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12‐ to 22‐Membered Bridged β‐Lactams as Potential Penicillin‐Binding Protein Inhibitors
Author(s) -
Sliwa Aline,
Dive Georges,
MarchandBrynaert Jacqueline
Publication year - 2012
Publication title -
chemistry – an asian journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.18
H-Index - 106
eISSN - 1861-471X
pISSN - 1861-4728
DOI - 10.1002/asia.201100732
Subject(s) - steric effects , stereochemistry , lactam , chemistry , penicillin binding proteins , ring (chemistry) , ring closing metathesis , ab initio , bicyclic molecule , nucleophile , side chain , combinatorial chemistry , penicillin , metathesis , biochemistry , antibiotics , organic chemistry , polymer , catalysis , polymerization
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.