Theoretical Study of the Reaction from 6-Methylidene Penem to Seven-Membered Ring Intermediates

Abstract

A sort of beta-lactamase inhibitor, 6-methylidene penem can inhibit both class A and class C serine beta-lactamase. Its inhibition mechanism involves yielding a seven-membered ring intermediate after acylation of the serine. Density functional theory (DFT) method was used on the molecular model to determine the mechanism of producing the seven-membered ring intermediate. Solvent effects were considered via polarizable continuum model (PCM). Moreover, a water-assisted process was considered in the hydrogen transfer process. The results show that the seven-membered ring intermediate can be obtained via two possible mechanisms, namely, concerted mechanism and stepwise mechanism. In stepwise mechanism, a new thiirane intermediate which has never been reported was found. The product of stepwise mechanism, e, has five tautomerics, and they can be tautomerized by hydrogen transfer.

Computational Modeling Study on Formation of Acyclic Clavulanate Intermediates in Inhibition of Class A β-Lactamase: Water-Assisted Proton Transfer

“…In our earlier work, this method has been used on the study of the 6-methylidene penem inhibition mechanism. 29 This method does not consider the interaction between the water molecule and the reactant sufficiently, so the results show that the monohydration hardly affects the mono-hydrate's relative stability. However, the error should be small and cannot affect the reaction paths.…”

“…In path a − c , N4 is linked to a hydrogen bond, so the hydrate energy (Eaw2) is −1355.415291 au. In our earlier work, this method has been used on the study of the 6-methylidene penem inhibition mechanism . This method does not consider the interaction between the water molecule and the reactant sufficiently, so the results show that the monohydration hardly affects the monohydrate’s relative stability.…”

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

“…In this article, the atoms C2 and N4 are involved, so we evaluate the hydrogen bond energy of (CH 3 )2NH-OH 2 (0.00433 au) and (CH 3 )2CH 2 -OH 2 (0.00172 au) to be E H approximately, respectively. In our earlier work, we have applied this method on 6-methylidene penem system [13].…”

“…The five-membered ring, where the C6 and C7 have sp3 hybrid orbital, is not planar. The seven-membered ring is foldaway, and the analogic structure can exist in intermediate of 6-Methylidene Penem with lactamase [13].…”

“…Besides, DVR-II-41S can undergo enamine-imine tautomerism via hydrogen transfer. The similar reaction has been studied before [13], and this process can be assisted by water moleculer. Taking this into consideration, the final product should have two tautomers, viz.…”