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

Abstract

AbstractÐReadily 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 ampicillin (Fan et al., Bioorg. Med. Chem. Lett. 1997, 7, 3107). We found that the b-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. #

Accumulation and Oriented Transport of Ampicillin in Caco-2 Cells from Its Pivaloyloxymethylester Prodrug, Pivampicillin

“…4. This behavior is, however, not surprising because the degradation of both prodrugs is known to involve at least two pathways, one of which leads to the liberation of free ampicillin, as demonstrated here, and the second of which leads to ␤-lactam ring opening and the appearance of degradation products (36), for which assays were not conducted in the present study.…”

“…This eventually led us to directly reexamine the transport and ampicillin delivery capabilities of PIVA using as controls ampicillin itself and its phthalimidomethylester (PIMA; this compound is not an acyloxymethylester and, therefore, is less susceptible to hydrolysis by serum and cell esterases (36). Both PIVA and PIMA are weak bases and are therefore positively charged at neutral pH.…”

Synthesis and characterization of some penicillins modified with germanium‐containing moieties

“…Some authors assigned an imidazolidinone structure rather than a Schiff base. 5 Without isolation, 3 was reacted with an appropriate halide in the presence of some base to give the protected ester. It was assumed that the subsequent hydrolysis of this ester with aqueous HCl would give the desired ampicillin ester.…”

“…Typically, to an anhydrous DMF (50 ml) solution of 1 (1.86 g, 0.005 mol) was added dropwise an anhydrous DMF (20 ml) solution of 4a (1.435 g, 0.005 mol) at room temperature with stirring for 24 h. The mixture was added to ice water and the organic layer was separated, washed with 2% NaHCO 3 solution and water, and finally dried over 1 [5] 4a [5] 9a [49] 1 [5] 4b [5] 9b [52] 1 [5] 4c [5] 9c [41] 2 [4] 4a [5] 10a [49] 2 [5] 4b [5] 10b [55] 2 [4] 4c [5] 10c [39] 3 [5] 4a [5] 11a [29] 3 [5] 4b [5] 11b [25] 3 [5] 4c [5] carboxylate (9a) as a colorless viscous liquid in 49% yield (1.24 g, 0.002 mol). The other reactions were carried out similarly.…”

“…It must be added that several attempts to prepare new antibiotics have been made by esterification of penicillins. 4,5 Thus, we expected that these penicillins (as a free acid or as a potassium salt) will react with 3-(trimethylgermyl)-1-propyl iodide (4a), 3-(triethylgermyl)-1-propyl iodide (4b) and 3-(triphenylgermyl)-1-propyl iodide (4c) to afford the germyl esters. In one instance, a diiodide, bis(3-iodo-1-propyl)diphenylgermane (4d) was used.…”