Theoretical study of the reaction from 7-alkylidenecephalosporin sulfone to bicyclic intermediates in inhibiting β-lactamase

Abstract

Density functional theory (DFT) calculations have been performed on the 7-alkylidenecephalosporin sulfone in order to study the mechanism of producing the bicyclic intermediate. The solvent effect was considered via polarizable continuum model (PCM) computations. The results show that in the acyl-enzyme intermediate, the side chain pyridine nitrogen atom attacks the C6 atom, which is followed by cleavage of the C6-S1 bond. The unsaturated C7 is attacked by the leaving sulfinate, and a tricyclic structure yields. This structure is unstable, and the proton is transferred from C6 to the sulfone to yield the bicyclic end product. Besides, the reactant can undergo enamine-imine tautomerism. This suggests the end products have two forms, viz. imine and enamine.

Interplay of thermochemistry and Structural Chemistry, the journal (volume 19, 2008) and the discipline

“…Another theoretical study, by Li and Feng [176], is based on a quantum chemical modeling, using DFT to study the reaction mechanism of the 7-alkylidenecephalosporin sulfone forming bicyclic intermediates in inhibiting b-lactamases, that represents a serious and growing threat to the efficacy of antibacterial chemotherapy. The equilibrium constant, and therefore the Gibbs energy, of the enamine \=[ imine interconversion of the b-lactamase ring opened product of sulfur-containing substituted cephalosporins has been reported [177].…”