title: 12- to 22-membered bridged β-lactams as potential penicillin-binding protein inhibitors.
abstract: 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.
authors.affiliation: Institute of Condensed Matter and Nanosciences (IMCN), Molecules, Solids and Reactivity (MOST), Université catholique de Louvain, Bâtiment Lavoisier, Place Louis Pasteur L4.01.02, 1348 Louvain-la-Neuve, Belgium.
authors.forename: Aline
authors.initials: A
authors.lastname: Sliwa
authors.forename: Georges
authors.initials: G
authors.lastname: Dive
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Marchand-Brynaert
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003198:Computer Simulation; D047028:Macrocyclic Compounds / Q000737:chemistry*; D015394:Molecular Structure; D046915:Penicillin-Binding Proteins / Q000037:antagonists & inhibitors*; D011485:Protein Binding / Q000187:drug effects; D013816:Thermodynamics; D047090:beta-Lactams / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D047028:Macrocyclic Compounds; D046915:Penicillin-Binding Proteins; D047090:beta-Lactams