22 carbons in the alkyl chains, with little to modest asymmetry, led to optimal activity; (3) bicephalic compounds were generally comparable to conventional amphiphiles, though only about 12 carbons in the alkyl chains were solubilized in water by each cationic nitrogen; (4) the effects of counterion identity were not evident between chlorides and bromides; however, the presence of the iodide counterion inhibited dissolution in all compounds tested. Three isomeric compounds with little to no asymmetry in tail length, PQ-11,11, PQ-12,10, and PQ-14,8, prepared as the bromide salts, showed comparable and highly potent activity, with MIC levels around 2 μM against 3 of 4 bacteria tested. The simple (one- to two-step) syntheses of potent antimicrobials portend well for future optimization.
authors.affiliation: Department of Chemistry, Villanova University, 800 E. Lancaster Avenue, Villanova, PA 19085, USA.
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Grenier
authors.forename: Robert W
authors.initials: RW
authors.lastname: Davis
authors.forename: Kelsey L
authors.initials: KL
authors.lastname: Wilson-Henjum
authors.forename: Jade E
authors.initials: JE
authors.lastname: LaDow
authors.forename: Jacob W
authors.initials: JW
authors.lastname: Black
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Caran
authors.forename: Kyle
authors.initials: K
authors.lastname: Seifert
authors.forename: Kevin P C
authors.initials: KP
authors.lastname: Minbiole
mesh_terms: D000478:Alkylation; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D003116:Color; D006090:Gram-Negative Bacteria / Q000187:drug effects* / Q000254:growth & development; D006094:Gram-Positive Bacteria / Q000187:drug effects* / Q000254:growth & development; D007536:Isomerism; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D010084:Oxidation-Reduction; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D011726:Pyridinium Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D012995:Solubility; D013329:Structure-Activity Relationship; D013501:Surface-Active Agents / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D011725:Pyridines; D011726:Pyridinium Compounds; D013501:Surface-Active Agents; C034306:4,4'-bipyridyl