Synthesis, reactivity and biochemical evaluation of 1,3-substituted azetidin-2-ones as enzyme inhibitors

Beauve, Cécile; Bouchet, Michèle; Touillaux, Roland; Fastrez, Jacques; Marchand‐Brynaert, Jacqueline

doi:10.1016/s0040-4020(99)00819-4

Cited by 21 publications

(5 citation statements)

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“…In this perspective, the C=C acts as an electron-withdrawing group following the model for inhibitory activity of monocyclic b-lactams. [13] We focused the design of the new 4-alkylideneb-lactams on monocyclic N-unsubstituted azetidinones bearing a polyphenolic side chain at the C3 or C4 position of the blactam ring. Concerning antibacterial activity, the 4-alkylideneazetidinones show significant inhibitory activity against Grampositive pathogens, generally undifferentiated against both MRSA and methicillin-susceptible S. aureus (MSSA).…”

Section: Introductionmentioning

confidence: 99%

Antibacterial Agents and Cystic Fibrosis: Synthesis and Antimicrobial Evaluation of a Series of N‐Thiomethylazetidinones

et al. 2011

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The increasing emergence of multidrug-resistant microorganisms is one of the greatest challenges in the clinical management of infectious disease. New antimicrobial agents are therefore urgently required, particularly in the treatment of chronic and recurrent infections often associated with antibiotic-resistant pathogens, as in the case of cystic fibrosis (CF) patients. This study reports the antibacterial activity of a series of monocyclic β-lactams with an alkylidenecarboxyl chain or electron-withdrawing groups such as 4-OAc, 4-SAc, and 4-SO(2)Ph at the C4 position of the ring. N-Unsubstituted and N-thiomethyl derivatives were compared. A total of 33 azetidinones were tested for their activity against Gram-positive and Gram-negative bacterial clinical isolates. The combination of an N-thiomethyl group and a benzyl ester on the 4-alkylidene side chain were found to increase the potency against Gram-positive bacteria. The N-thiomethyl group clearly elevated the activity of 4-acetoxyazetidinones relative to the corresponding NH derivatives. The most active compounds showed minimum inhibitory concentration (MIC) values of 4 and 8 mg L(-1) against methicillin-resistant Staphylococcus aureus isolated from pediatric patients with CF.

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Section: Introductionmentioning

confidence: 99%

Antibacterial Agents and Cystic Fibrosis: Synthesis and Antimicrobial Evaluation of a Series of N‐Thiomethylazetidinones

et al. 2011

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“…The majority of elastase inhibitors are based on other serine protease inhibitors and often act by acylating serine-195 in the active site of the enzyme . Interestingly, the classical β-lactams, traditionally used as anti-bacterial agents by inhibiting serine transpeptidases, have also been shown to be mechanism-based inhibitors of elastase when used as neutral derivatives …”

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confidence: 99%

Acylation versus Sulfonylation in the Inhibition of Elastase by 3-Oxo-β-Sultams

et al. 2005

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beta-Sultams are the sulfonyl analogues of beta-lactams, and 3-oxo-beta-sultams are both beta-lactams and beta-sultams and, therefore, susceptible to nucleophilic attack at either the acyl or the sulfonyl center. They are novel inactivators of serine enzymes. The second-order rate constant for the inactivation of elastase at pH 6 by N-benzyl-4,4-dimethyl-3-oxo-beta-sultam is 768 M-1 s-1, which is 103-fold greater than that with N-benzoyl beta-sultam. However, in contrast to N-acyl beta-sultams, which sulfonylate the active site serine residue to form a sulfonate ester, 3-oxo-beta-sultams inhibit the enzyme by acylation followed by slow deacylation to regenerate the active enzyme.

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“…N-acylation is usually performed in high yields by simply reacting the N-unsubstituted azetidinones with acylchlorides, chloroformates, or isocyanates in the presence of a base, thus obtaining imide-, urethane-or urea-like compounds, respectively (Scheme 7). If the N-acyl moiety is coupled with the presence of a potential leaving group on C-4, the obtainment of the so-called suicide inhibitors is also possible [50]. Scheme 8 depicts a mechanism-based inhibitionby a N-acyl-azetidinone which covalently binds to the active site of serine proteases.…”

Section: N-acyl-azetidinonesmentioning

confidence: 99%

Monocyclic β-Lactams: New Structures for New Biological Activities

Galletti

Giacomini

2011

CMC

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The azetidinone core-structure offers a unique approach to the design and synthesis of new derivatives with unique biological properties. During the last two decades researches convincingly demonstrated that the prospect of structural modifications of monocyclic β-lactams with specific substituents is an effective procedure for the detection and improvement of important pharmacological effects different from antibacterial activity. As a matter of fact, new β-lactam compounds demonstrated biological activity as inhibitors of a wide range of enzymes. This review reports the latest developments on monocyclic β-lactam compounds activity as anticancer, antitubercular, HFAAH inhibitors, HDAC inhibitors, anti-inflammatory drugs (tryptase inhibitors), Cathepsin K inhibitors, and vasopressin inhibitors. We attempted to highlight the intertwined relationships between structural features and biological activities, by analysing groups anchored on the three positions of the azetidinone ring as sources of molecular diversity.

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Synthesis, reactivity and biochemical evaluation of 1,3-substituted azetidin-2-ones as enzyme inhibitors

Cited by 21 publications

References 43 publications

Antibacterial Agents and Cystic Fibrosis: Synthesis and Antimicrobial Evaluation of a Series of N‐Thiomethylazetidinones

Antibacterial Agents and Cystic Fibrosis: Synthesis and Antimicrobial Evaluation of a Series of N‐Thiomethylazetidinones

Acylation versus Sulfonylation in the Inhibition of Elastase by 3-Oxo-β-Sultams

Monocyclic β-Lactams: New Structures for New Biological Activities

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Synthesis, reactivity and biochemical evaluation of 1,3-substituted azetidin-2-ones as enzyme inhibitors

Cited by 21 publications

References 43 publications

Antibacterial Agents and Cystic Fibrosis: Synthesis and Antimicrobial Evaluation of a Series of N‐Thiomethylazetidinones

Antibacterial Agents and Cystic Fibrosis: Synthesis and Antimicrobial Evaluation of a Series of N‐Thiomethylazetidinones

Acylation versus Sulfonylation in the Inhibition of Elastase by 3-Oxo-β-Sultams

Monocyclic &#946;-Lactams: New Structures for New Biological Activities

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Monocyclic β-Lactams: New Structures for New Biological Activities