Penicillins as β-lactamase-dependent prodrugs: enabling role of a vinyl ester exocyclic to the lactam ring

Abstract

Incorporation of a vinyl ester exocyclic to the beta-lactam ring of a penicillin nucleus enables this to act as a beta-lactamase-dependent prodrug - rapid release of the (unactivated) alkoxy component of the vinyl ester is triggered by enzyme-catalysed hydrolysis of the beta-lactam ring, whilst buffer-catalysed hydrolysis of the structure at neutral pH is particularly slow.

Antibiotic Hybrids: the Next Generation of Agents and Adjuvants against Gram-Negative Pathogens?

“…In addition, achieving synergistic antibacterial activity through the hybrid prodrug approach is a possibility. As the prodrug reaches its target bacterial compartment, the hybrid entity is expected to be cleaved into two functioning drugs The mechanisms for the nonenzymatically driven release of the leaving group for panels A and B were elucidated thorough NMR experiments (185,186). Enzymatic hydrolysis may be due to ␤-lactamases, such as serine or metallo-based ␤-lactamases (not depicted above), or the ␤-lactam target enzyme transpeptidase.…”

Exploring the chemistry of penicillin as a β-lactamase-dependent prodrug

“…9 The benzhydryl esters 4-7 were prepared using commercially available Wittig reagents and, where required, the corresponding sodium salts were obtained by removal of the benzhydryl group. 6 Preparation of 8 was achieved by removal of the allyl group of 5 followed by DCC mediated coupling of the resulting free acid with 7-hydroxy-4-methylcoumarin (below referred to as coumarin) and, finally, removal of the benzhydryl group. This structure is a potential reporter molecule/diagnostic for the presence of b-lactamase enzyme as 8 is non-fluorescent, whereas coumarin itself is highly fluorescent.…”

“…Structures 1 and 2 are prototypic examples: enzyme-catalysed scission of the b-lactam ring brings two potential nucleophiles into play-the thiazolidine-ring sulfur and nitrogen atoms-resulting in a rapid intramolecular reaction for synthetic variation of the leaving group. In a preliminary communication 6 we reported on the preparation and reaction of a variety of compounds of structure type 2 bearing distinct leaving groups; in this paper we expand on the chemistry of these penicillins and on the scope and limitations of their capability to act as b-lactamase-dependent prodrugs.…”

Dual Action-Based Approaches to Antibacterial Agents

“…The main benefit of the vinyl ester release mechanism lies in its synthetic versatility for the production of analogues, although there have been no reports in the literature of applying this to a cephalosporin nucleus. Unfortunately the true potential of these dual release prodrugs have not been realized from a designed antibacterial viewpoint, as all Smyth's compounds [32] incorporated leaving groups resulting in simple alcohols. However, extension of this work to antibodydirected enzyme prodrug therapy for the selective release of both coumate and R-(+)-aminoglutethimide as sulfatase and aromatase inhibitors respectively for the reduction of estrogen hormone-dependent breast cancer has been reported [33].…”

“…Another elegant design development [32] was to change the release mechanism for the C7 substituent on the cephalosporin nucleus. Vinyl esters bearing a simple ester (40 ) were developed as an alternative to the S-aminosulfeneimine moiety.…”