John K. Swartzendruber

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 carbapenems

Abstract γ-Lactam analogues of carbapenems have been synthesized using a [3+2] cyclization approach. Slight antibiotic activity was observed in one case.

Bicyclic pyrazolidinones, steric and electronic effects on antibacterial activity

Abstract Bicyclic pyrazolidinones were synthesized as γ-lactam analogs of the β-lactam antibiotics. Several of these compounds exhibited broad spectrum in vitro antibacterial activity.

C(3)-azido cephem II

Abstract The major product from the thermolysis and photolysis of C(3)-azido cephem 2 is the ring expanded 1,4,6-thiadiazepine azetidinone.