Correlation lactams

Studies on the mechanism of action of /3-lactam antibiotics have shed considerable light on how these agents kill bacteria. They also help explain qualitative differences between various agents and why there is a correlation between the reactivity of the /3-lactam and antibacterial activity. However, it is also clear that reactivity is only one factor in determining how effectively a given /3-lactam antibiotic will inactivate bacterial enzymes (82BJ(203)223). 

MJ Pikal, AL Lukes, JE Lang, K. Gaines. Quantitative crystallinity determinations for beta-lactam antibiotics by solution calorimetry Correlations with stability. J Pharm Sci 67(6) 767-773, 1978. 

The large number and diversity of available /3-lactams, mainly penicillins and cephalosporins, necessitate their classification. Penicillins can be classified primarily according to chemical structure. Table 5.2 shows that there is good correspondence between chemical structure and properties. The categorization of cephalosporins into chemically similar groups is not useful because their antimicrobial spectrum is not closely correlated with chemical structure, and classification into generations is based on their spectrum of microbial activity (Table 5.3). 

Structure-activity correlations in the P-lactam antibiotic field have required drastic re-evaluation in view of the novel structures described above. Apparently, only the intact P-lactam ring is an absolute requirement for activity. The sulfur atom can be replaced (moxalactam) or omitted (thienamycin), and the entire ring itself is, in fact, unnecessary (nocardicin). The carboxyl group, previously deemed essential, can be replaced by a tetrazolyl ring (as a bioisostere), which results in increased activity and lactamase resistance. The amide side chain, so widely varied in the past, is also unnecessary, as shown in the example of thienamycin. There is a considerable literature analyzing the classical structure-activity relationships of the penicillin and cephalosporin groups. 

A different approach to enantiotopic group differentiation in bicyclic anhydrides consists of their two-step conversion, first with (/ )-2-amino-2-phcnylethanol to chiral imides 3, then by diastereoselective reduction with sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al) to the corresponding chiral hydroxy lactames 4, which may be converted to the corresponding lactones 5 via reduction with sodium borohydride and cyclization of the hydroxyalkyl amides 101 The overall yield is good and the enantioselectivity ranges from moderate to good. Absolute configurations of the lactones are based on chemical correlation. 

Pikal, M. J., Lukes, A. L., Lang, J. E., and Gaines, K. (1978), Quantitative crystalhne determinations for b-lactam antibiotics by solution calorimetry Correlation with stability, /. Pharm. Sci., 67,767-773. 

Figure 1.1 Correlation between activation free energy for aqueous hydrolysis of -lactams and lactam C-N bond lengths as determined from X-ray crystallography (data entirely fictitious)...

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