title: Bis-phosphonium salts of pyridoxine: the relationship between structure and antibacterial activity.
abstract: A series of 23 novel bis-phosphonium salts based on pyridoxine were synthesized and their antibacterial activities were evaluated in vitro. All compounds were inactive against gram-negative bacteria and exhibited the structure-dependent activity against gram-positive bacteria. The antibacterial activity enhanced with the increase in chain length at acetal carbon atom in the order n-Pr>Et>Me. Further increasing of length and branching of alkyl chain leads to the reduction of antibacterial activity. Replacement of the phenyl substituents at the phosphorus atoms in 5,6-bis(triphenylphosphonio(methyl))-2,2,8-trimethyl-4H-[1,3]-dioxino[4,5-c]pyridine dichloride (compound 1) with n-butyl, m-tolyl or p-tolyl as well as chloride anions in the compound 1 with bromides (compound 14a) increased the activity against Staphylococcus aureus and Staphylococcus epidermidis up to 5 times (MICs=1-1.25 μg/ml). But in practically all cases chemical modifications of compound 1 led to the increase of its toxicity for HEK-293 cells. The only exception is compound 5,6-bis[tributylphosphonio(methyl)]-2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridine dichloride (10a) which demonstrated lower MIC values against S. aureus and S. epidermidis (1 μg/ml) and lower cytotoxicity on HEK-293 cells (CC(50)=200 μg/ml). Compound 10a had no significant mutagenic and genotoxic effects and was selected for further evaluation. It should be noted that all bis-phosphonium salt based on pyridoxine were much more toxic than vancomycin.
authors.affiliation: Research and Educational Center of Pharmacy, Kazan Federal University, Kazan 420008, Russia.
authors.forename: Mikhail V
authors.initials: MV
authors.lastname: Pugachev
authors.forename: Nikita V
authors.initials: NV
authors.lastname: Shtyrlin
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Sapozhnikov
authors.forename: Lubov P
authors.initials: LP
authors.lastname: Sysoeva
authors.forename: Alfiya G
authors.initials: AG
authors.lastname: Iksanova
authors.forename: Elena V
authors.initials: EV
authors.lastname: Nikitina
authors.forename: Rashid Z
authors.initials: RZ
authors.lastname: Musin
authors.forename: Olga A
authors.initials: OA
authors.lastname: Lodochnikova
authors.forename: Eugeny A
authors.initials: EA
authors.lastname: Berdnikov
authors.forename: Yurii G
authors.initials: YG
authors.lastname: Shtyrlin
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D008826:Microbial Sensitivity Tests; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000494:pharmacology; D011736:Pyridoxine / Q000737:chemistry* / Q000494:pharmacology*; D012492:Salts / Q000737:chemistry / Q000494:pharmacology; D013203:Staphylococcal Infections / Q000188:drug therapy*; D013211:Staphylococcus aureus / Q000187:drug effects*; D013212:Staphylococcus epidermidis / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D009943:Organophosphorus Compounds; D012492:Salts; D011736:Pyridoxine
keywords: Antibacterial activity; Lipophilicity; Pyridoxine; Quaternary phosphonium salts; Structure–activity relationship