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Acyloxymethyl as a Drug Protecting Group. Part 3. Tertiary O-Amidomethyl Esters of Penicillin G: Chemical Hydrolysis and Anti-Bacterial Activity

Abstract

Purpose. O-(N-alkylamido)methyl esters of penicillin G were studied as a new class of prodrugs.

Methods. Their hydrolysis in aqueous buffers containing 20 % (v/v) of acetonitrile was investigated by HPLC.

Results. A U-shaped pH-rate profile was seen with a pH-independent process extending from pH ca. 2 to pH ca. 10. This pathway is characterised by kinetic data that are consistent with a uni-molecular mechanism involving rate-limiting iminium ion formation and penicillinoate expulsion. Penicillin G and the corresponding amide are the ultimate products detected and isolated, indicating that β-lactam ring opening is much slower than ester hydrolysis. The O-(N-alkylamido)methyl esters of penicillin G displayed similar in vitro antibacterial activity to penicillin G itself.

Conclusions. Compared to the penicillin G derivatives, the much higher stability of the O-(N-methylbenzamido)methyl benzoate, acetate and valproate esters (which gave rise to a Bronsted βlg value of ca. -1) suggests that tertiary N-acyloxymethylamides may be useful prodrugs for carboxylic acid drugs with pKa >4.

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Moreira, R., Calheiros, T., Cabrita, J. et al. Acyloxymethyl as a Drug Protecting Group. Part 3. Tertiary O-Amidomethyl Esters of Penicillin G: Chemical Hydrolysis and Anti-Bacterial Activity. Pharm Res 13, 70–75 (1996). https://doi.org/10.1023/A:1016077200460

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  • DOI: https://doi.org/10.1023/A:1016077200460

  • O-amidomethylation
  • penicillin G
  • carboxylic acids
  • prodrugs
  • hydrolysis kinetics
  • mechanism of hydrolysis
  • antibacterial activity