12- to 22-membered bridged β-lactams as potential penicillin-binding protein inhibitors

As potential inhibitors of penicillin-binding proteins (PBPs), we focused our research on the synthesis of non-traditional 1,3-bridged β-lactams embedded into macrocycles. We synthesized 12- to 22-membered bicyclic β-lactams by the ring-closing metathesis (RCM) of bis-ω-alkenyl-3(S)-aminoazetidinone precursors. The reactivity of 1,3-bridged β-lactams was estimated by the determination of the energy barrier of a concerted nucleophilic attack and lactam ring-opening process by using ab initio calculations. The results predicted that 16-membered cycles should be more reactive. Biochemical evaluations against R39 DD-peptidase and two resistant PBPs, namely, PBP2a and PBP5, revealed the inhibition effect of compound 4d, which featured a 16-membered bridge and the N-tert-butyloxycarbonyl chain at the C3 position of the β-lactam ring. Surprisingly, the corresponding bicycle, 12d, with the PhOCH(2)CO side chain at C3 was inactive. Reaction models of the R39 active site gave a new insight into the geometric requirements of the conformation of potential ligands and their steric hindrance; this could help in the design of new compounds.