Theoretical aspects of cephalosporin isomerism
- Pharmatec, Inc., Alachua, FL (USA) Univ. of Florida, Gainesville (USA)
- Schering-Plough Corp., Bloomfield, NJ (USA)
The {triangle}{sup 3} double bond of cephalosporins isomerizes to the {triangle}{sup 2} position, resulting in biological inactivation of these antibiotics. This phenomenon occurs slowly in the case of cephalosporanic acids, but is rapid when the 4-carboxylate moiety is esterified or otherwise derivatized, leading to an equilibrium between the {triangle}{sup 2} and {triangle}{sup 3} forms. A theoretical study of this isomerization is described in the framework of two semiempirical all-valence electron molecular orbital (MO) approximations, namely MNDO and AMI. Specifically, the methyl ester and free carboxylate derivatives of both the {triangle}{sup 3} and {triangle}{sup 2} isomers of 7-phenylacetamidocephalosporin were studied. The results obtained indicated that the {triangle}{sup 3} derivatives were thermodynamically more stable than were the {triangle}{sup 2} isomers both in the case of the free acids and methyl esters. These data are consistent with experimental findings and suggest that the more rapid isomerization demonstrated in the case of the esters is due primarily to kinetic rather than to thermodynamic factors. Examination of the calculated molecular structures lend support to various theories that correlate the inactivity of the {triangle}{sup 2} isomers with spatial considerations and the degree of {beta}-lactam amide resonance.
- OSTI ID:
- 6415724
- Report Number(s):
- CONF-8904365-; CODEN: IJQCB
- Journal Information:
- International Journal of Quantum Chemistry; (USA), Vol. 16; Conference: International symposium on quantum biology and quantum pharmacology, St. Augustine, FL (USA), 1-8 Apr 1989; ISSN 0020-7608
- Country of Publication:
- United States
- Language:
- English
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