TI: Syntheses and hydrolysis of basic and dibasic
ampicillin esters tailored for intracellular accumulation.
AU: Paternotte,-I; Fan,-H-J; Screve,-P; Claesen,-M; Tulkens,-P-M;
Sonveau,-E
AD: Unite de Chimie Pharmaceutique et de Radiopharmacie, Universite
Catholique de Louvain, Bruxelles, Belgium.
SO: Bioorg-Med-Chem. 2001 Feb; 9(2): 493-502
JN: Bioorganic-and-medicinal-chemistry
PY: 2001
AB: Readily hydrolysable basic and dibasic esters of ampicillin
were synthesised by alkylation of the carboxylate function of ampicillin
to obtain prodrugs that may accumulate in cells and allow for an intracellular
delivery of ampicillian (Fan et al., Bioorg. Med. Chem. Lett. 1997, 7,
3107). We found that the beta-lactam ring cleavage and the hydrolysis of
the ester function were competitive reactions. The prerequisite for biological
activity of compounds of this type is therefore that ester hydrolysis proceeds
faster than ring opening. Some synthesised compounds show promise as prodrugs
since they displayed a reasonable stability and regenerate large quantities
of bioactive ampicillin in broth.