Ab Initio Calculations on Neutral and Alkaline Hydrolyses of β-Lactam Antibiotics. A Theoretical Study Including Solvent Effects

Abstract

In this work we present a theoretical study of neutral and alkaline hydrolyses of N-methylazetidinone as a model of biological hydrolysis of β-lactam antibiotics. Calculations have been carried out at the HF and MP2 levels using the 3-21G, 6-31G*, and 6-31+G* basis sets. Solvent effects have been included by means of a polarizable continuum model. Our results indicate two possible reaction mechanisms for the β-lactam hydrolysis: concerted and stepwise. In both the neutral and alkaline hydrolyses the concerted mechanism presents a free energy barrier lower than that of the stepwise mechanism.

The Mechanism of Formamide Hydrolysis in Water from Ab Initio Calculations and Simulations

“…A number of theoretical studies have been devoted to the acid- [11][12][13][14][15] or base-catalyzed [11,[15][16][17][18][19][20][21][22][23] hydrolysis of amides as well as to the enzyme-catalyzed hydrolysis of peptides. [24][25][26][27][28][29][30][31][32][33][34] The catalysis of b-lactam-ring hydrolysis has also been studied, [35,36] in particular by Donoso and co-workers (see refs. [34,[37][38][39] and references cited therein) because of its relevance to the understanding of bacteria resistance to antibiotics.…”

A Theoretical Study on the Reactivity of a Rhenium Hydroxo‐Carbonyl Complex Towards β‐Lactams

“…Taking into account experimental studies on metal-promoted peptide hydrolysis [34][35][36][37] and theoretical investigations on the neutral [38,39] and enzymatic [40] hydrolysis of β-lactams, and the neutral hydrolysis of acyclic amides, [41][42][43][44] four different reaction mechanisms (see Scheme 1) can be envisaged for the reaction of [Re(OH)-(CO) 3 (N 2 C 2 H 4 )] with azetidin-2-one and 3-formylamino-Nsulfonatoazetidin-2-one. The mechanism related to the proposal D in Scheme 1 was not investigated here because the energy required for the cleavage of the HO-Re bond of the complex is higher than the 65.0 kcal mol Ϫ1 reported in a theoretical study of the reactivity of molybdenum and rhenium hydroxo-carbonyl complexes with phenyl acetate.…”

Novel Large‐Ring 1,3‐Bridged 2‐Azetidinones as Potential Inhibitors of Penicillin‐Binding Proteins

“…Basic hydrolysis of b-lactams has been intensively studied, theoretically [30][31][32][33][34] and experimentally [35,36]. Ring opening is a two-step process involving (i) the formation of a tetrahedral intermediate by nucleophilic addition of OH À onto the azetidinone carbonyl C2 atom, followed by (ii) the cleavage of the N1-C2 bond, this second step being the rate determining one.…”