In Silico Design and Enantioselective Synthesis of Functionalized Monocyclic 3‐Amino‐1‐carboxymethyl‐β‐lactams as Inhibitors of Penicillin‐Binding Proteins of Resistant Bacteria
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In Silico Design and Enantioselective Synthesis of Functionalized Monocyclic 3‐Amino‐1‐carboxymethyl‐β‐lactams as Inhibitors of Penicillin‐Binding Proteins of Resistant Bacteria
As a complement to the renowned bicyclic β‐lactam antibiotics, monocyclic analogues provide a breath of fresh air in the battle against resistant bacteria. In that framework, the present study discloses the in silico design and unprecedented ten‐step synthesis of eleven nocardicin‐like enantiomerically pure 2‐{3‐[2‐(2‐aminothiazol‐4‐yl)‐2‐(methoxyimino)acetamido]‐2‐oxoazetidin‐1‐yl}acetic acids starting from serine as a readily accessible precursor. The capability of this novel class of monocyclic 3‐amino‐β‐lactams to inhibit penicillin‐binding proteins (PBPs) of various (resistant) bacteria was assessed, revealing the potential of α‐benzylidenecarboxylates as interesting leads in the pursuit of novel PBP inhibitors. No deactivation by representative enzymes belonging to the four β‐lactamase classes was observed, while weak inhibition of class C β‐lactamase P99 was demonstrated.
As a complement to the renowned bicyclic β‐lactam antibiotics, monocyclic analogues provide a breath of fresh air in the battle against resistant bacteria. In that framework, the present study discloses the in silico design and unprecedented ten‐step synthesis of eleven nocardicin‐like enantiomerically pure 2‐{3‐[2‐(2‐aminothiazol‐4‐yl)‐2‐(methoxyimino)acetamido]‐2‐oxoazetidin‐1‐yl}acetic acids starting from serine as a readily accessible precursor. The capability of this novel class of monocyclic 3‐amino‐β‐lactams to inhibit penicillin‐binding proteins (PBPs) of various (resistant) bacteria was assessed, revealing the potential of α‐benzylidenecarboxylates as interesting leads in the pursuit of novel PBP inhibitors. No deactivation by representative enzymes belonging to the four β‐lactamase classes was observed, while weak inhibition of class C β‐lactamase P99 was demonstrated.
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