Theoretical studies on β-lactam antibiotics. VI. Conformational analysis and structure-activity relationships of penicillin sulfoxides and cephalosporins

Abstract

Conformational energy calculations were carried out on penicillin α- and β-sulfoxides and Δ²- and Δ₃- cephalosporins, in order to identify the structural features governing their biological activity. Results on penicillin α-sulfoxide indicated that in its favoured conformation, the orientation of the aminoacyl group was different from the one required for biological activity. Penicillin a sulfoxide, like penicillin sulfide, favoured two conformations of nearly equal energies, but separated by a much higher energy barrier. The reduced activity of the sulfoxides despite the nonplanarity of their lactam peptide indicated that the orientations of the aminoacyl and carboxyl groups might also govern biological activity. Δ³- cephalosporins favoured two conformations of nearly equal energies, whereas Δ²-cephalosporins favoured only one conformation. The lactam peptide was moderately nonplanAr in the former, but nearly planar in the latter. The differences in the.preferred orientations of the carboxyl group between penicillins and cephalosporins were correlated with the resistance of cephalosporins to penicillinases.