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Lactam Ring (lactam + ring)

Distribution by Scientific Domains
Chemistry80%
Life Sciences20%

Selected Abstracts

ChemInform Abstract: A Study of the Photochemical Isomerization in ,-Lactam Rings.

CHEMINFORM, Issue 31 2001
Roberto Alcazar
Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source]

Molecular basis of antibiotic resistance and ,-lactamase inhibition by mechanism-based inactivators: perspectives and future directions

FEMS MICROBIOLOGY REVIEWS, Issue 3 2000
Christian Therrien
Abstract Antibacterial chemotherapy is particularly striking in the family of penicillins and cephalosporins. Over 40 structurally different ,-lactam molecules are available in 73 formulations and the majority of them are currently prescribed for medical use in hospitals. ,-Lactams are well tolerated by humans with few side effects. They interact very specifically with their bacterial target, the d -alanyl- d -alanine carboxypeptidase-transpeptidase usually referred to as dd -peptidase. The outstanding number of ,-lactamases produced by bacteria represent a serious threat to the clinical utility of ,-lactams. The discovery of ,-lactamase inhibitors was thought to solve, in part, the problem of resistance. Unfortunately, bacteria have evolved new mechanisms of resistance to overcome the inhibitory effects of ,-lactamase inactivators. Here, we summarize the diversified mechanistic features of class A ,-lactamases interactions with mechanism-based inhibitors using available microbiological, kinetic and structural data for the prototype TEM ,-lactamases. A brief historical overview of the strategies developed to counteract ,-lactamases will be presented followed by a short description of the chemical events which lead to the inactivation of TEM ,-lactamase by inhibitors from different classes. Finally, an update on the clinical prevalence of natural and inhibitor-resistant enzyme mutants, the total chemical synthesis to design and synthesize a new structure and produced a broad spectrum ,-lactamase inhibitor that mimics the ,-lactam ring, but does not contain it is discussed. [source]

Quantum chemical study of penicillin: Reactions after acylation

INTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY, Issue 10 2007
Rui Li
Abstract The density functional theory methods were used on the model molecules of penicillin to determine the possible reactions after their acylation on ,-lactamase, and the results were compared with sulbactam we have studied. The results show that, the acylated-enzyme tetrahedral intermediate can evolves with opening of ,-lactam ring as well as the thiazole ring; the thiazole ring-open products may be formed via ,-lactam ring-open product or from tetrahedral intermediate directly. Those products, in imine or enamine form, can tautomerize via hydrogen migration. In virtue of the water-assisted, their energy barriers are obviously reduced. © 2007 Wiley Periodicals, Inc. Int J Quantum Chem, 2007 [source]

Electronic structure and physicochemical properties of selected penicillins

INTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY, Issue 3 2007
Catalina Soriano-Correa
Abstract Traditionally, penicillins have been used as antibacterial agents due to their characteristics and widespread applications with few collateral effects, which have motivated several theoretical and experimental studies. Despite the latter, their mechanism of biological action has not been completely elucidated. We present a theoretical study at the Hartree,Fock and density functional theory (DFT) levels of theory of a selected group of penicillins such as the penicillin-G, amoxicillin, ampicillin, dicloxacillin, and carbenicillin molecules, to systematically determine the electron structure of full ,-lactam antibiotics. Our results allow us to analyze the electronic properties of the pharmacophore group, the aminoacyl side-chain, and the influence of the substituents (R and X) attached to the aminoacyl side-chain at 6, (in contrast with previous studies focused at the 3, substituents), and to corroborate the results of previous studies performed at the semiempirical level, solely on the ,-lactam ring of penicillins. Besides, several density descriptors are determined with the purpose of analyzing their link to the antibacterial activity of these penicillin compounds. Our results for the atomic charges (fitted to the electrostatic potential), the bond orders, and several global reactivity descriptors, such as the dipole moments, ionization potential, hardness, and the electrophilicity index, led us to characterize: the active sites, the effect of the electron-attracting substituent properties and their physicochemical features, which altogether, might be important to understand the biological activity of these type of molecules. © 2006 Wiley Periodicals, Inc. Int J Quantum Chem, 2007 [source]

Influence of substituent groups at the 3-position on the mass spectral fragmentation pathways of cephalosporins

RAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 14 2010
Jin Li
The structural fragment ions of nine cephalosporins were studied by electrospray ionization quadrapole trap mass spectrometry (Q-Trap MSn) in positive mode. The influence of substituent groups in the 3-position on fragmentation pathway B, an ,-cleavage between the C7C8 single bond, coupled with a [2,4]-trans-Diels-Alder cleavage simultaneously within the six-membered heterocyclic ring, was also investigated. It was found that when the substituent groups were methyl, chloride, vinyl, or propenyl, fragmentations belonging to pathway B were detected; however, when the substituents were heteroatoms such as O, N, or S, pathway B fragmentation was not detected. This suggested that the [M,R3]+ ion, which was produced by the bond cleavage within the substituent group at the 3-position, had a key influence on fragmentation pathway B. This could be attributed to the strong electronegativity of the heteroatoms (O, N, S) that favors the production of the [M,R3]+ ion. Moreover, having the positive charge of the [M,R3]+ ion localized on the nitrogen atom in the 1-position changed the electron density distribution of the heterocyclic structure, which prohibits a [2,4]-reverse-Diels-Alder fragmentation and as a result fragmentation pathway B could not occur. The influence of the substituent group in the 3-position was determined by the intensity ratio (e/d) of ions produced by fragmentation pathway A, a [2,2]-trans-Diels-Alder cleavage within the quaternary lactam ring, including the breaking of the amide bond and the C6C7 single bond (ion d), and fragmentation pathway B (ion e). The results indicate that the electronegativity of the substituent group was a key influencing factor of pathway B fragmentation intensity, because the intensity ratio (e/d) is higher for a chlorine atom, a vinyl, or a propenyl group than that of a methyl group. This study provided some theoretical basis for the identification of cephalosporin antibiotics and structural analysis of related substances in drugs. Copyright © 2010 John Wiley & Sons, Ltd. [source]

Reduction of in-source collision-induced dissociation and thermolysis of sulopenem prodrugs for quantitative liquid chromatography/electrospray ionization mass spectrometric analysis by promoting sodium adduct formation

RAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 20 2008
Chad E. Wujcik
Six chromatographically resolved sulopenem prodrugs were monitored for their potential to undergo both in-source collision-induced dissociation (CID) and thermolysis. Initial Q1 scans for each prodrug revealed the formation of intense [Prodrug2,+,H]+, [Prodrug2,+,Na]+, [Prodrug,+,Na]+, and [Sulopenem,+,Na]+ ions. Non-adduct-associated sulopenem ([Sulopenem,+,H]+) along with several additional lower mass ions were also observed. Product ion scans of [Prodrug3,+,Na]+ showed the retention of the sodium adduct in the collision cell continuing down to opening of the , -lactam ring. In-source CID and temperature experiments were conducted under chromatographic conditions while monitoring several of the latter ion transitions (i.e., adducts, dimers and degradants/fragments) for a given prodrug. The resulting ion profiles indicated the regions of greatest stability for temperature and declustering potential (DP) that provided the highest signal intensity for each prodrug and minimized in-source degradation. The heightened stability of adduct ions, relative to their appropriate counterpart (i.e., dimer to dimer adduct and prodrug to prodrug adduct ions), was observed under elevated temperature and DP conditions. The addition of 100,µM sodium to the mobile phase further enhanced the formation of these more stable adduct ions, yielding an optimal [Prodrug,+,Na]+ ion signal at temperatures from 400 to 600°C. A clinical liquid chromatography/tandem mass spectrometry (LC/MS/MS) assay for sulopenem prodrug PF-04064900 in buffered whole blood was successfully validated using sodium-fortified mobile phase and the [PF-04064900,+,Na]+ ion for quantitation. A conservative five-fold increase in sensitivity from previously validated preclinical assays using the [PF-04064900,+,H]+ precursor ion was achieved. Copyright © 2008 John Wiley & Sons, Ltd. [source]

N -(p -Chloro­phenyl)-3,3-di­phenyl-4-(,-phenyl­styryl)azetidin-2-one

ACTA CRYSTALLOGRAPHICA SECTION C, Issue 5 2000
Mehmet Kabak
In the title compound, C35H26ClNO, the four-membered ,-lactam ring is essentially planar, with a maximum deviation of 0.012,(1),Å for the N atom. The C,C bond lengths in the ,-lactam ring are 1.591,(2) and 1.549,(2),Å. The two phenyl rings attached to the ,-lactam ring are nearly perpendicular to each other [83.2,(1)°]. [source]

Studies on Stereoselective [2+2] Cycloadditions between N,N-Dialkylhydrazones and Ketenes

CHEMISTRY - A EUROPEAN JOURNAL, Issue 23 2004
Eloísa Martín-Zamora Dr.
Abstract Staudinger-like cycloadditions between chiral, non-racemic N,N-dialkylhydrazones 1 and functionalized ketenes constitute an efficient methodology for the stereoselective construction of the ,-lactam ring. The potential for fine tuning of the dialkylamino auxiliary structure, the availability of a high-yielding deprotection method for the release of the free azetidinones, and the high thermal and chemical stability of hydrazones as N-dialkylamino imines are highlighted as the key elements for the success of the strategy. This last aspect is of particular importance concerning generality: even hydrazones from easily enolizable aldehydes or from formaldehyde reacted to afford the corresponding cycloadducts with high chemical and stereochemical yields. The syntheses of the ,-amino-,-hydroxyacids (2R,3S)-phenylisoserine (42) and (2R,3S)-norstatin (45) were accomplished as illustrative examples of the synthetic utility of this procedure. A model system for the cycloaddition of g series auxiliaries was studied by ab initio computational methods. The collected results support a two-step mechanism through zwitterionic intermediates, and explain the observed absolute and relative stereochemistry in terms of the preferred outward cycloaddition to the Re face of the hydrazone. La reacción de cicloadición [2+2] de tipo Staudinger entre cetenas funcionalizadas y las hidrazonas quirales 1 constituye un método eficiente para la construcción estereoselectiva del anillo de azetidinona. La modulación de la estructura del grupo dialquilamino empleado como auxiliar, la disponibilidad de un procedimiento eficiente para la desprotección de las , -lactamas libres y la alta estabilidad química y térmica de las hidrazonas como N-dialquilamino iminas son los puntos clave para el éxito de la estrategia. Este último aspecto es de particular importancia por su implicación en la generalidad del método: hidrazonas derivadas de aldehídos fácilmente enolizables o incluso las derivadas de formaldehído reaccionan para dar lugar a los correspondientes cicloaductos con excelentes rendimientos químicos y estereoquímicos. La síntesis de los , -amino- , -hidroxiácidos (2R,3S)-fenilisoserina (42) y (2R,3S)-norestatina (45) se llevaron a cabo como ejemplos ilustrativos del potencial sintético del método. Estudios computacionales ab initio realizados sobre una reacción modelo basada en los auxiliares de la serie g sugieren un mecanismo en dos pasos a través de intermedios zwitteriónicos. Los resultados obtenidos explican la estereoquímica absoluta y relativa, así como el alto grado de inducción observado para estos auxiliares, por la preferencia de la aproximación "outward" de la cetena sobre la cara Re de la hidrazona. [source]

Synthesis of Cyclic Peptides by Photochemical Decarboxylation of N -Phthaloyl Peptides in Aqueous Solution

HELVETICA CHIMICA ACTA, Issue 12 2002

The synthesis of a variety of cyclic peptides from N -phthaloyl-protected di-, tri-, tetra-, and pentapeptides with different aminocarboxylic acid tethers by photodecarboxylation , initiated by intramolecular electron transfer , has been explored in aqueous media. The progress and the chemoselectivity of the follow-up processes after CO2 extrusion were traced by the respective pH/time-profiles, as well as by the overall change in pH after completion of the reaction. The competition between cyclization and simple oxidative decarboxylation depends on spacer length and geometry, H-bonding interaction between the electron accepting phthalimide CO groups and amide H-atoms, as well as the geometric reorganization coupled with the radical combination step and the formation of the lactam rings. With progressing reaction, hydrolysis of the phthalimide chromophore becomes an increasingly important side reaction due to the constant increase in pH. The use of phosphate-buffered aqueous media consequently improved the cyclization yields. The ground-state interactions between amide groups and the terminal COO, group with the imide CO groups were studied for the model system [N -(phthaloyl)glycyl]sarcosine (1) by NMR spectroscopy where the amide (E/Z)-equilibrium depends on the presence of carboxylate vs. free carboxylic acid, demonstrating the role of H-bonding and metal coordination. [source]

Antibiotic Resistance in Bacteria: Novel Metalloenzyme Inhibitors

CHEMICAL BIOLOGY & DRUG DESIGN, Issue 4 2009
Sung-Kun Kim
,-Lactam antibiotics are among the most important drugs used to fight bacterial infection. Overuse and misuse of ,-lactam antibiotics has caused the evolution of resistance mechanisms, allowing pathogenic bacteria to survive antibiotic treatment. The major source of resistance to ,-lactam antibiotics occurs through production of enzymes called ,-lactamases capable of catalyzing hydrolysis of the ,-lactam rings in these drug compounds. The metallo-,-lactamases have become a major threat due to their broad substrate specificities; there are no clinically useful inhibitors for these metalloenzymes. We have obtained single-stranded DNA's that are potent inhibitors of the Bacillus cereus 5/B/6 metallo-,-lactamase. These are rapid, reversible, non-competitive inhibitors of the metalloenzyme, with Ki and Ki, values in the nanomolar range. The inhibition patterns and metal ion dependence of their inhibition suggest that the oligonucleotides alter the coordination of the active site metal ion(s); inhibition is efficient and highly specific. Microbiological growth experiments, using combinations of ssDNA with the ,-lactam antibiotic cephalexin, reveal that the inhibitor is capable of causing cell death in liquid cultures of both Gram-positive and Gram-negative metallo-,-lactamase producing bacteria in the micromolar concentration range. [source]