Β-lactam Derivatives Research Articles

Efficient synthesis of highly enantiopure β-lactam derivatives from biocatalytic transformations of amides and nitriles

Catalyzed by Rhodococcus erythropolis AJ270, a nitrile hydratase and amidase containing microbial strain, under mild conditions, kinetic resolution of racemic amides provides an efficient and scalable route to highly enantioenriched R-4-carboxymethyl-β-lactams and S-4-carbamoylmethyl-β-lactams despite the substrates contain a stereogenic center that is β-positioned to amide functionality. Synthetic potential of the method was demonstrated by the constructions of novel β-lactam-fused heterocyclic compounds through convenient and practical chemical transformations.

Synthesis, Antimicrobial Evaluation, and Structure–Activity Relationship of α-Pinene Derivatives

Several (+)- and (-)-α-pinene derivatives were synthesized and evaluated for their antimicrobial activity toward Gram-positive bacteria Micrococcus luteus and Staphylococcus aureus, Gram-negative bacterium Escherichia coli, and the unicellular fungus Candida albicans using bioautographic assays. (+)-α-Pinene 1a showed modest activity against the test organisms, whereas (-)-α-pinene 1b showed no activity at the tested concentration. Of all the α-pinene derivatives evaluated, the β-lactam derivatives (10a and 10b) were the most antimicrobial. The increase in the antimicrobial activity of 10a compared to 1a ranged from nearly 3.5-fold (C. albicans) to 43-fold (S. aureus). The mean ± standard deviation for the zone of inhibition (mm) for 10a (C. albicans) was 31.9 ± 4.3 and that for S. aureus was 51.1 ± 2.9. Although (-)-α-pinene 1b was not active toward the test microorganisms, the corresponding β-lactam 10b, amino ester 13b, and amino alcohol 14b showed antimicrobial activity toward the test microorganisms. The increase in the antimicrobial activity of 10b compared to 1b ranged from 32-fold (S. aureus) to 73-fold (M. luteus). The mean ± standard deviation for the zone of inhibition (mm) for 10b (S. aureus) was 32.0 ± 0.60 and that for M. luteus was 73.2 ± 0.30.

SYNTHESIS AND EVALUATION OF SOME NOVEL TRIAZOLO BETA-LACTAM DERIVATIVES FOR THEIR ANTI-INFLAMMATORY ACTIVITY

A series of substituted triazole based β-Lactam derivatives were synthesized. The structures of the synthesized compounds were characterized and confirmed by IR, 1H- NMR and CHN analysis. The synthesized compounds were evaluated for their anti-inflammatory activity. All the compounds have shown promising anti-inflammatory activity when compared with standard drug Ibuprofen.

Synthesis of novel β-Lactam derivative and it’s application

In this study, synthesis of novel β-Lactam derivative comprising of β-Lactam moiety and NEPA-NCA ((R)-ethyl 2-(((S)-4-methyl-2,5-dioxo oxazolidin-3-yl)methyl)-4-phenylbutanoate) is disclosed. The antibacterial activity of compound-X, was screened by assaying against Staphylococcus aureus, Escherichia coli and Bacillus subtilis. Compound-X showed significant activity in vitro against the three tested bacteria at concentrations of 1 mg/1 ml, 1 mg/5ml and 1 mg/10ml. A suspension of (6R,7R)-7-amino-3-chloro-8-oxo-5-thia-1-aza-bicyclo(4,2,0)oct-2-ene-2-carboxylic acid (I) (25 g; 106.53 mili moles) and dichloromethane (300 ml) was heated to reflux with 107.91 milimoles of hexamethyldisilazane (HMDS) and 42.92 milimoles of trimethylchlorosilane (TMCS) for 4-6 hours. The solution containing (6R,7R)-trimethylsilyl-7-amino-3-chloro-8-oxo-5-thia-1-aza-bicyclo (4,2,0)oct-2-ene-2- carboxylate (II) i.e. silylated 7-ACCA was gradually cooled to room temperature (20-30°C) and subsequently added 122.5 milimoles of compound (III) i.e. NEPA-NCA. The above mixture was stirred for 2-3 hours then added water (250 ml) and tetrahydrofuran (125 ml) over a period of 10-20 minutes. The mixture was stirred at the same temperature for 30 -60 minutes to precipitate the product. Filtered the material and washed with

Novel β-Lactam derivative: Synthesis and application

In this study, synthesis of novel β-Lactam derivative comprising of 7-ACA and NEPA-NCA ((R)-ethyl 2-(((S)-4-methyl-2,5-dioxo oxazolidin-3-yl)methyl)-4-phenylbutanoate) justifying advancement in their stability and more biological activity at comparatively lower concentration over earlier reported analogous material (IOSR Journal of Applied Chemistry (IOSR-JAC) e-ISSN: 2278-5736.Volume 7, Issue 7 Ver. I. (July. 2014), PP 16-20, is disclosed. The antibacterial activity of compound-Y was screened by assaying against Staphylococcus aureus, Escherichia coli and Bacillus subtilis. Compound-Y showed significant activity in vitro against the three tested bacteria at concentrations of 1 mg/ml, 1 mg/5ml and 1 mg/10ml.

Class D β-Lactamases: A Reappraisal after Five Decades

Despite 70 years of clinical use, β-lactam antibiotics still remain at the forefront of antimicrobial chemotherapy. The major challenge to these life-saving therapeutics is the presence of bacterial enzymes (i.e., β-lactamases) that can hydrolyze the β-lactam bond and inactivate the antibiotic. These enzymes can be grouped into four classes (A-D). Among the most genetically diverse are the class D β-lactamases. In this class are β-lactamases that can inactivate the entire spectrum of β-lactam antibiotics (penicillins, cephalosporins, and carbapenems). Class D β-lactamases are mostly found in Gram-negative bacteria such as Pseudomonas aeruginosa , Escherichia coli , Proteus mirabilis , and Acinetobacter baumannii . The active-sites of class D β-lactamases contain an unusual N-carboxylated lysine post-translational modification. A strongly hydrophobic active-site helps create the conditions that allow the lysine to combine with CO2, and the resulting carbamate is stabilized by a number of hydrogen bonds. The carboxy-lysine plays a symmetric role in the reaction, serving as a general base to activate the serine nucleophile in the acylation reaction, and the deacylating water in the second step. There are more than 250 class D β-lactamases described, and the full set of variants shows remarkable diversity with regard to substrate binding and turnover. Narrow-spectrum variants are most effective against the earliest generation penicillins and cephalosporins such as ampicillin and cephalothin. Extended-spectrum variants (also known as extended-spectrum β-lactamases, ESBLs) pose a more dangerous clinical threat as they possess a small number of substitutions that allow them to bind and hydrolyze later generation cephalosporins that contain bulkier side-chain constituents (e.g., cefotaxime, ceftazidime, and cefepime). Mutations that permit this versatility seem to cluster in the area surrounding an active-site tryptophan resulting in a widened active-site to accommodate the oxyimino side-chains of these cephalosporins. More concerning are the class D β-lactamases that hydrolyze clinically important carbapenem β-lactam drugs (e.g., imipenem). Whereas carbapenems irreversibly acylate and inhibit narrow-spectrum β-lactamases, class D carbapenemases are able to recruit and activate a deacylating water. The rotational orientation of the C6 hydroxyethyl group found on all carbapenem antibiotics likely plays a role in whether the deacylating water is effective or not. Inhibition of class D β-lactamases is a current challenge. Commercially available inhibitors that are active against other classes of β-lactamases are ineffective against class D enzymes. On the horizon are several compounds, consisting of both β-lactam derivatives and non-β-lactams, that have the potential of providing novel leads to design new mechanism-based inactivators that are effective against the class D enzymes. Several act synergistically when given in combination with a β-lactam antibiotic, and others show a unique mechanism of inhibition that is distinct from the traditional β-lactamase inhibitors. These studies will bolster structure-based inhibitor design efforts to facilitate the optimization and development of these compounds as class D inactivators.

Synthesis and Studies on Some Spiro and Fused of Quinone Derivatives

Some new Spiro β-lactam, Spiro thiazolidine derivatives were synthesized by the reaction of new Schiff bases (5a-c, 8a-c ) with chloroacetyl chloride and/or mercaptoacetic acid to give new Spiro β-lactam (6a-c, 9a-c ) and new Spiro thiazolidinone derivatives (7a-c, 10a-c ) . Also, new fused pyrazolo derivatives (12a-c, 13a-c) fused isoxazolo derivatives (14a-c) and pyrimidine derivatives (15a-c, 16a-c) were synthesized by the reaction of new arylidine derivatives (11a-c) with hydrazine hydrate, phenyl hydrazine, hydroxylamine hydrochloride, urea and thiourea, respectively.

Preparation and ring transformation of isomeric β-lactam derivatives of bicyclic 1,3-thiazines

Ketene–imine cycloaddition reactions between cis- and trans-2-aryl-4a,5,6,7,8,8a-hexahydro-4H-3,1-benzothazines and chloroacetyl chloride in the presence of base were investigated. Because of the diastereotopic CN faces of cyclohexane-condensed thiazines, both of the possible Staudinger addition product monochloro-β-lactam stereoisomers were obtained for both the cis and the trans compounds. The novel azetidin-2-ones were transformed into the corresponding 3-ethoxycarbonyl-2-aryl-1,5,5a,6,7,8,9,9a-octahydro-4,1-benzothiazepines with sodium ethoxide in a one-step procedure. Structural and stereochemical analyses of the synthesized compounds were carried out by means of IR and NMR spectroscopy.

Synthesis and studies of pyrazolo[3,4-b]piperidin-4-one derivatives

A series of isolated/fused of pyrazole, isoxazolo, pyrimidine, pyrimidine thione, spiro thiazolodine and spiro β-lactam derivatives incorporating to 4-acetyl-5-amino-3-methyl-1-phenyl-2-pyrazoline have been synthesized by different methods of chemical reactions. The structure assignments of these compounds, based on chemical and spectroscopic evidence were deduced from their IR, 1 H NMR, elemental analysis and mass spectrometry.

Synthesis and studies of pyrazolo[3,4-b]pyridin-4-one derivatives

A series of isolated/fused of pyrazole, isoxazolo, pyrimidine, pyrimidine thione, spiro thiazolodine and spiro β-lactam derivatives incorporating to 4-acetyl-5-imino-3-methyl-1-phenyl-2-pyrazoline have been synthesized by different methods. The structure of chemical reactions based on chemical and spectroscopic evidence. The detailed synthesis and spectroscopic data were reported.

Aromatic Spiroketal Bisphosphine Ligands: Palladium‐Catalyzed Asymmetric Allylic Amination of Racemic Morita–Baylis–Hillman Adducts

Showing a backbone: The spiroketal backbone of the bis(phosphine) ligand 1 led to good regio- and enantioselectivity in the palladium-catalyzed asymmetric allylic amination of racemic Morita–Baylis–Hillman adducts with aromatic amines. The methodology provides a facile and efficient synthesis of precursors for optically active β-lactam derivatives, including the cholesterol drug Ezetimibe.

Synthesis of β-lactams with π electron-withdrawing substituents

β-Lactams are crucial structural feature of β-lactam antibiotics and important intermediates in synthetic and pharmaceutical chemistry. Synthetic methods for β-lactams with π electron-withdrawing substituents, such as formyl (carbaldehyde), acyl, imino, carboxylic acids, carboxylates, carboxamides, cyano (carbonitriles), and nitro groups, on their 3- and/or 4-position(s) are presented in this review. The methods are divided mainly into intramolecular cyclizations, cycloaddition, and other methods, for example, Ugi-type reaction of β-keto acids, amines, and isonitriles, and modification of β-lactam derivatives. Cyclizations include cyclization of haloacetamidoacetates(malonates), intramolecular carbene insertion of α-diazoalkanamides, ring-opening cyclization of α,β-epoxyalkanamidoacetates, oxidative coupling of 3-oxoalkanamidoacetates, oxidative cyclization of N-p-hydroxyphenyl β-oxoalkanamides, intramolecular cyclization of aspartic acid derivatives or β-hydroxyalkanamides, and radical cyclization of N-vinyl β-oxoalkanamides. Cycloadditions incorporate Staudinger cycloaddition of ketenes and imines, cycloaddition of nitrones and alkynes, cycloaddition of nitrones and alkylidenecycopropanes and subsequent acidic rearrangement, and condensation of imines and enolates (ethers) of esters. The scope, limitation, and stereoselectivity are also discussed for some methods. Most of the β-lactam derivatives are key intermediates or precursors for preparation of β-lactam antibiotics and their analogs.

Rh2(OAc)4 catalyzed substrate selective [4+2]/[2+2] cycloaddition of acylketenes: a highly chemo- and regioselective synthesis of spiro(oxindolyl)oxazinones and β-lactams

A rhodium(II) catalyzed [4+2]/[2+2] cycloaddition reaction of N-protected isatin-3-arylimine with acylketene derived from α-diazocarbonyl compounds has been achieved for the first time for the preparation of a novel class of spiro(oxindolyl)oxazinone and spiro(oxindolyl)-β-lactam derivatives.

Stereoselective synthesis of sugar-based β-lactam derivatives: docking studies and its biological evaluation

Highly diastereoselective synthesis of cis-β-lactams via [2+2] cycloaddition reactions of sugar-imine derivative possessing free hydroxyl groups at C-2 and C-3 positions and ketenes is described. exo-Approach of sugar-imine with ketene leads to the stereoselective formation of cis product and it is facilitated by hydrogen bonding interaction of C2–OH with carbonyl group of ketene. Docking studies show that these derivatives are having greater affinity towards PBP and it has been validated by in vivo studies. Among the different sugar-based azetidine-2-ones, compounds 6a and 6d were superior in activity to the commercial antibiotic tetracycline.

Synthesis of Some New Isolated/Spiro β-Lactam and Thiazolidinone Incorporating Fused Thieno Pyrimidine Derivatives

Some new spiro β-Lactam and thiazolidinone derivatives were prepared from the reaction of 5 with different aromatic amine to give Schiff bases 6a-c followed by cycloaddition reaction with chloroacetyl chloride and/or mercaptoacetic acid to give spiro β-Lactam derivatives 7a-c and spiro thiazolidinone 8a-c. Also Isolated β-Lactam 11a-c and Isolated thiazolidinone were prepared by the reaction of Schiff bases 10a-c with chloroacetyl chloride and/or mercaptoacetic acid, pyrazolo 14,10a-c. Isoxazolo 16a-c, pyrimidino 17a c, pyrimidin thiono 18a-c Incorporating thieno pyrimidine 9 has been synthesized by cyclocondensation addition reaction of hydrazine hydrate, phenyl hydrazine, hydroxylamine hydrochloride, urea and thiourea

Synthesis of new steroid-β-lactam hybrids via palladium-catalyzed aminocarbonylation

Steroid-β-lactam and steroid-β-lactam-ferrocene conjugates were synthesized via palladium-catalyzed carbonylation of steroidal 17-iodo-16-enes in the presence of 3-amino-azetidin-2-ones. β-Lactam derivatives have been used for the first time as nucleophiles in the aminocarbonylation reaction. The products were obtained in good yields and were characterized by 1H and 13C NMR, IR and HRMS.

Crotonase Catalysis Enables Flexible Production of Functionalized Prolines and Carbapenams

The biocatalytic versatility of wildtype and engineered carboxymethylproline synthases (CMPSs) is demonstrated by the preparation of functionalized 5-carboxymethylproline derivatives methylated at C-2, C-3, C-4, or C-5 of the proline ring from appropriately substituted amino acid aldehydes and malonyl-coenzyme A. Notably, compounds with a quaternary center (at C-2 or C-5) were prepared in a stereoselective fashion by engineered CMPSs. The substituted-5-carboxymethyl-prolines were converted into the corresponding bicyclic β-lactams using a carbapenam synthetase. The results demonstrate the utility of the crotonase superfamily enzymes for stereoselective biocatalysis, the amenability of carbapenem biosynthesis pathways to engineering for the production of new bicyclic β-lactam derivatives, and the potential of engineered biocatalysts for the production of quaternary centers.

Facile synthesis of 3-(1-(4'-(3-chloro-2-(substituted phenyl)-4-oxoazetidin-1-yl)biphenyl-4-yl)-5-oxo-2-phenyl-1H-imidazol-4(5H)-ylidene)indolin-2-ones: β-Lactam derivatives as antimicrobes

A facile synthesis of b-lactam derivatives; 3-(1-(4'-(3-chloro-2-(substituted phenyl)-4-oxoazetidin-1-yl)biphenyl-4-yl)-5-oxo-2-phenyl-1 H -imidazol-4(5 H )-ylidene)indolin-2-ones ( 6a - e ) and 3-(1-(3-chloro-2-(substituted phenyl)-4-oxoazetidin-1-yl)-5-oxo-2-phenyl-1 H -imidazol-4(5 H )-ylidene)indolin-2-ones ( 7a - e ) is described herein. The title compounds 6a - e and 7a - e were evaluated for their in vitro antimicrobial activity against Candida albicans and Bacillus subtilis respectively using a two fold serial dilution technique. Investigation revealed that 2-hydroxy phenyl function at b-lactam ring in compounds 6d and 7d is a key factor for both antifungal and antibacterial activity, as newly designed compounds 6d and 7d exhibited good biological activity with minimum inhibitory concentration (MIC)12.5 mg/mL against Candida albicans and Bacillus subtilis respectively.

Purification, crystallization and preliminary X-ray crystallographic analysis of PBP4 fromListeria monocytogenes

Penicillin-binding proteins (PBPs), which catalyze peptidoglycan synthesis, have been extensively studied as a well established target of antimicrobial agents, including β-lactam derivatives. However, remarkable resistance to β-lactams has developed among pathogenic bacteria since the clinical use of penicillin began. Recently, the glycosyltransferase (GT) domain of class A PBPs has been proposed as an attractive target for antibiotic development as moenomycin-bound GT-domain structures have been determined. In this study, a class A PBP4 from Listeria monocytogenes was overexpressed, purified and crystallized using the hanging-drop vapour-diffusion method. Diffraction data were collected to 2.1 Å resolution using synchrotron radiation. The crystal belonged to the primitive orthorhombic space group P2(1)2(1)2, with unit-cell parameters a = 84.6, b = 127.8, c = 54.9 Å. The structural information will contribute to the further development of moenomycin-derived antibiotics possessing broad-spectrum activity.

Pd-Catalyzed Carbonylation of Diazo Compounds at Atmospheric Pressure: A Catalytic Approach to Ketenes

The carbonylation of carbenes through catalytic cycles is highly desirable due to the importance of ketene-mediated reactions in organic synthesis. In this investigation, a highly efficient and mild catalytic approach toward ketene intermediates has been developed based on Pd-catalyzed carbonylation of diazo compounds with CO. When α-diazocarbonyl compounds or N-tosylhydrazone salts are heated in the presence of a palladium catalyst under atmospheric pressure of CO, ketene intermediates are formed in situ, where they undergo further reactions with various nucleophiles such as alcohols, amines, or imines. The Pd-catalyzed tandem carbonylation-Staudinger cycloaddition gives β-lactam derivatives in good yields with excellent trans diastereoselectivity. The results from DFT calculation on the reaction mechanism suggest that Pd is involved in the [2 + 2] cycloaddition process and affects the diastereoselectivity of the β-lactam products by assisting isomerization of the addition intermediate. On the other hand, the acylketenes generated from the Pd-catalyzed carbonylation of α-diazoketones react with imines in a formal [4 + 2] cycloaddition manner to afford 1,3-dioxin-4-one derivatives. This straightforward carbonylation provides a new approach toward highly efficient catalytic generation of ketene species under mild conditions.