Structure-activity correlations in the cephalosporin C series using extended Hückel theory and CNDO-2.

Using two different molecular orbital methods which treat all valence electrons, namely extended Huckel theory and CNDO/2,a correlation has been found between the biological activity of cephalosporin derivatives and certain aspects of the electronic structure of the /3lactam ring. Electron populations of the carbonyl carbon and bond strength indices of both the carbonyl carbon-nitrogen bond and the carbonyl carbon-oxygen bond in a number of cephalosporin derivatives are correlated with the inhibition of seven strains of gram-negative bacteria by the cephalosporin derivatives. The agreement is more consistent using CNDO/2, which accounts better for long-range inductive effects. It has been found that side chains on the six-membered ring having a positive inductive effect corresponding to the withdrawal of electrons enhance biological activity.