Broad-spectrum cyclic boronate ß-lactamase inhibitors featuring an intramolecular prodrug for oral bioavailability.
Bioorg Med Chem
; 62: 116722, 2022 05 15.
Article
em En
| MEDLINE
| ID: mdl-35358864
ABSTRACT
Early efforts to broaden the spectrum and potency of cyclic boronic acid ß-lactamase inhibitor vaborbactam included a series of 7-membered ring boronates. Exploration of stereoisomers and incorporation of heteroatoms allowed identification of the all-carbon cyclic boronate with substituents trans as the preferred core structure, showing inhibition of Class A and C enzymes. Crystal structures of one analog bound to important ß-lactamase enzymes were obtained. When isolated under acidic conditions, these compounds spontaneously formed a neutral cyclic anhydride (intramolecular prodrug) which was shown to have much-improved oral bioavailability (52-69%) compared to the ring-opened carboxylate salt (9%).
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Pró-Fármacos
/
Inibidores de beta-Lactamases
Idioma:
En
Revista:
Bioorg Med Chem
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Estados Unidos