Effect of Substituents in Hydrolyzed Cephalosporins on Intramolecular O–H···N Bond

Abstract

Model molecular systems structurally similar to the transition state of the limiting step of the hydrolysis of cephalosporin antibiotics by the L1 metallo-β-lactamase are studied. The series of fluorinated compounds show that the nature of substituents in thiazine and β-lactam rings have a great impact on the strength of the intramolecular O–H···N hydrogen bond that determines the catalytic parameters in real biological systems. The strengthening or weakening of the O–H···N bond is registered via a quantum topological analysis of the electron density, supplemented with various bonding descriptors’ study. The obtained data are confirmed by the analysis of the vibrational frequency shift relatively to the nonfluorinated compound for the O‒H stretching mode of the carboxylic group involved in the O–H···N bond formation. The absence of the monotonic dependence of the hydrogen bond strength on the donor-acceptor effects of substituents shows that considered bonding descriptors do not provide a complete understanding of the bonding mechanisms in the active center of L1 metallo-β-lactamase.