Syntheses and hydrolysis of basic and dibasic ampicillin esters tailored for intracellular accumulation.
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.
Paternotte
I
I
Unité de Chimie Pharmaceutique et de Radiopharmacie, Université Catholique de Louvain, Bruxelles, Belgium.
Fan
H J
HJ
Scrève
P
P
Claesen
M
M
Tulkens
P M
PM
Sonveaux
E
E
D000667:Ampicillin / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D001682:Biological Availability; D004355:Drug Stability; D004952:Esters / Q000138:chemical synthesis / Q000378:metabolism / Q000493:pharmacokinetics; D006207:Half-Life; D006868:Hydrolysis; D007700:Kinetics; D007769:Lactams / Q000378:metabolism; D013058:Mass Spectrometry; D008826:Microbial Sensitivity Tests; D011355:Prodrugs / Q000138:chemical synthesis / Q000493:pharmacokinetics; D013211:Staphylococcus aureus / Q000187:drug effects
D004952:Esters; D007769:Lactams; D011355:Prodrugs; D000667:Ampicillin