The Synthesis and Evaluation of Diethyl Benzylphosphonates as Potential Antimicrobial Agents

Brodzka, Anna; Kowalczyk, Paweł; Trzepizur, Damian; Koszelewski, Dominik; Kramkowski, Karol; Szymczak, Mateusz; Wypych, Aleksandra; Lizut, Rafał; Ostaszewski, Ryszard

The Synthesis and Evaluation of Diethyl Benzylphosphonates as Potential Antimicrobial Agents

Abstract

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.