The Synthesis and Evaluation of Diethyl Benzylphosphonates as Potential Antimicrobial Agents
Anna Brodzka,
Paweł Kowalczyk,
Damian Trzepizur,
Dominik Koszelewski,
Karol Kramkowski,
Mateusz Szymczak,
Aleksandra Wypych,
Rafał Lizut,
Ryszard Ostaszewski
Affiliations
Anna Brodzka
Institute of Organic Chemistry PAS, Kasprzaka 44/52, 01-224 Warsaw, Poland
Paweł Kowalczyk
Department of Animal Nutrition, The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, Instytucka 3, 05-110 Jabłonna, Poland
Damian Trzepizur
Institute of Organic Chemistry PAS, Kasprzaka 44/52, 01-224 Warsaw, Poland
Dominik Koszelewski
Institute of Organic Chemistry PAS, Kasprzaka 44/52, 01-224 Warsaw, Poland
Karol Kramkowski
Department of Physical Chemistry, Medical University of Bialystok, Kilińskiego 1 Str., 15-089 Białystok, Poland
Mateusz Szymczak
Department of Molecular Virology, Institute of Microbiology, Faculty of Biology, University of Warsaw, Miecznikowa 1, 02-096 Warsaw, Poland
Aleksandra Wypych
Centre for Modern Interdisciplinary Technologies, Nicolaus Copernicus University in Toruń, Wileńska 4, 87-100 Toruń, Poland
Rafał Lizut
Institute of Mathematics, Informatics and Landscape Architecture, The John Paul II Catholic University of Lublin, 20-708 Lublin, Poland
Ryszard Ostaszewski
Institute of Organic Chemistry PAS, Kasprzaka 44/52, 01-224 Warsaw, Poland
The impact of substituent at phenyl ring of diethyl benzylphosphonate derivatives on cytotoxic activity was studied. The organophosphonates were obtained based on developed palladium-catalyzed α, β-homodiarylation of vinyl esters protocol. The new synthetic pathway toward 1,2-bis(4-((diethoxyphosphoryl)methyl)phenyl)ethyl acetate was proposed which significantly improves the overall yield of the final product (from 1% to 38%). Several newly synthesized organophosphonates were tested as new potential antimicrobial drugs on model Escherichia coli bacterial strains (K12 and R2-R3). All tested compounds show the highest selectivity and activity against K12 and R2 strains. Preliminary cellular studies using MIC and MBC tests and digestion of Fpg after modification of bacterial DNA suggest that selected benzylphosphonate derivatives may have greater potential as antibacterial agents than typically used antibiotics such as ciprofloxacin, bleomycin and cloxacillin. These compounds are highly specific for pathogenic E. coli strains based on the model strains used and may be engaged in the future as new substitutes for commonly used antibiotics, which is especially important due to the increasing resistance of bacteria to various drugs and antibiotics.
