Design of organyl phosphate-based pro-drugs: comparative analysis of the antibiotic action of alkyl protecting groups with different degree of fluorination

Abstract

Background. Molecular structures combining a phosphorus-containing counterpart and non-polar radicals are employed in design of pro-drugs as structural and functional groups necessary for transportation of drugs through cellular barriers. It is assumed that the carrier itself does not exhibit biological activity. However, the “organic phosphate – alkyl radical” complex may possess its own metabolic and pharmacological properties even in the absence of a drug moiety.The aim. To study the effect of fluorinated alkyl phosphates on the growth of bacterial test cultures in an agar medium and to identify conjugated metabolic markers using UV/visible spectroscopy.Materials and methods. The effect of six organyl phosphates on the growth of five types of bacteria under aerobic conditions was evaluated by the method of wells in an agar medium. For solutions containing cell metabolites of Pseudomonas aeruginosa, the absorption spectra were recorded at 250–280 nm. The principal component analysis (PCA) was used for multivariate comparative analysis of the spectra. Results. The studied organyl phosphates bearing the ethyl and propyl radicals are potential temporary carriers of the drug moiety, since they are capable of penetrating through cellular barriers. However, the fluorinated compounds exhibit bactericidal properties, the degree of which depends on the arrangement of fluorine atoms in the radical. The most active compounds are those exhaustively halogenated at the terminal carbon atom of the ethyl radical (-СН2-СF3), while non-fluorinated organyl phosphate is the least active. UV/visible spectra of P. aeruginosa cultivation products, according to PCA data, contain patterns reflecting the metabolic effects mediated by these structural features of the radicals.Conclusion. In terms of practical application of the studied compounds, the activity of a proantibiotic based on organyl phosphate with a non-fluorinated ethyl(propyl) radical will be determined only by the specificity of the drug moiety. Exactly the same molecule, but exhaustively fluorinated at the terminal carbon atom of the alkyl radical, is likely to be characterized by lower specificity and higher activity under the additive (or synergistic) action of metabolically active groups.