N-Aryl 3-halogenated azetidin-2-ones and benzocarbacephems, inhibitors of .beta.-lactamases

Abstract

N-(3-Carboxy-6-methylphenyl)-3-fluoroazetidin-2-one and a series of related N-aryl-3-halo- and -3,3-dihaloazetidinones 3, in which the halo substituent is a fluorine or a bromine atom, were prepared by using the Wasserman procedure of cyclization of beta-bromopropionamides as a key step. Their affinities for the TEM-1 beta-lactamase were determined and compared with those of a series of tricyclic azetidinones, the benzocarbacephems 2, and known beta-lactamase inhibitors. The beta-lactams 2 and 3 behave as competitive inhibitors and not as substrates of the enzyme; neither halogen substitution (series 3) nor ring strain (series 2) induces enzymatic hydrolysis.

Synthesis of fluorinated δ-lactams via cycloisomerization of gem-difluoropropargyl amides

“…Commonly, β- and γ-lactams are present in many natural products and pharmaceuticals, and the introduction of a gem -difluoromethylene moiety has been reported to improve their biological activities. For example, a gem -difluoro-γ-lactam can inhibit γ-lactamase, which is responsible for bacterial resistance to γ-lactam antibiotics [2–4]. Additionally, α,α-difluoro lactams are precursors of some biologically active compounds [5–8].…”

Tri- and tetrafluoropropionamides derived from chiral secondary amines – synthesis and the conformational studies

“…X-ray crystal structure analysis of 5a (CCDC 989111): † formula C 12 General procedure for the synthesis of enamines Chiral secondary amine (1 equiv.) and dried solvent (3 mL) were placed in a glass pressure-vessel.…”

“…For example, gem-difluoro-glactam inhibits g-lactamase, an enzyme responsible for bacterial resistance to g-lactam antibiotics. 12 Moreover gem-difluoropropargyl amides are useful as suitable building blocks for the synthesis of fluorinated d-lactams via cycloisomerization. 13 Another example for application of the fluorine-containing compounds in synthesis is trifluoroacetamide analogues that serve as efficient enantioselective nucleophilic trifluoromethylating reagents.…”

Synthesis of Chlorinated, Heteroatom‐Rich and Differently Fused Tricyclic β‐Lactams by Cu(I)‐Catalyzed Halogen Atom Transfer Radical Cyclization

“…[9] Few more structural analogs of sanfetrinem were synthesized and are known to possess a broad spectrum of antibacterial activities. [7a] Some tricyclic β-lactams acted as inhibitors of β-lactamases [10][11][12] and other medicinally relevant mammalian enzymes implicated in many diseases. [13,14] Thus, tricyclic β-lactams constituted a new generation of β-lactam antibiotics which are resistant to a wide range of β-lactamases and exhibit improved metabolic stability.…”