The Hydrolysis of Lactams

The Hydrolysis of Lactams

Lactams are cyclic amides that have several features in common with their ester counterparts (lactones). As with lactones, the ring opening of lactams should be regarded as hydration rather than hydrolysis, since lactams, unlike amides and esters, yield only one product or metabolite. There are other similarities between lactams and lactones. Both lactam and lactone bonds become chemically more stable with increasing ring size, and five and six membered rings can, in both cases, be formed spontaneously from the appropriate precursor. The difference between these ring systems lies in their reactivity: lactams are generally less reactive than lactones, in the same sense that amides are more stable than esters. The differences in the mechanisms of hydrolytic cleavage of the amide and lactam bond will be discussed in this chapter. The greatest part of this text is devoted to the smallest lactam ring of significance in medicinal chemistry, namely the b-lactam ring. This four-membered ring is a well-known structural element of β-lactam antibiotics (e.g., penicillins and cephalosporins). The reactivity of the β-lactam ring largely determines the chemical and pharmacological behavior of these molecules. In the following sections, we will discuss the important role that ring opening plays in the antibacterial activity of β-lactams, in their resistance to blactamases, in the activity of β-lactamase inhibitors, and, finally, in the resistance of β-lactams to chemical hydrolysis.  Most of this chapter (Sect. 5.2) focuses on the chemical reactivity of the lactam bond and its hydrolysis by bacterial enzymes (lactamases), rather than to its metabolic degradation by mammalian enzymes. This is in contradistinction to other chapters of this book, where metabolism in mammals is the focus of discussion. The reason for the attention given here to the chemical reactivity and bacterial degradation of b-lactams is that these issues have caused more pharmaceutical and clinical problems than metabolic hydrolysis. This also explains why the chemical stability of b-lactams and their resistance to b-lactamases have been the subject of countless studies, while the metabolism of these compounds has received less attention. Three short sections complete this chapter. In Sect. 5.3, we examine the metabolism of nonantibiotic lactams of medicinal or toxicological interest. Sect. 5.4 is concerned with complex lactams defined as containing one or more additional heteroatoms in the ring. Finally, we will discuss in Sect. 5.5 the fate of lactams generated as metabolites by the oxidation of heterocycles containing a N-atom.

β-Lactam Antibiotics

Structural Diversity (Keragaman Struktur)

Since the discovery of penicillin, research has produced a large number of different types of derivatives with the aim to extend antibacterial activity and to improve pharmacokinetic properties. The b-lactam family can be divided into several groups according to the basic skeleton (Table 5.1), which always contains a b-lactam ring. Except for monocyclic lactams, the b-lactam ring is fused through the N-atom and the adjacent tetrahedral C-atom to a second ring, be it five-membered or sixmembered. The penams, oxapenams, cephems, and monobactams occur naturally, whereas oxacephams, carbacephams, and penems are synthetic analogues.

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Hydrolysis in Drug and Prodrug Metabolism Chemistry, Biochemistry, and Enzymology: Bernard Testa, Joachim M. Mayer