Azetidinone Ring Research Articles

Acid Hydrolytic Degradation Profiling of Ezetimibe: Identification, Isolation, and Structural Elucidation of Its Degradants

ABSTRACTEzetimibe (EZE) is a dyslipidemic agent used to treat hyperlipidemia along with statins and diet changes. To ascertain the drug's degradation profile, stress tests were conducted on it in accordance with International Council for Harmonization recommendations. An ultrahigh‐performance liquid chromatography–mass spectrometry method was developed and validated for the identification and quantification of EZE and its degradants. Using preparative high‐performance liquid chromatography, all impurities were isolated, and their structures were characterized thoroughly using advanced spectral techniques. The drug was relatively stable in basic, peroxide, photolytic, and thermal conditions; however, five degradants were observed in acid degradation. Among the five degradants, three degradation products eluted as Peak‐1, Peak‐2, and Peak‐3 which were found to be novel impurities that were not reported previously. However, the remaining two impurities were identified as Peak‐4 and Peak‐5, despite the insufficient information available. The present study has focused on the isolation of these five acid degradation products and the structural confirmation of these degradants by highly efficient spectral techniques. Moreover, the possible degradation mechanism of the azetidinone ring in the presence of acid has been explained, which might be helpful in determining the quality and purity of EZE and similar pharmaceutical compounds.

Synthesis and Antibacterial Activities of Amidine Substituted Monocyclic β-Lactams.

Mononcyclic β-lactams are regarded as the most resistant class of β-lactams against a series of β-lactamases, although they possess limited antibacterial activity. Aztreonam, being the first clinically approved monobactam, needs broad-spectrum efficacy through structural modification. We strive to synthesize a number of monocyclic β-lactams by varying the substituents at N1, C3, and C4 positions of azetidinone ring and study the antimicrobial effect on variable bacterial strains. Seven new monobactam derivatives 23a-g, containing substituted-amidine moieties linked to the azetidinone ring via thiazole linker, were synthesized through multistep synthesis. The final compounds were investigated for their in vitro antibacterial activities using the broth microdilution method against ten bacterial strains of clinical interest. The minimum inhibitory concentrations (MICs) of newly synthesized derivatives were compared with aztreonam, ceftazidime, and meropenem, existing clinical antibiotics. All compounds 23a-g showed higher antibacterial activities (MIC 0.25 μg/mL to 64 μg/mL) against tested strains as compared to aztreonam (MIC 16 μg/mL to >64 μg/mL) and ceftazidime (MIC >64 μg/mL). However, all compounds, except 23d, exhibited lower antibacterial activity against all tested bacterial strains compared to meropenem. Compound 23d showed comparable or improved antibacterial activity (MIC 0.25 μg/mL to 2 μg/mL) to meropenem (MIC 1 μg/mL to 2 μg/mL) in the case of seven bacterial species. Therefore, compound 23d may be a valuable lead target for further investigations against multi-drug resistant Gram-negative bacteria.

Substituted-Amidine Functionalized Monocyclic β-Lactams: Synthesis and In Vitro Antibacterial Profile

Background. Owing to the intrinsic stability against common β-lactamases and metallo-lactamases, monobactams gathered special attention in antibiotic drug development. However, so far, aztreonam is the only monobactam approved by FDA for clinical use. We designed new derivatives of aztreonam to enhance its antibacterial efficacy. Methods. We synthesized a series of monocyclic β-lactams by modifying mainly at the C3 position of azetidinone ring. NH2 group at C3 of azetidinone was attached to thiazole and thiadiazole which in turn was linked to nitrogenous heterocyclic rings via amidine moieties. We then investigated the in vitro antibacterial activities of synthesized compounds against ten bacterial strains of clinical interest in comparison to aztreonam and ceftazidime. Results. All compounds showed improved antibacterial activities against tested strains compared to reference drugs. Compounds 14d and 14e were most potent and showed the highest potency against all bacterial strains, with MIC values ranging from 0.25 µg/mL to 8 µg/mL, as compared to aztreonam (MIC 16 µg/mL to >64 µg/mL) and ceftazidime (MIC >64 µg/mL). These compounds (14d and 14e) may be valuable lead targets against multidrug-resistant Gram-negative bacteria.

The Odd Couple(s): An Overview of Beta-Lactam Antibiotics Bearing More Than One Pharmacophoric Group.

β-lactam antibiotics are among the most important and widely used antimicrobials worldwide and are comprised of a large family of compounds, obtained by chemical modifications of the common scaffolds. Usually these modifications include the addition of active groups, but less frequently, molecules were synthesized in which either two β-lactam rings were joined to create a single bifunctional compound, or the azetidinone ring was joined to another antibiotic scaffold or another molecule with a different activity, in order to create a molecule bearing two different pharmacophoric functions. In this review, we report some examples of these derivatives, highlighting their biological properties and discussing how this strategy can lead to the development of innovative antibiotics that can represent either novel weapons against the rampant increase of antimicrobial resistance, or molecules with a broader spectrum of action.

New compounds for a good old class: Synthesis of two Β-lactam bearing cephalosporins and their evaluation with a multidisciplinary approach

Antimicrobial resistance is spreading massively in the world and is becoming one of the main health threats of the 21st century. One of the possible strategies to overcome this problem is to modify the known classes of antibiotics in a rational way, with the aim of tuning their efficacy. In this paper, we present the synthesis and the evaluation of the biological activity of a series of two β-lactam bearing cephalosporin derivatives, in which an additional isolated azetidinone ring, bearing different substituents, is joined to the classical cephalosporanic nucleus by a chain of variable length. A computational approach has been also applied in order to predict the molecular interactions between some representative derivatives and selected penicillin-binding proteins, the natural targets of β-lactam antibiotics. All these derivatives are active against Gram-positive bacteria, with MIC100 comparable or even better than that of the reference antibiotic ceftriaxone, and show no or very low cytotoxic activity on different cell lines. Overall, these molecules appear to be able to exert their activity in particular against microorganisms belonging to some of the species more involved in the development of multidrug resistance.

Design, synthesis, and evaluation of antitubercular activity of a novel benzothiazole-containing an azetidinone ring

DOI: 10.5152/IstanbulJPharm.2018.320135 Recent studies have demonstrated that 2-amino-substituted benzothiazole derivatives exhibit significant antitubercular activity. In this study, new compounds of benzothiazole-containing azetidinone derivatives were designed and synthesized using substituted benzaldehydeN-(5fluoro-1,3-benzothiazol-2-yl) semicarbazone, chloroacetyl chloride, and triethylamine in DMF. The structures of the synthesized compounds were characterized by TLC, IR, elemental analysis, and 1H NMR. In vitro screening data revealed that all the designed and synthesized compounds A6–A10 exhibited the ability to inhibit the growth of Mycobacterium tuberculosis in terms of MIC. Variable and modest activity was observed against the investigated strains of bacteria; however, the compound A6 exhibited significant antitubercular activity against M. tuberculosis H37Rv (MTCC 200) compared to that of the reference drugs isoniazid and rifampicin. These experimental data were consistent with our computational predictions in terms of the compound A6 that exhibited a satisfactory backbone for the antitubercular activity, perhaps due to an increase in hydrophobicity resulting in better penetration through the cell wall of M. tuberculosis.

Photoassisted access to complex polyheterocycles containing a β-lactam moiety.

Intramolecular cycloadditions of aza-o-xylylenes generated via excited state intramolecular proton transfer (ESIPT) to furanacetic acid-based unsaturated pendants was shown to overcome the unfavorable energetics of the azetidinone ring formation, offering rapid access to β-lactams as primary photoproducts. These 2,3- and 3,4-dihydrofuran-containing reactive intermediates are suitable for a broad spectrum of postphotochemical transformations yielding complex polyheterocyclic molecular architectures possessing the β-lactam moiety.

ChemInform Abstract: Highly Stereoselective Synthesis of Isoindole Derivatives Containing an Azetidinone Ring.

AbstractIsoindolylbutanoic acid (I) reacts with aromatic imines [e.g. (II) and (IV)] to give trans‐β‐lactams [e.g. (III) and (V)] stereoselectively via [2 + 2]‐cycloaddition of a ketene intermediate and imines.

Approach to Monobactams and Nocardicins via Diastereoselective Kinugasa Reaction.

A Kinugasa reaction between copper(I) acetylides and cyclic nitrones derived from chiral amino alcohols and glyoxylic acid is reported. The stereochemical preferences observed in this reaction are discussed. The alkyne molecule approaches the nitrone exclusively anti to the large substituent next to the nitrogen atom to provide the cis-substituted β-lactam ring preferentially. The six-membered oxazinone ring can be opened by reduction with lithium borohydride. Deprotection of the β-lactam nitrogen atom can be achieved by lithium in liquid ammonia reduction or by CAN oxidation, depending on the substituents attached to the four-membered azetidinone ring. The adducts obtained by the Kinugasa reaction provide an attractive entry to a variety of monocyclic β-lactam structures related to monobactams and nocardicins.

Synthesis of Thienamycin methyl ester from 2-deoxy-D-ribose via Kinugasa reaction.

A novel synthesis of thienamycin is described. The crucial step of the synthesis is based on Cu(I)-mediated Kinugasa cycloaddition/rearrangement cascade reaction between terminal acetylene derived from D-lactic acid and suitable, partially protected, five-membered cyclic nitrone obtained from 2-deoxy-D-ribose. The reaction was performed in the presence of tetramethylguanidine as a base to provide 5,6-trans substituted carbapenam as the main product. Thus obtained carbapenam 11 with (5R,6S) configuration at the azetidinone ring was subsequently subjected to oxidation/deprotection/oxidation reaction sequence to afford the β-keto ester 20, which was directly transformed into N,O-protected methyl ester of thienamycin.

Highly Stereoselective Synthesis of Isoindole Derivatives Containing an Azetidinone Ring

Isoindole derivatives containing an azetidin-2-one moiety were prepared from phthalic anhydride by an approach that involves a [2π+2π] cycloaddition of an imine to a novel ketene generated in situ, and an electrocyclic reaction of a zwitterionic intermediate. The reactions were highly stereoselective and trans-β-lactams were obtained as the sole observed products.

Isolation and structure determination of the first example of the azeto[2,3-c]quinolizinedione ring system

An unexpected azeto[2,3-c]quinolizinedione has been isolated during synthetic studies on the base catalyzed condensation of ethyl 6-methylpyridin-2(1H)-on-1-ylacetate with benzil. Closure of a fused four-membered azetidinone ring occurred when potassium hexamethyldisilazide was employed as the base. The structure of the product was confirmed by synchrotron X-ray crystallography. A possible mechanism for the formation of the product is considered.

Synthesis of Benzthiazole Derivatives Grouping with Substituted Azetidinone Ring and its Functional Behaviour

A series of Schiff derivatives (5a-q) and azetidinone by way of amide linkage analogues (6a-q) containing 2-amino benzthiazole have been synthesized. Amide linkage were adapted from acid via reaction with hydrazine hydrate followed by reaction with different substituted aldehyde derived various Arylidene derivatives comprising with various donor and acceptor functional group. The structures of the new synthesized azetidinone derivatives were characterized on the basis of 1H-NMR, Mass, IR and elemental analysis data.

Synthesis of Benzthiazole Derivatives Grouping with Substituted Azetidinone Ring and its Functional Behaviour

A series of Schiff derivatives (5a-q) and azetidinone by way of amide linkage analogues (6a-q) containing 2-amino benzthiazole have been synthesized. Amide linkage were adapted from acid via reaction with hydrazine hydrate followed by reaction with different substituted aldehyde derived various Arylidene derivatives comprising with various donor and acceptor functional group. The structures of the new synthesized azetidinone derivatives were characterized on the basis of 1H-NMR, Mass, IR and elemental analysis data.

Synthesis of 2-(3-methyl-2-oxoquinoxalin-1(2H)-yl)acetamide-based azetidinone derivatives as potent antibacterial and antifungal agents

Twelve compounds belonging to series N-[3-chloro-2-oxo-4-(substituted)phenylazetidin-1-yl]-2-(3-methyl-2-oxoquinoxalin-1(2H)-yl)acetamide (5a–l) were synthesized. These compounds were evaluated for their in vitro antibacterial against E. coli, S. aureus, K. pneumoniae, P. aeruginosa and antifungal activity against C. albicans, A. niger and A. flavus by cup-plate method. Structures of all the newly synthesized compounds were confirmed by their spectral data interpretation. Compound 5g having p-dimethylaminophenyl group on 4-position of azetidinone ring attached to N-atom of acetamido group on 1-position of 3-methyl-1H-quinoxaline-2-one, was found to be active against all the bacterial and fungal strains under investigation. A new series of compounds belonging to N-[3-chloro-2-oxo-4-(substituted) phenylazetidin-1-yl]-2-(3-methyl-2-oxoquinoxalin-1(2H)-yl)acetamide was synthesized and all the newly synthesized compounds were evaluated for their in vitro antibacterial and antifungal activities.

Monocyclic β-Lactams: New Structures for New Biological Activities

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.

A Formal Synthesis of Ezetimibe via Cycloaddition/Rearrangement Cascade Reaction

A formal synthesis of a powerful cholesterol inhibitor, ezetymibe 1, is described. The crucial step of the synthesis is based on Cu(I)-mediated Kinugasa cycloaddition/rearrangement cascade reaction between terminal acetylene derived from acetonide of L-glyceraldehyde and suitable C,N-diarylnitrone. The adduct with (3R,4S) configuration at the azetidinone ring, obtained with high stereoselectivity, was subsequently subjected to deprotection of the diol side chain followed by glycolic cleavage and base-induced isomerization at the C3 carbon atom to afford the (3S,4S) aldehyde, which has been already transformed into ezetimibe by the Schering-Plough group.

Synthesis, evaluation and structural studies of antiproliferative tubulin-targeting azetidin-2-ones

A series of azetidin-2-ones substituted at positions 1, 3 and 4 of the azetidinone ring scaffold were synthesised and evaluated for antiproliferative, cytotoxic and tubulin-binding activity. In these compounds, the cis double bond of the vascular targeting agent combretastatin A-4 is replaced with the azetidinone ring in order to enhance the antiproliferative effects displayed by combretastatin A-4 and prevent the cis/ trans isomerisation that is associated with inactivation of combretastatin A-4. The series of azetidinones was synthetically accessible via the Staudinger and Reformatsky reactions. Of a diverse range of heterocyclic derivatives, 3-(2-thienyl) analogue 28 and 3-(3-thienyl) analogue 29 displayed the highest potency in human MCF-7 breast cancer cells with IC 50 values of 7 nM and 10 nM, respectively, comparable to combretastatin A-4. Compounds from this series also exhibited potent activity in MDA-MB-231 breast cancer cells and in the NCI60 cell line panel. No significant toxicity was observed in normal murine breast epithelial cells. The presence of larger, bulkier groups at the 3-position, for example, 3-naphthyl derivative 21 and 3-benzothienyl derivative 26, resulted in relatively lower antiproliferative activity in the micromolar range. Tubulin-binding studies of 28 (IC 50 = 1.37 μM) confirmed that the molecular target of this series of compounds is tubulin. These novel 3-(thienyl) β-lactam antiproliferative agents are useful scaffolds for the development of tubulin-targeting drugs.

ChemInform Abstract: Synthesis of 4‐Aryl‐azetidinones via Intramolecular Alkylation of Nucleophilic Arenes Using Acyliminium Cations.

AbstractVinyloxy‐ or formyloxyazetidinones bearing N‐(arylthiomethyl) or N‐(aryloxymethyl) substituents (I) and (IX) undergo Lewis acid‐mediated intramolecular arylation of the azetidinone ring to give azetidine‐fused thiazine (II) or oxazine derivatives (X).

ChemInform Abstract: Preparation of Chiral 3-Unsubstituted β-Lactams from 3-Hydroxy . beta.-Lactams by Using the Alkoxyketene-Imine Cycloaddition Reaction as an Approach to the Azetidinone Ring: A Formal Synthesis of the Carbapenem Antibiotic (+)-PS-5 (I)

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