Synthesis and 3'-substituent effects of some 7 alpha-methoxy-1-oxacephems on antibacterial activity and alkaline hydrolysis rates.

Abstract

Relationships between intrinsic antibacterial activity and beta-lactam chemical reactivity of 7 beta-(phenylacetamido)-7 alpha-methoxy-1-oxacephems with various 3'-substituents were studied in order to clarify the effect of the 3'-substituent on the antibacterial activity. The chemical reactivity of the beta-lactam ring estimated by pseudo-first-order rate constants log kobsdNMR of alkaline hydrolysis at pD 10.4 and 35.0 degrees C correlates well linearly with 13C NMR chemical shift differences (delta delta(4-3], infrared stretching frequencies of the beta-lactam carbonyl (vC = O), and sigma I values. Values of log (1/CN), averaged for the MIC values for Escherichia coli, E. coli NIH JC-2, E. coli EC-14, and Klebsiella pneumoniae SRC-1, were taken as an estimation of the intrinsic antibacterial activity. The log (1/CN) values of the compounds without good leaving groups correlated fairly well with log kobsdNMR values. The comparatively high antibacterial activity of compounds with good leaving groups may be attributable to the different course of decomposition of these compounds.