Chemical Reactivity of Penicillins and Cephalosporins. Intramolecular Involvement of the Acyl-Amido Side Chain

Abstract

The rate of degradation of 6-epi-ampicillin in acidic, neutral, and alkaline aqueous solutions was followed at 35°C and an ionic strength of 0.5 mol dm -3 (KCl) by high-performance liquid chromatography (HPLC) and spectrophotometric assays. Pseudo-first-order rate constants were determined in a variety of buffer solutions, and the overall pH-rate profile was obtained by extrapolation to zero buffer concentration. The hydrolysis of 6-epi-ampicillin is subject to acid and hydroxide-ion catalysis and, for a penicillin, an unusual pH-independent reaction. Intramolecular general base-catalyzed hydrolysis by the side chain amido group is proposed to explain the enhanced rate of neutral hydrolysis of 6-epi-ampicillin and cephalosporins. The -lactam of 6-epi-ampicillin also undergoes intramolecular aminolysis by nucleophilic attack of the 6-R side chain amino group to give a stable piperazine-2,5-dione derivative. The low effective molarity for intramolecular aminolysis of only 40 M is partly attributed to the unfavorable trans to cis isomerization about the 6-amide side chain required for ring closure. Theoretical calculations show that the intramolecular aminolysis of 6-epi-ampicillin nucleophilic attack occurs from the R-face of the -lactam ring with an activation energy of 14.4 kcal/mol.

Mapping the Distribution of Conformational Information Throughout a Protein Sequence

“…In good agreement with previous reports, 34 we determined that the uncatalyzed first-order rate for benzyl penicillin (BP) hydrolysis in buffer A (100 mM sodium phosphate, (pH 7.0 at 25 8C)) is 2.6!10 K7 s K1 . Also, we found that the rate in the presence of lysozyme or bovine serum albumin (BSA) is similar to that in buffer alone (Table 2).…”

Role of minor determinants of amoxicillin in the diagnosis of immediate allergic reactions to amoxicillin

“…1. AX was obtained from Glaxo Smithkline Beecham (Madrid, Spain), amoxicilloic acid was prepared following the same approach as for benzylpenicilloic acid (7), and diketopiperazine was prepared according to Llins (12).…”

Theoretical study of thiolysis in penicillins and cephalosporines

“…All involve the transfer of acyl groups via a covalent bond between the carbon atom in the carbonyl group and the attacking nucleophile to form a tetrahedral intermediate T that subsequently undergoes cleavage of the C N bond in the ␤-lactam ring (see Scheme 1). In these processes, the nucleophilic attack can take place on both the ␣ and ␤ sides of the antibiotic; in penicillins, however, the approach on the ␤ side is sterically hindered by the C 3 -␤-proton and the 2-␤-methyl group, so the attack occurs preferentially on the ␣ side [20].…”