Azetidine Derivatives Research Articles

Synthesis and neuroprotective activity of 3-aryl-3-azetidinyl acetic acid methyl ester derivatives.

A library of 3-aryl-3-azetidinyl acetic acid methyl ester derivatives was prepared from N-Boc-3-azetidinone employing the Horner-Wadsworth-Emmons reaction, rhodium(I)-catalyzed conjugate addition of arylboronic acids, and subsequent elaborations to obtain N-unprotected hydrochlorides, N-alkylated and N-acylated azetidine derivatives. The compounds were evaluated for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity, revealing several derivatives to possess AChE inhibition comparable to that of the AChE inhibitor rivastigmine. The binding mode of the AChE inhibitor donepezil and selected active compounds 26 and 27 within the active site of AChE was studied using molecular docking. Furthermore, the neuroprotective activity of the prepared compounds was evaluated in models associated with Parkinson's disease (salsolinol-induced) and aspects of Alzheimer's disease (glutamate-induced oxidative damage). Compound 28 showed the highest neuroprotective effect in both salsolinol- and glutamate-induced neurodegeneration models, and its protective effect in the glutamate model was revealed to be driven by a reduction in oxidative stress and caspase-3/7 activity.

Photosensitized [4+2]- and [2+2]-Cycloaddition Reactions of N-Sulfonylimines.

The synthesis of polycyclic compounds is of high interest due to the prevalence of these motifs in drugs and natural products. Herein, we report on the stereoselective construction of 3D bicyclic scaffolds and azetidine derivatives by modulation of N-sulfonylimines to achieve either [4+2]- or [2+2]-cycloaddition reactions. The utility of the method was established by further modulation of the product. Mechanistic studies are also included, which support reaction via Dexter energy transfer.

Photosensitized [4+2]‐ and [2+2]‐Cycloaddition Reactions of N‐Sulfonylimines

AbstractThe synthesis of polycyclic compounds is of high interest due to the prevalence of these motifs in drugs and natural products. Herein, we report on the stereoselective construction of 3D bicyclic scaffolds and azetidine derivatives by modulation of N‐sulfonylimines to achieve either [4+2]‐ or [2+2]‐cycloaddition reactions. The utility of the method was established by further modulation of the product. Mechanistic studies are also included, which support reaction via Dexter energy transfer.

Theoretical Study of Azetidine Derivative by Quantum Chemical Methods, Molecular Docking and Molecular Dynamic Simulations

AbstractAzetidine substituent group has a wide range of application in organic chemistry and medical field. In this study, a novel azetidine derivative and its reaction mechanism has been reported. Using quantum chemical method spectroscopic analysis and other parameters such as electronic and thermodynamic properties were studied to understand the physical as well as chemical behavior of the reported compound. Additionally, to study the antiviral activity, molecular docking studies were carried out against Hepatitis virus C (HCV) NS5B genotype and Norovirus as target protein. In order to validate the docking results molecular dynamic (MD) simulation and Molecular Mechanics‐Poisson‐Boltzmann Surface Area (MM‐PBSA) were calculated at 90 ns. The RMSD was obtained within the range 0.75 Å to 1.5 Å and binding energies (ΔGbind) for the two complexes was found to be −18.34 kJ/mol and −16.10 kJ/mol for each respective targets.It was found that reported compound can act as potential inhibitor for HCVand Norovirus.

Current and Future Prospects of Azetidine Derivatives an Overview

Due to the intrinsic ring strain of azetidine derivatives, there are numerous challenges involved in their synthesis. Its derivatives have several important applications, such as antibacterial, antifungal, anticancer, antitubercular, antioxidant, etc. This review provides the impact of recent advances in the synthesis of azetidines and their derivatives. It gives an overview of the different therapeutic uses of azetidines, with various structures and degrees of control. This elaborate review will furnish a basis for the progress of future azetidines to fight the various microbes which have developed their resistance against current medications.

Optical fiber bundle fluorescence sensor for a triacetone triperoxide vapor detection of trace explosives

A novel optical fiber bundle sensor was proposed for a triacetone triperoxide (TATP) vapor detection of a volatile trace explosive, which was coated with the azetidine derivative of naphthalene diimides (DNNDI) fluorescence film on a reflection probe. The sensor mechanism was studied based on a fluorescence quenching principle. The effects of the sensor structural parameters on the fiber fluorescence coupling efficiency were analyzed by a Monte Carlo method. The results show that the coupling efficiency increases with the increase of the thickness of the film and the core diameter of the collection fiber. When the core diameter of the collection fiber was 400 µm, the thickness of the film was 16 µm, and the coupling distance was 2000 µm, the fluorescence efficiency reached 9%. The DNNDI was synthesized, and the fluorescent film was prepared through a respiratory pattern method. The sensitivity of the two sensors with the film thickness of 12.85 µm and 16.11 µm for the TATP vapor was 446.50/ ppb and 405.50/ ppb, respectively. The limits of detection reached 19.40 ppb and 21.40 ppb, respectively.

Synthesis of some new oxazepine compounds derived from cyanoethyl acetate and study their inhibitory activity against some pathogenic bacterial species

Involves synthesis of Schiff bases (hydrazone) by the reaction of acid hydrazide(D1) (which is prepared from the reaction of cyanoethyl acetate with hydrazine hydrate at (85%) with aromatic aldehydes to obtain compounds (D2-6) and by the reaction of compounds (D2-6) with phthalic anhydride Compounds (D7-11) are obtained, the biological activity of the prepared compounds is studied through two types of Gram-positive and Gram-negative bacteria Staph. aureus, Escherichia Coli and Compare it with one type of antibiotic (Gentamycin). The validity of the structures is confirmed by spectroscopic methods (FTIR, 1H-NMR, 13C-NMR, MASS). The disk diffusion assay technique was used to investigate the antibacterial activity in vitro against two types of bacteria: gram-positive and gram harmful bacteria. The minimum inhibitory concentration [MIC] was measured using standard medications. The findings revealed that azetidine derivatives outperformed drugs in inhibiting the growth of both gram-positive and gram-negative bacteria.

MOLECULAR DOCKING STUDIES, IN SILICO ADMET SCREENING OF SELECTED NOVEL AZETIDINE SUBSTITUTED NAPHTHALENE’S TARGETING PROTEASE ENZYME AGAINST SARS COV-19

The emergence and dissemination of SARS COVID-19 has resulted in a high death rate, necessitating a large-scale search for viable antiSARS COVID-19 therapeutics. The binding mechanisms of 25 azetidines bearing naphthalene derivatives as Anti-SARS COVID-19 inhibitors, targeting protease enzyme via molecular docking, ADME and Toxicity Prediction (TOPKAT) investigations were investigated in this work, and they were compared to the FDA-approved medicine remdesivir. Compounds 22, 18, 17, 14 had the highest Lib Dock score among the 25 derivatives, with the X-ray crystallographic structure of M pro (PDB ID: 6LU7) revealing important interactions with residues Glu166, Gln192, Ala191, Thr190, Ser144, Cys145. These findings imply that these azetidine derivatives may be useful in the development of more effective anti-SARS COVID-19 agents. Keywords: Main protease enzyme, SARS COVID-19, Azetidines, Naphthalenes, In-silicoscreening

Material design and biologically activity of some new azetidines and azetidine-2-ones as antioxident

The antioxidant activity of the produced compounds was tested in vitro. The DPPH radical scavenging activity of azetidinens and azetidine-2-ones seemed promising. The synthesis of azetidine derivatives is the focus of this research. With modest yields, these compounds were made by reacting alkyl halides with (imines) in ethanol at 70–60 °C (51–75 percent). Also, the response. The main focus of this research is on the synthesis and characterization of Imine compounds. These compounds are made by reacting an amine with an aldehyde or ketones in methanol and then adding drops of glacial acetic acid under reflux. The synthesis and characterisation of Azitidine-2-one 2 are also part of this research (A-). These chemicals are made by combining Schiff's bases with triethylamine and chloroacetyle chloride in the presence of triethylamine. Moderately administer the appropriate beta-lactams in dry dichloromethane withStir at 0 °C.

Reusable ZnCr2O4 Nano Catalyzed One Pot Three-Component Cycloaddition Reaction for Synthesis of Azetidine Derivatives under Ultrasound Irradiation

A versatile and effectual, three-component one pot (2π + 2π) cycloaddition reaction to the synthesis of substituted azetidines in the excellent yields is described. The reaction of isonicotinic acid hydrazide (1) as starting materials. Design and preparation of N-(7-R)-2-oxa-8-azabicyclo[4.2.0]octan-8-yl)isonicotinamide derivatives (4a-h) was carried out by condensation of isoniazid (1) with aromatic aldehyde (2a-h), ZnCr2O4 nano catalyzed one-pot cycloaddition of isoniazid Schiff base with pyran (3) under ultrasonic irradiation. Moreover, the Prepared ZnCr2O4 nanoparticles were easily recovered by corresponding solvent and reused for next synthesis of derivatives without significant loss of their catalytic activity. Prepared ZnCr2O4 nanoparticles were confirmed by XRD, EDX, TEM, HRTEM, TGA-DTA and all substituted azetidines were characterized by 1H NMR, 13C NMR, FT-IR, mass and elemental analysis.

Theoretical Study on the Photo-Oxidation and Photoreduction of an Azetidine Derivative as a Model of DNA Repair.

Photocycloreversion plays a central role in the study of the repair of DNA lesions, reverting them into the original pyrimidine nucleobases. Particularly, among the proposed mechanisms for the repair of DNA (6-4) photoproducts by photolyases, it has been suggested that it takes place through an intermediate characterized by a four-membered heterocyclic oxetane or azetidine ring, whose opening requires the reduction of the fused nucleobases. The specific role of this electron transfer step and its impact on the ring opening energetics remain to be understood. These processes are studied herein by means of quantum-chemical calculations on the two azetidine stereoisomers obtained from photocycloaddition between 6-azauracil and cyclohexene. First, we analyze the efficiency of the electron-transfer processes by computing the redox properties of the azetidine isomers as well as those of a series of aromatic photosensitizers acting as photoreductants and photo-oxidants. We find certain stereodifferentiation favoring oxidation of the cis-isomer, in agreement with previous experimental data. Second, we determine the reaction profiles of the ring-opening mechanism of the cationic, neutral, and anionic systems and assess their feasibility based on their energy barrier heights and the stability of the reactants and products. Results show that oxidation largely decreases the ring-opening energy barrier for both stereoisomers, even though the process is forecast as too slow to be competitive. Conversely, one-electron reduction dramatically facilitates the ring opening of the azetidine heterocycle. Considering the overall quantum-chemistry findings, N,N-dimethylaniline is proposed as an efficient photosensitizer to trigger the photoinduced cycloreversion of the DNA lesion model.

Gold(I)-catalyzed divergent and diastereoselective synthesis of azepines by ammoniumation/ring-expansion reactions

Gold(I) catalysts enable the chemoselective addition of tailor-made N-sulfonylated azetidine derivatives onto alkynes, affording bicyclic vinyl-ammonium gold intermediates. Intramolecularly intercepted by an adequately positioned nucleophilic carbonate or ester function, these ammoniums efficiently lead to ring-expanded azepine products, which are important pharmacophore fragments. Depending on the substitution pattern of the starting material, divergent deauration pathways occur, stereoselectively producing monomeric or original dimeric nitrogenated seven-membered rings in good to excellent yields, such as cis -tetrahydroazepin-4,5-diol carbonate, ( E )-alkylidene tetrahydroazepin-4-yl ester, and cis -bis(azepinyl)cyclobutane derivatives. One of the synthetic methods was extended to the formation of dihydrobenzazepines of high pharmaceutical value. A mechanistic study including kinetics and labeling experiments allowed us to fully understand the origin of the high chemo- and diastereoselectivity of these rearrangements. Overall, this work demonstrates the underlying synthetic potential of the ammoniumation catalyzed by gold for the future development of reaction cascades and preparation of bioactive compounds. • Gold-catalyzed ammoniumation of alkynes gives biologically relevant azepines • Functional groups on the starting material define the mechanistic pathway • NMR labeling and kinetic studies explain the chemo- and stereoselectivities observed • A dimeric bis(azepinyl)cyclobutane original scaffold is reported In the family of nitrogen heterocyclic drugs, azepine and its derivatives are very important pharmacophore fragments present in several pharmaceutical and a few agrochemical products. Currently, synthetic access to (hydro)azepine systems starting from simple and robust building blocks remains challenging, especially when targeting densely functionalized motifs. From tailor-made azetidine derivatives, we developed three diastereoselective methods to reach azepines with broad flexibility in good to excellent yields by using the unmatched ability of gold, a quasi-nontoxic metal, to promote nucleophilic additions onto unsaturated carbon-carbon bonds. The work described herein could offer efficient and modular routes to the preparation of useful intermediates in drug development. Azepines are fragments found in natural products possessing relevant biological activities. Our method provides access to multiple azepine derivatives from simple azetidine derivatives in the presence of a gold catalyst. Small variations on the starting material conduct to different reaction cascades whose mechanisms have been thoroughly studied to explain and control the observed selectivity. This journey led to the discovery of original azepine scaffolds along the way, whose biological activity remains to be studied.

Monoprotected Diamines Derived from 1,5‐Disubstituted (Aza)spiro[2.3]hexane Scaffolds

AbstractSynthesis of monoprotected diamines derived from 1,5‐disubstituted spiro[2.3]hexane and 5‐azaspiro[2.3]hexane scaffolds is described. In both cases, the method relied on the cyclopropanation of the corresponding cyclobutane or azetidine derivatives. In the case of monoprotected 1,5‐diaminospiro[2.3]hexanes, the title products were obtained as single diastereomers. X‐Ray diffraction studies supported by exit vector plot (EVP) analysis showed that the obtained building blocks are promising piperidine/cycloalkane isosteres with potential utility to drug discovery. Also, conformations observed in the crystalline state for the two different diastereomers of 1,5‐diaminospiro[2.3]hexane derivatives prompt their application in design of β‐turn and sheet‐like peptidomimetics, respectively.

Design, Synthesis, In Silico Studies and In Vitro Anticancer Activity of 3‐(4‐Methoxyphenyl)azetidine Derivatives

AbstractA series of 3‐(4‐methoxyphenyl)azetidine analogues were synthesized and screened for their in vitro anticancer activity against nine different human cancer cell lines using the cell counting kit‐8 (CCK‐8) assay. The synthesized molecules were characterized by 1H NMR, 13C NMR, LCMS and IR analysis. The toxicity, bioavailability and lipophilicity of all the synthesized compounds were predicted by using osiris and molinspiration model. Molecular docking study revealed that, compound 6‐(3‐(3‐(2‐aminopyridin‐4‐yl)‐4‐methoxyphenyl)azetidin‐1‐yl)picolinonitrile (4 A‐17) and 6‐(3‐(4‐methoxy‐3‐(2‐methoxypyridin‐4‐yl)phenyl)azetidin‐1‐yl)picolinonitrile (4 A‐19) were found to be potential inhibitor of human topoisomerase IIα. The cell viability studies exhibited promising antiproliferative activities of the novel synthesized compounds. 4 A‐17 (EC50 0.03 μM) was found to be more potent than standard Doxorubicin (EC50 0.07 μM) in U251 cancer cell lines. Similarly, 4 A‐19 showed considerable potency against four different cancer cell lines (HepG2, U251, A431, 786‐O) with EC50 values ranging from 0.46 to 2.13 μM. These primary findings supported that molecule 4 A‐17 and 4 A‐19 should be subjected to further studies and lead optimization.

Chemistry and biological activities of 2-azetidinone derivatives – A mini-review

2-Azetidinone skeleton is well established as the pharmacophore of β-lactam antibiotics. β-lactam antibiotics are the most widely employed class of antibiotics. The structural diversity of biologically active β-lactam antibiotics led to the development of many novel methods for the construction of appropriately substituted azetidine with attendant control of functional group and stereochemistry. Azetidine derivatives are reported to show a variety of antimicrobial, antitubercular, anticonvulsant, anti-inflammatory and cardiovascular activities. These activities showed that the minor change in the substitution pattern activities of azetidine derivatives have enhanced dramatically.

Intermolecular Allene Functionalization by Silver-Nitrene Catalysis.

Under silver catalysis conditions, using [Tp*,BrAg]2 as the catalyst precursor, allenes react with PhI═NTs in the first example of efficient metal-mediated intermolecular nitrene transfer to such substrates. The nature of the substituent at the allene seems crucial for the reaction outcome since arylallenes are converted into azetidine derivatives, whereas methylene aziridines are the products resulting from alkylallenes. Mechanistic studies allow proposing that azetidines are formed through unstable cyclopropylimine intermediates, which further incorporate a second nitrene group, both processes being silver-mediated. Methylene aziridines from alkylallenes derive from catalytic nitrene addition to the allene double bonds. Both routes have resulted to be productive for further synthetic transformations affording aminocyclopropanes.

Biological Significance of Ultrasound Assisted Synthesized Polycyclic Azetidine Derivatives

Synthesized N-(7-R)-2-oxa-8-azabicyclo[4.2.0]octan-8-yl)isonicotinamide derivatives (4a-n) and N-(2,4-dioxo-3-oxa-6-azabicyclo[3.2.0]heptan-6-yl)isonicotinamide derivatives (5a-m) were screened for biologically activity. Both azetidine derivatives (4a-n) and (5a-m) were screened for antibacterial activity by ‘Disk Diffusion method’ using Escherichia coli (ATCC 25922), Pseudomonas aeruginosa (ATCC 27853) and Staphylococcus aureus (ATCC 25923) and antifungal activity using candida sp. Similar series of azetidine derivatives (4a-n) and (5a-m) were screened for in vitro antituberculosis activity by ‘Clairo Combi method’ using Mycobacterium tuberculosis and in vitro anti-inflammatory activity was evaluated using ‘HRBC membrane stabilization method’. Experimented azetidine derivatives excellent biological activities, (N-(7-R)-2-oxa-6-azabicyclo [3.2.0] heptan-6-yl) isonicotinamide derivatives (4a-n) against S. aureus bacteria and N-(2,4-dioxo-3-oxa-6-azabicyclo[3.2.0] heptan-6-yl) isonicotinamide derivatives (5a-m) against M. tuberculosis (T.B.). Both series of azetidine derivatives (4a-n) and (5a-m) show potent anti-inflammatory activity. All synthesized azetidine derivatives (4a-n) and (5a-m) were characterized by IR, 1H NMR, 13C NMR and elemental analysis.

Design and synthesis of new azetidine‐steroid derivative with inotropic activity in a heart failure model

AbstractSeveral steroid derivatives have prepared as inotropic drugs; however, there are few reports on azetidine‐steroid derivatives with inotropic activity. The aim of this study was to synthesize four azetidine‐steroid derivatives (compounds 3 to 6) to evaluate their biological activity on left ventricular pressure. The first stage was achieved by preparation of azetidine‐derivatives using reactions of etherification and addition. The second stage involves the evaluation of biological activity from azetidine derivatives on left ventricular pressure in a heart failure model using estrone as control. The results showed that only compound 3 increases left ventricular pressure compared with estrone, compounds 2 and 4 to 6. In conclusion, the positive inotropic effect exerted by compound 3 depends on the functional groups involved in their chemical structure.

Ultrasound assisted, synthesis of N‐(7‐(R)‐2‐oxa‐8‐azabicyclo[4.2.0]octan‐8‐yl)isonicotinamide derivatives and their biological evaluation

AbstractIn this study, new series of azetidine derivatives were synthesized (4a‐n) from isoniazide (1), Aromatic aldehydes (2a‐n), dihydropyran (3) using SnCl2 catalyst, via one pot multicomponent reaction/cycloaddition reaction. The synthesized azetidine derivatives were characterized by IR, 1H NMR and 13C NMR and have been screened for antimicrobial, antituberculosis and anti‐inflammatory activities. In relation to Staphylococcus aureus (ATCC 25923) promising antibacterial activity was shown, compounds 4e and 4k, followed by compounds 4h, 4n, 4f, 4g and 4l. The synthesized azetidine derivatives, 4a, 4e, 4j and 4m (with zone 12 mm) displayed antituberculosis activity. But its lower potential than, the standard streptomycin (with zone 18 mm). Further 4d compound alone displayed similar activity.

Palladium-catalyzed \u03b1-arylation for the addition of small rings to aromatic compounds

Small, strained rings have rigid, defined conformations and unique electronic properties. For these reasons, many groups seek to use these subunits to form biologically active molecules. We report a generally applicable approach to attach small rings to a wide range of aromatic compounds by palladium-catalyzed α-arylation of cyclopropyl, cyclobutyl and azetidinyl esters. The direct α-arylation of cyclopropyl esters and cyclobutyl esters is achieved in high yield by ensuring that the rate of coupling exceeds the rate of Claisen condensation. The α-arylation of azetidines is achieved without ring opening of the strained saturated heterocycle by conducting the reactions with an azetidine derivative bearing a benzyl protecting group on nitrogen. Mechanistic studies show that the α-arylation of small rings is challenging because of the weak acidity of α C-H bond (cyclopropanes), strong sensitivity of the strained esters to Claisen condensation (cyclobutatanes), or facile decomposition of the enolates (azetidinyl esters).