Theoretical study of thiolysis in penicillins and cephalosporines

Abstract

Semiempirical calculations were used to conduct a comprehensive study of the thiolysis of the fundamental core of penicillins and cephalosporins. The significance of the intramolecular protonation of the β-lactam nitrogen in the formation and cleavage of the tetrahedral intermediate (T in Scheme 1) was examined in two thiols bearing substituents of different basicity in β with respect to the thiol group in the attacking nucleophile, namely 2-mercaptoethanol (6) and 2-mercaptoethylamine (7). Based on the results, the rate-determining step in the reaction of penicillins is the cleavage of the tetrahedral intermediate, consistent with an intramolecular acid catalysis process in their thiolysis by 2-mercaptoethylamine. On the other hand, the rate-determining step in the reaction of cephalosporins, which possess an appropriate leaving group at position 3 , is the formation of the tetrahedral intermediate, so the desolvation energy of the nucleophile is a major contributor to the overall energy of the process. This differential behavior between the two types of β-lactam bicycles arises from the presence of the acetate group at 3 and the delocalization of π electrons over the N 5 -C 4 -C 3 system in cephalosporins; this favors the formation of a thiolate with the 5-ethoxymethylene-1,3-thiazine group in the cleavage of the tetrahedral intermediate, which is stabilized by an intramolecular hydrogen bond between N 5 and the alcohol or amine group in β of the attacking thiol. The theoretical results are consistent with previous experimental data showing that, unlike penicillins, cephalosporins undergo no intramolecular acid catalysis in their thiolysis.

Amoxicillin Inactivation by Thiol-Catalyzed Cyclization Reduces Protein Haptenation and Antibacterial Potency

“…In agreement with this, our results have showed a complete inactivation of AX by L-cysteine, but this involves a chemical reaction with amino groups rather than with the thiol groups of cysteine. More recent studies have described in detail the thiol-catalyzed hydrolysis of BP (Llinas et al, 2000;Garcías et al, 2005), in which the catalytically reactive form of the thiol is the thiolate anion (Llinas et al, 2000). This result is in agreement with our observations, which indicate a higher reactivity between BP and the thiol at basic pH.…”

Amoxicillin inactivation by thiol-catalyzed cyclization reduces protein haptenation and antibacterial potency

“…Early studies detected a loss of the antibacterial activity of penicillin induced by cysteine, which was attributed to chemical reactions involving the thiol and/or amino groups of the amino acid [30][31][32]. More recent studies have described in detail the thiolcatalyzed hydrolysis of BP [33,34], in which the catalytically reactive form of the thiol is the thiolate anion [33]. This result is in agreement with our observations, which indicate a higher reactivity between BP and the thiol at basic pH.…”

Design, Synthesis, and Biological Activity of Unnatural Enediynes and Related Analogues Equipped with pH-Dependent or Phototriggering Devices

“…One other small ring that satisfies these conditions is certainly the β-lactam systems; it is biorecognizable, and its inherent strain has been exploited in almost all of the designs of β-lactam antibiotics . The advantage of using β-lactam as a molecular lock lies in the fact that, in addition to the strain that it imparts into an enediyne fused onto it, the ring can also be easily opened by the nucleophile (thiol), enzymes, such as transpeptidase or β-lactamase, or under basic conditions . The first use of β-lactam as a molecular lock was reported from our laboratory and is manifested in β-lactam-fused bispropargyl sulfones.…”