Synthesis, hydrolysis, biochemical and theoretical evaluation of 1,4-bis(alkoxycarbonyl)azetidin-2-ones as potential elastase inhibitors

Abstract

AbstractÐA series of 1,4-bis(alkoxycarbonyl)azetidin-2-ones, designed as potential suicide-inhibitors of serine proteases, has been synthesized and evaluated against porcine pancreatic elastase (PPE). The most active compound (K i ,10 mM; reversible inhibitor) was equipped with phenethyloxycarbonyl and benzyloxycarbonyl side-chains at positions N1 and C4, respectively, with the (S)-con®guration. 1 H NMR spectroscopic analysis of the reaction mixtures showed that the ester function is preferentially hydrolyzed, in both chemical and enzyme-catalyzed reactions, with regard to the azetidinone and urethane functions. Considering the three potentially sensitive carbonyl functions and the two stereoisomers, ab initio calculations were performed to determine the energetic barriers required to reach the transition state structures of hydrolysis in a model of the enzyme pocket. q

Novel Large‐Ring 1,3‐Bridged 2‐Azetidinones as Potential Inhibitors of Penicillin‐Binding Proteins

“…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.…”

Synthesis and Antimicrobial Activity of Some Novel N-Mannich Bases of Imidazole Phenylazetidin-2-one

“…The structure of these newly synthesized compounds of 7(a-d) were established by IR, 1 H-NMR, 13 C-NMR, mass data and elemental analysis. 1366 (bending vibrations of imidazole ring), 1140 (C-O) and 725 cm -1 (C-Cl).…”

“…The structure of these newly synthesized compounds of 7(e-h) were established by IR, 1 H-NMR, 13 C-NMR, mass data and elemental analysis. 4-(1-((4-methylpiperazin-1-yl) (1-((4-methylpiperazin-1-yl -4-(1-((4-methylpiperazin-1-yl -4-(1-((4-methylpiperazin-1-yl)…”

“…The various synthetic approaches to obtain heterocyclic 2-azetidinones have been reported [5][6][7][8][9][10][11][12][13][14]. In the present paper, we describe the synthesis of heterocycles comprising Azetidin-2-one of N-Mannich Bases of Imidazole phenylazetidin-2-ones which can be an attractive target to obtain a series of novel compounds with potentially wide range of biological activity such as cholesterol absorption inhibitors, enzyme inhibitors, anticancer, cytotoxic, antitubercular, antitumor and antimicrobial (Scheme 1).…”

Synthesis, in‐vitro Antimicrobial and Cytotoxic Studies of Novel Azetidinone Derivatives

“…Azetidinones are a very important class of compounds possessing a wide range of biological activities such as antimicrobial [4], anti-inflammatory [5], anticonvulsant [6], antibiotic [7], anticancer [8], anti-elastase [9], antiviral [10], antitumor [4], and anti-HCMV [11] activities. Recently, it has been reported that b-lactams have novel biological properties such as acting as cytomegalovirus protease inhibitors [12], thrombin and tryptase inhibitors [13], cholesterol absorption inhibitors [14], human leukocyte elastease (HLE) inhibitors [15], porcine pancreatic elastease (PPE) inhibitors [16], HIV-1 protease [17], and peroxisome proliferator-activated receptors (PPARs) [18]. Besides their biological activities, the importance of b-lactams as synthetic intermediates has been widely recognized in organic synthesis [19] for example in the semi-synthesis of Taxol [20].…”