Syntheses and hydrolysis of basic and dibasic ampicillin esters tailored for intracellular accumulation

Readily hydrolysable basic and dibasic esters of ampicillin were synthesise d by alkylation of the carboxylate function of ampicillin to obtain prodrug s that may accumulate in cells and allow for an intracellular delivery of a mpicillin (Fan ct al., Bioorg. Med. Chem. Lett. 1997, 7, 3107). We found th at the B-lactam ring cleavage and the hydrolysis of the ester function were competitive reactions. The prerequisite for biological activity of compoun ds of this type is therefore that ester hydrolysis proceeds faster than rin g opening. Some synthesised compounds show promise as prodrugs since they d isplayed a reasonable stability and regenerate large quantities of bioactiv e ampicillin in broth. (C) 2001 Elsevier Science Ltd. All rights reserved.