Electronic structures of cephalosporins and penicillins. 4. Modeling acylation by the beta-lactam ring.
Molecular orbital calculations by the CNDO/2 method are used to study the molecular and electronic details involved in the initial phases of the opening of the beta-lactam ring of a model cephalosporin structure, 7-amino-3-acetoxymethyl-3-cephem. The effect of a simple nucleophile, OH-, approaching the carbonyl carbon center of the beta-lactam ring is monitored by following the charge redistributions that occur in the bicyclic system and in the 3 side chain. A migration of electron density to the ester oxygen of the CH2OAc group is observed with concomitant weakening of the CH2-OAc bond. The results are discussed in relation to the mechanism of acylation of bacterial cell wall enzymes by beta-lactam antibiotics and in relation to the hydrolysis of these molecules. The results indicate that the ability of the 3' substituent of cephalosporins to stabilize electron density transferred to it, i.e., the leavability of the 3' moiety, can be an important factor in activating the beta-lactam toward nucleophilic attack.
D000215:Acylation; D002511:Cephalosporins; D055598:Chemical Phenomena; D002621:Chemistry; D008956:Models, Chemical; D008968:Molecular Conformation; D010406:Penicillins; D011789:Quantum Theory; D047090:beta-Lactams
D002511:Cephalosporins; D010406:Penicillins; D047090:beta-Lactams