Michael Dean Kinnick

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.

An enantioselective synthesis of loracarbef (LY163892/KT3777)

Abstract An enantioselective synthesis of the new, orally absorbable, totally synthetic β-lactam antibiotic, loracarbef (LY163892/KT3777) is described.

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.

Stereoselective synthesis of cis-substituted azetidinones from penicillin : a formal total synthesis of loracarbef

Abstract A new method for the synthesis of chiral azetidinones bearing a carbon-carbon bond at the 4-position is described. The preparation involves a stereoselective alkylation-reduction of a silylated 4-phenylsulfonyl azetidinone. The utility of this method was demonstrated by a formal total synthesis of loracarbef.

Fused bicyclic Gly-Asp β-turn mimics with potent affinity for GPIIb-IIIa. Exploration of the arginine isostere

6-[4-Amidinobenzoyl]amino]-tetralone-2-acetic acid is a potent antagonist of GPIIb-IIIa. Substitution in the meta position of the benzamidine, or replacement with a heteroaryl amidine was tolerated in this series. Use of an acyl-linked 4-alkyl piperidine as an arginine isostere also provided active compounds. Compounds from this series provided substantial systemic exposure in the rat following oral administration.

Rearrangement of exomethylenecephams to homocephams

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

An Improved Process for the Preparation of Oxazolino-azetidinones and 1-Oxadethiacephams from Exomethylenecepham Sulfoxides

Abstract Oxazolino-azetidinones and 1-oxadethiacephams have been prepared in one and two steps, respectively, from exomethylene-cepham sulfoxides.