- Antibacterial Agents and Cystic Fibrosis: Synthesis and Antimicrobial Evaluation of a Series of N-Thiomethylazetidinones
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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-SO2Ph 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 8mgL-1 against methicillin-resistant Staphylococcus aureus isolated from pediatric patients with CF.
- Galletti, Paola,Cocuzza, Clementina E. A.,Pori, Matteo,Quintavalla, Arianna,Musumeci, Rosario,Giacomini, Daria
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scheme or table
p. 1919 - 1927
(2012/06/04)
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- 2-Azetidinones: Synthesis of new bis(indolyl)butyl-β-lactams
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New β-lactam compounds containing a bis(indolyl)-framework were synthesized. The key step in the synthetic strategy was a nucleophilic addition of unprotected indole to a suitable butyl aldehyde anchored on the C-4 side chain of azetidinone intermediates.
- Galletti, Paola,Quintavalla, Arianna,Ventrici, Caterina,Giannini, Giuseppe,Cabri, Walter,Giacomini, Daria
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scheme or table
p. 2861 - 2866
(2011/02/27)
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- Convergent synthesis of (2R,3R,8R,9R)-N-Boc-ADDA
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(Figure Presented) The convergent synthesis of N-Boc-(2R,3R,8R,9R,4E,6E)-3- amino-9-methoxy-2,6,8-trimethyl-10-phenyldecadenoic acid (enantio-N-Boc-ADDA) is reported. Our flexible approach takes advantage of highly efficient non-aldol aldol and cross-metathesis methodologies.
- Meiries, Sebastien,Marquez, Rodolfo
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p. 5015 - 5021
(2008/12/20)
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- Kinetics and Mechanism of Hydrolysis of N-Acyloxymethyl Derivatives of Azetidin-2-one
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The pH-independent, acid-catalyzed and base-catalyzed hydrolyses of N-acyloxymethylazetidin-2-ones all occur at the ester function. The pH-independent hydrolysis involves rate-limiting alkyl C-O fission and formation of an exocyclic β-lactam iminum ion. This iminium ion is then trapped by water at the exocyclic iminium carbon atom, rather than at the β-lactam carbonyl carbon atom, to form the corresponding N-hydroxymethylazetidin-2-ones. Calculations carried out at the B3LYP/6-31+G(d) level of theory also support that nucleophilic attack by water takes place at the exocyclic carbon rather than at the β-lactam carbonyl carbon of the iminium ion. The mechanism for the acid-catalyzed pathway involves a preequilibrium protonation, probably at the β-lactam nitrogen, followed by rate-limiting alkyl C-O fission with formation of an exocyclic iminum ion. The base-catalyzed hydrolysis involves rate-limiting hydroxide attack at the ester carbonyl carbon. These results imply formation of a β-lactam system containing a positively charged amide nitrogen atom that hydrolyzes via a pathway that preserves the β-lactam structure in the product and provide further evidence that cleavage of the β-lactam C-N bond is not as facile as is commonly imagined.
- Valente, Emilia,Gomes, Jose R. B.,Moreira, Rui,Iley, Jim
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p. 3359 - 3367
(2007/10/03)
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- Design, synthesis and stability of N-acyloxymethyl- and N-aminocarbonyloxymethyl-2-azetidinones as human leukocyte elastase inhibitors
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A series of N-acyloxymethyl- and N-aminocarbonyloxymethyl derivatives of 2-azetidinones, 3, with different substituent patterns at the β-lactam C-3 and C-4 positions, were designed as potential mechanism-based inhibitors for human leukocyte elastase and f
- Clemente,Domingos,Grancho,Iley,Moreira,Neres,Palma,Santana,Valente
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p. 1065 - 1068
(2007/10/03)
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- New approach to β-lactam-fused enediynes ('Lactenediynes') by stereoselective pinacol coupling
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A short synthesis of unfunctionalized lactenediyne 3 by closure of the ten-membered ring at the double bond site is reported. After failure of the known methodologies, this closure was eventually successfully achieved thanks to a highly stereoselective, v
- Banfi, Luca,Guanti, Giuseppe,Basso, Andrea
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p. 939 - 946
(2007/10/03)
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- β-Secondary Kinetic Isotope Effects in the Clavaminate Synthase-Catalyzed Oxidative Cyclization of Proclavaminic Acid and in Related Azetidinone Model Reactions
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Clavaminate synthase is an Fe(II)/α-ketoglutarate-dependent oxygenase that catalyzes three mechanistically distinct reactions in the course of clavulanic acid biosynthesis. Clavulanic acid is of significant chemical importance as a potent inhibitor/inactivator of β-lactamase enzymes, a prominent means of bacterial resistance to, for example, penicillin. Primary and α-secondary T(V/K) kinetic isotope effects have been determined in earlier work for the clavaminate synthase-catalyzed oxidative cyclization of proclavaminic acid, one of the three reactions mediated by this enzyme. In this paper the β-secondary deuterium kinetic isotope effect for this reaction has been determined using remote 3H and 14C labels in an attempt to distinguish between radical or cationic intermediates in the reaction as suggested by the magnitudes of the primary and secondary α-effects. The presence of the adjacent azetidinone nitrogen and the intervention of an azetinone intermediate, formally antiaromatic in the resonance form of the amide, make interpretation of the low β-secondary effect (1.056 ± 0.002 for dideuteriation at C-3′) problematic. To assist interpretation of this result, a 4-chloroazetidinone model system has been constructed dideuteriated at C-3 identically to proclavaminic acid and bearing remote radiolabels. Reaction of this substrate at 25°C under both radical and solvolysis conditions afforded β-secondary kinetic isotope effect data for direct comparison to the enzymic reaction. The measured effects are similarly small but strongly dependent on the polarity/acidity of the reaction medium. These results are discussed in terms of the commitment to catalysis and the extent to which amide resonance may be favored in the transition state of the oxidative cyclization.
- Iwata-Reuyl, Dirk,Basak, Amit,Townsend, Craig A.
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p. 11356 - 11368
(2007/10/03)
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- Synthesis of 3-amino-3-vinylpropanoic acid and its conversion to 4-amino-5-hydroxy-4,5-dihydrofuran-2-one hydrochloride (HAD), a cyclic stabilised form of aspartate 1-semialdehyde hydrochloride
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3-amino-3-vinylpropanoic acid hydrochloride 4 was obtained from 4-acetoxyazetidin-2-one 1 in 3 steps. The ozonolysis of 4 yielded 3-amino-4-oxopropanoic acid hydrochloride (aspartate 1-semialdehyde hydrochloride 6). This labile α-aminoaldehyde is isolated
- Cheung, Kwai-Ming,Shoolingin-Jordan, Peter M.
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p. 15807 - 15812
(2007/10/03)
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- Synthesis of the Alkaloids Hopromine, Hoprominol and Hopromalinol, using Transamidation Methods
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Synthesis of the unsymmetrical Homalium alkaloids hopromine, hoprominol and hopromalinol, in diastereoisomeric mixture form, is reported.The component eight-membered azalactams are first prepared.N-(3-Halogenopropyl)-4-pentyl- and -4-heptyl-azetidin-2-ones are aminated and ring expanded in liquid ammonia to give, after reductive methylation, the corresponding 4-alkyl-5-methyl-1,5-diazacyclooctan-2-ones.Synthesis of the 4-(2-hydroxyheptyl)-5-methyl-1,5-diazacyclooctan-2-one required for hoprominol and hopromalinol is carried out via 4-allyl β-lactam ring expansion to the eight-membered 4-allylazalactam, followed by methylation, epoxidation and epoxide opening with lithium dibutylcuprate.A similar epoxidation-cuprate sequence was carried out on the epoxypropyl β-lactam, as its N-tert-butyldimethylsilyl derivative, and led to a convenient copper-catalysed N- to O-migration of the protection; this migration is examined.Alkylation gave O-TBDMS-protected N-(3-chloropropyl)-4-(2-hydroxyheptyl)azetidin-2-one which could be aminated and transamidated in excellent yield, to give, after methylation, a superior sequence to the required eight-membered hydroxy azalactam.Although satisfactory for attachment of the first azalactam unit, a dibromobutane coupling system proved unreactive for the second.Couplings with unmethylated, methylated, and benzyloxycarbonyl-protected azalactams were examined using (E)-1,4-dibromobutene and (Z)-1,4-dichlorobutene as the bridging unit.Employing the latter, coupling the first N-methylated azalactam with potassium bis(trimethylsilyl)amide as the base, and then the second with bis(trimethylsilyl)amide-sodium hydride as the base system, provided a satisfactory synthetic outcome.Hydrogenation under acidic conditions gave the unsymmetrical structures hopromine, hoprominol and hopromalinol, as well as the more simple and symmetrical alkaloid, homaline.
- Crombie, Leslie,Haigh, David,Jones, Raymond C. F.,Mat-Zin, Ab. Rasid
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p. 2055 - 2068
(2007/10/02)
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