Inhibition of human leukocyte elastase by functionalized N-aryl azetidin-2-ones: substituent effects at C-3 and benzylic positions

Vergely, Isabelle; Boggetto, Nicole; Okochi, V. I.; Golpayegani, S; Reboud‐Ravaux, Michèle; Kobaiter, Randa; Joyeau, Roger; Wakselman, Michel

doi:10.1016/0223-5234(96)88226-2

Cited by 31 publications

(12 citation statements)

References 27 publications

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“…During the lifetime of the acyl-enzyme, the alkylation is probably prevented by an incorrect position of the benzylic group towards His57 due to the steric hindrance of the Z group. We previously demonstrated that this active site amino acid group was alkylated by the N-arylazetidin-2-one 1 with X = C1 and Z = H (Vergely 1994).…”

Section: Discussionmentioning

confidence: 99%

Synthesis and Inhibition of Human Leucocyte Elastase by Functionalized N-Aryl Azetidin-2-ones: Effect of Different Substituents on the Aromatic Ring

Joyeau

Felk

Guilaume

et al. 1996

Journal of Pharmacy and Pharmacology

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N-aryl-3,3-difluoroazetidin-2-ones featured by a latent electrophilic methylene quinoniminium function have been synthesized and evaluated as inhibitors of human leucocyte elastase. To promote hydrophobic interactions with the enzyme, to increase the rates of beta-lactam ring opening and of benzylic group departure, or to induce hydrosolubility, these compounds incorporate on their aromatic ring either an alkyl moiety, a methoxy substituent or a carboxylic group. Some of these beta-lactams proved to be good inactivators of human leucocyte elastase.

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Section: Discussionmentioning

confidence: 99%

Synthesis and Inhibition of Human Leucocyte Elastase by Functionalized N-Aryl Azetidin-2-ones: Effect of Different Substituents on the Aromatic Ring

Joyeau

Felk

Guilaume

et al. 1996

Journal of Pharmacy and Pharmacology

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“…The related C4 unsubstituted azetidinones (Scheme 1, R 2 = H) are scarcely described in the previous literature; [12][13][14] only one method of synthesis of 3,3-difluoroazetidin-2-one derivatives has been reported by Wakselman et al, based on the N1-C4 cyclization of Naryl-3-bromo-2,2-difluoropropionamides under strongly basic conditions. The precursor of the required anilides was ethyl 3-bromo-2,2-difluoropropanoate obtained by fluorination of ethyl bromopyruvate with sulfur tetrafluoride in an autoclave.…”

Section: Methodsmentioning

confidence: 99%

Synthesis of N -Protected 3,3-Difluoroazetidin-2-ones

Lacroix¹,

Cheguillaume²,

Gérard³

et al. 2003

Synthesis

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Representative N-protected 3,3-difluoroazetidin-2-ones 3 were obtained, either in one step by cycloaddition of zinc enolate 1 derived from ethyl bromodifluoroacetate onto N,N¢,N¢¢-trisubstituted hexahydro-1,3,5-triazines 2 (Schiff base trimer) in the case of 3a [N-(p-methoxybenzyl) derivative], or in two steps consisting of a Reformatsky-type reaction for the preparation of N-substituted 3-amino-2,2-difluoropropanotes 8 followed by N1-C2 cyclization under basic conditions in the cases of 3b (N-anisyl derivative) and 3c (N-benzhydryl derivative).

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“…The capacity of several b-lactam antibiotics [46,47] and monocyclic b-lactams [48][49][50][51][52] to inhibit elastase has been previously reported.…”

Section: Biochemical Evaluationmentioning

confidence: 97%

Large ring 1,3-bridged 2-azetidinones: Experimental and theoretical studies

Urbach

Dive

Tinant

et al. 2009

European Journal of Medicinal Chemistry

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a b s t r a c tThe relationship between angular strain and (re)activity of bicyclic 2-azetidinones is still an open question of major concern in the field of penicillin antibiotics. Our study deals with original 13-membered-ring 1,3-bridged 2-azetidinones related to the carbapenem family, and featuring a ''planar amide'' instead of the ''twisted amide'' typical of penam derivatives. The bicycles 11 and 12 were obtained from acetoxy-azetidinone 7, via the key-intermediate 10, by using the RCM (ring closing metathesis) strategy. Theoretical predictions and experimental results of hydrolysis showed that the large bicycle 12, endowed with high conformational flexibility, is more reactive than the bicycle 11, including a C]C bond of E configuration, and the monocyclic 2-azetidinone precursor 10. The processing of 2-azetidinones 10-12 in the active site of serine enzymes has been computed by ab initio methods, considering three models. Due to geometrical parameters of the enzymic cavity (nucleophilic attack from the a-face), precursor 10 was predicted more active than 11 and 12 in the acylation step by Ser-OH.Indeed, bicycles 11 and 12 are modest inhibitors of PBP 2a , while 10 is a good to excellent inhibitor of PBP 2a and R39 bacterial enzymes.

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Inhibition of human leukocyte elastase by functionalized N-aryl azetidin-2-ones: substituent effects at C-3 and benzylic positions

Cited by 31 publications

References 27 publications

Synthesis and Inhibition of Human Leucocyte Elastase by Functionalized N-Aryl Azetidin-2-ones: Effect of Different Substituents on the Aromatic Ring

Synthesis and Inhibition of Human Leucocyte Elastase by Functionalized N-Aryl Azetidin-2-ones: Effect of Different Substituents on the Aromatic Ring

Synthesis of N -Protected 3,3-Difluoroazetidin-2-ones

Large ring 1,3-bridged 2-azetidinones: Experimental and theoretical studies

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