Substituent effects on reactivity and spectral parameters of cephalosporins

Abstract

The chemical reactivity of a series of a cephalosporins is examined as a function of the substituents at positions 3 and 7. In most cases, the nature of the C7 side chain has a minor influence on the .beta.-lactam reactivity. In the case of amino-containing C7 substituents, when intramolecular nucleophilic attack may occur, the reactivity may be greatly increased. The spectroscopic and structural characteristics of the .beta.-lactam linkage do not correlate with the chemical reactivity of studied compounds. The hydrolysis rates are linked neither with the IR frequency or 13C NMR chemical shift of the carbonyl .beta.-lactam nor with the geometry of the .beta.-lactam ring. A relationship is confirmed between the .beta.-lactam ring opening rate and the polarity of the C3-C4 double bond, reflected in the different 13C NMR chemical shifts of those atoms. The results are an experimental verification of the theoretical calculations of Boyd et al. on cephalosporin model compounds, which foresee that a C3 substituent could favor the opening of the .beta.-lactam cycle by stabilizing a transition state involved in alkaline hydrolysis. [The penicillins and cephalosporins are .beta.-lactam antibiotics that inhibit the peptidoglycan transpeptidation step by inactivating certain enzymes involved in the synthesis of bacterial cell walls.].