Thomas K. Elzey

Molecular modeling of γ-lactam analogues of β-lactam antibacterial agents: synthesis and biological evaluation of selected penem and carbapenem analoques

Abstract Computational chemistry made possible the prediction of the three-dimensional structures of γ-lactam analogues of penems and carbapenems before the analogues were made. Molecular superpositioning showed that these novel structures with a 7β-acylamino side-chain present the pharmacophoric groups in close spatial similarity to the groups in biologically active cephalosporin and penicillin antibiotics. This suggests that 8-oxo-7-acylamino-1-azabicyclo[3.3.0]-oct-2-ene-2-carboxylates and the 4-thia-analogues can be accommodated in the same active sites of essential bacterial penicillin-binding proteins where cephalosporins and penicillins are recognized. The syntheses of these compounds are reported. The γ-lactams exhibit low, but detectable levels of antibacterial activity and suggest promise that substantial activity can be achieved with other γ-lactams.

γ-Lactam analogues of the penems

Abstract Racemic γ-lactam analogues of the penems have been prepared and tested for biological activity. The 7-acylamino derivatives exhibited low levels of antibiotic activity.

3-oxa-5-carba analogues of β-lactam antibiotics

Abstract The syntheses of some 3-oxa-l-azabicyclo[4.2.0]octan-8-one carboxylic acid salts is described using Hg+2-assisted intramolecular cyclization of an allyl-azetidinone alcohol.

Rearrangement of exomethylenecephams to homocephams

Exomethylenecephans rearrange by reaction with diazo compounds in the presence of cupric sulfate to generaye the homocepham ring-system

The [2,3]sigmatropic rearrangement of sulfilimines from 3-exomethylenecephams

-3-Exomethylenecepham sulfides react with phthalimidonitrene and the resulting sulfilimine undergoes a [2,3] sigmatropic rearrangement to give the 1,2,6-thiadiazepine azetidinone ring system