Synthesis and biological evaluation of aryl phosphoramidate prodrugs of fosfoxacin and its derivatives

Aryl phosphoramidate prodrug of fosfoxacine analogues. [Display omitted] •Application of the proTide technology to the synthesis of new antibacterial prodrug.•Synthesis of aryl phosphoramidate progrugs of fosfoxacin homologs.•ProTide strategy might not be appropriated for antibacterial drug design....

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Bibliographic Details
Published in:Bioorganic chemistry 2019-08, Vol.89, p.103012-103012, Article 103012
Main Authors: Munier, Mathilde, Tritsch, Denis, Lièvremont, Didier, Rohmer, Michel, Grosdemange-Billiard, Catherine
Format: Article
Language:English
Subjects:
Antimicrobials
Chemical Sciences
DXR
MEP pathway
Mycobacterium tuberculosis
Phosphate prodrug
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Summary:Aryl phosphoramidate prodrug of fosfoxacine analogues. [Display omitted] •Application of the proTide technology to the synthesis of new antibacterial prodrug.•Synthesis of aryl phosphoramidate progrugs of fosfoxacin homologs.•ProTide strategy might not be appropriated for antibacterial drug design. Aryl phosphoramidate prodrugs of fosfoxacin derivatives 15a-b and 8a-b were synthesized and investigated for their ability to target bacteria. No growth inhibition was observed neither for Mycobacterium smegmatis nor for Escherichia coli on solid medium, demonstrating the absence of release of the active compounds in the bacterial cells. Investigation of the stability of the prodrugs and their multienzymatic cleavage in abiotic and biotic conditions showed that the use of aryl phosphoramidate prodrug approach to deliver non-nucleotides compounds is not obvious and might not be appropriate for an antimicrobial drug.
ISSN:0045-2068
1090-2120
DOI:10.1016/j.bioorg.2019.103012