As multidrug resistant bacterial strains proliferate, the necessity for effective therapy has prompted research into the design and synthesis of novel antimicrobial compounds. Often the limiting factor to the effectiveness of antibiotics is their permeability of the cellular membrane, which permits elimination of infection by intracellular pathogens. Unfortunately, many antibiotic classes do not penetrate the plasma membrane effectively. Drug disposition depends on the capability to cross membranes and hence there is a high correlation with measures of lipophilicity. Hydrophobic drugs with high partition coefficients are preferentially distributed to hydrophobic compartments such as lipid bilayers of cells while hydrophilic drugs preferentially are found in hydrophilic compartments such as blood serum. By attaching amino acid groups to heterocyclic antibiotic compounds, we seek to increase their antimicrobial activity by increasing the lipophilic properties of the molecule. Using benzotriazole acylation methodology, we report the coupling of ciprofloxacin, pipemidic acid, norfloxacin, metronidazole and sulfadiazine with Cbz-N-(aminoacyl)benzotriazoles in the synthesis of diverse classes of amino acid-antibiotic conjugates, as well as their evaluation through measures of lipophilicity and antimicrobial properties.

Synthesis and antimicrobial evaluation of amino acid-antibiotic conjugates

246th National Meeting (2013)

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