Functionalized N‐aryl azetidinones as novel mechanism‐based inhibitors of neutrophil elastase

Abstract

A I'unetionalixcd N.ar~'l .zetidinon¢ ha~t been drown to inactivate human leukt~eyt¢ ela=ta~ [HLE) and porcine panereatle elaMa~¢ (PPE) by an enzyme.mediated pro~¢=~. The inactivation is characterized by the t'ollewtn~ kinetic ¢on~ta nt~ at pH tk0 and ~7'C: k,p,.+~ -0,0~.~ s = z. g~ ~ 1,2 ~ I 0 =* M for HLE, 0,08 =t *~ and 2.'1 x 10 ''~ M for PPE, te,tpeetively. Two parent moleeule~¢ dc~voitt or the latent leavintl sroup tidied to inactivate HLE and PPE and bchawd as ~ubstrates of these enzymes, A ~uicide mechanism i~ postulated inv~lvinll the formation or an acyl-enxyme and the simuha. neous unmaskin$ of a latent quinonimmonium m~thid¢ ion which irrever~ib!y reacts with an active ~it© nudeophil¢. Moreover. the inhibitor t~ still ¢fl'~tive at inhibitinlt elasla~ preab~orbed ol~to ela~tin, /i.Laetam: Leukocyte ¢lastase; Suicide ~ub~trale

Coumarinic derivatives as mechanism-based inhibitors of α-chymotrypsin and human leukocyte elastase

“…The same feature occurs for the thioester 39. On the contrary, the amide function in 38 highly stabilizes the conformer a by an internal H-bond (C 2 O ...... HN 16 , Table 5 and Fig. 5).…”

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].…”

N-Aryl Lactams by Regioselective Ozonation of N-Aryl Cyclic Amines

“…[2] Their chemesthetic activity has been also recently demonstrated [3]. N -aryl derivatives of azetidinone have been shown to inactivate human leukocyte elastase (HLE) and porcine pancreatic elastase (PPE) [4]. They are also used as platelet inhibitor [5].…”