12- to 22-Membered Bridged [beta]-Lactams as Potential Penicillin-Binding Protein Inhibitors

• Published in: Chemistry, an Asian journal Vol. 7; no. 2; p. 425
• Main Authors: Sliwa, Aline, Dive, Georges, Marchand-Brynaert, Jacqueline
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley Subscription Services, Inc 01-02-2012
• Subjects: Bacteriology; Chemistry; Penicillin
• ISSN: 1861-4728; 1861-471X
• DOI: 10.1002/asia.201100732

As potential inhibitors of penicillin-binding proteins (PBPs), we focused our research on the synthesis of non-traditional 1,3-bridged [beta]-lactams embedded into macrocycles. We synthesized 12- to 22-membered bicyclic [beta]-lactams by the ring-closing metathesis (RCM) of bis-[omega]-alkenyl-3(S)-aminoazetidinone precursors. The reactivity of 1,3-bridged [beta]-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 [beta]-lactam ring. Surprisingly, the corresponding bicycle, 12d, with the PhOCH2CO 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. [PUBLICATION ABSTRACT]