Scheme 1. Mechanism of action of a β-lactamase (a) with a β-lactam (the antibiotic cephalothin) and (b) with a boronic acid. (c) Growing mimesis of cephalothin by boronic acids and their activity against the β-lactamase AmpC.

Scheme 2. Newly designed potential inhibitors of β-lactamases and (+)-pinanediol arylboronates, respectively, needed as their synthetic precursors.

Figure 1. Stereo view of the interactions observed between AmpC and compounds 6–8 in the modelled conformation. (A) Compound 6. (B) Compound 7. (C) Compound 8. Carbon atoms are coloured grey for the protein and orange for the ligands; oxygen atoms, red; nitrogen atoms, blue; sulfur atoms, yellow; boron atoms, magenta. Atomic interactions within hydrogen bonding distance are shown as dashed yellow lines. This figure was generated with Pymol (htpp://pymol.sourceforge.net/).

Scheme 3. Stereoselective synthesis of chiral boronic acids.

Figure 2. Stereo view of the active site region of the AmpC/8 complex determined to 2.0 Å resolution. (A) The 2F_o − F_c electron density map is shown in blue, contoured at 1.0 σ. (B) Interactions observed between AmpC and compound 8 in the crystallographic complex. Carbon atoms are coloured grey for the protein and cyan for the ligand; oxygen atoms, red; nitrogen atoms, blue; sulfur atoms, yellow; boron atoms, magenta. Dashed yellow lines represent key hydrogen bonds. Red spheres represent water molecules. (C) Overlay of the modelled and crystallographic conformations of compound 8 in the AmpC site. Carbon atoms of compound 8 in the modelled conformation, orange; carbon atoms of compound 8 in the crystal structure, cyan. This figure was generated with Pymol (htpp://pymol.sourceforge.net/).

K_i values of the cephalothin-analogue boronic acids versus AmpC

K_i values for compounds 5 and 8 against various β-lactamases

Crystallographic summary for the complex AmpC

Interactions in inhibitor bound and native AmpC β-lactamase