Isoxazolidine Derivatives Research Articles

TMSOTf‐Mediated Aminocyclization/[1,3]‐Sulfonyl Migration of N‐Homopropargyl Hydroxylamines for the Stereoselective Synthesis of 3‐Sulfonyl Cyclic Nitrones

AbstractTMSOTf‐mediated 5‐endo‐dig aminocyclization followed by N‐ to C‐[1,3]‐sulfonyl migration on N‐homopropargyl hydroxylamines gave diastereoselective access to trisubstituted 3‐sulfonyl cyclic nitrone (3‐sulfonyl pyrroline N‐oxide) derivatives. The synthetic utility of the 3‐sulfonyl cyclic nitrone products was demonstrated through the diastereoselective synthesis of the sulfonyl‐substituted nonaromatic N‐heterocycles such as N‐hydroxypyrrolidine, pyrrolidine‐fused isoxazoline, and isoxazolidine derivatives.

Synthesis, optical properties, DNA, β-cyclodextrin interactions, and antioxidant evaluation of novel isoxazolidine derivative (ISoXD2): A multispectral and computational analysis

ISoXD2 are well explored among versatile and outstanding class of pharmacophores for the preparation and discovery of drugs. Herein, the electronic absorption and emission spectra of ISoXD2 were investigated in three different solvents. The observed transition was attributed to π-π* with charge transfer character. Changes in the excited state and shift of the absorption and emission peaks to longer wavelengths are observed as a result of increasing solvent polarity, due to the interactions between the ISoXD2 molecule and the solvent molecules surrounding it. Changing the solvent confirms its solvatochromic effect. UV–vis and fluorescence analysis revealed that ISoXD2 binds to deoxyribonucleic acid (DNA) by intercalation mode, with a stoichiometric ratio of 1:1.5. Moreover, the fluorescence intensity of DNA bound to ethidium bromide (EB) in the presence of ISoXD2 was investigated. From this analysis, the Stern-Volmer quenching constant (Ksv), quenching rate constant (kq), binding constant (Kb) and binding sites number (n) were found to be 5.654 × 103 M−1, 2.827 × 1011 M−1 s−1, 3.81 × 104 M−1 and 1.225, respectively. The interaction between ISoXD2 and β-CD was investigated through absorption spectra analysis. Kb for this interaction was determined to be 4.9 × 104 M−1. The free radical-scavenging ability of the prepared ISoXD2, examined by DPPH and ABTS assays have shown a good antioxidant activity. Furthermore, modeling study was conducted to explore their plausible binding mechanism with ISoXD2 and to support the experimental results.

New isoxazolidine derivatives: Synthesis, spectroscopic analysis, X-ray, DFT calculation, biological activity studies

The isoxazolidine skeleton is an important component of biologically active natural products, and many compounds containing isoxazolidine ring exhibit excellent antibacterial and anticancer activities. Based on the variously biological activity of isoxazolidines, a new series of isoxazolidine derivatives were designed and synthesized. All the structure of target compounds was characterized by NMR and HRMS. Especially, compound 8a ((Z)-2-methyl-4-(phenoxymethylene)-3-phenylisoxazolidine) was prepared for single crystal X-ray diffraction and FT-IR. Density functional theory (DFT) calculations were also performed on compound 8a at the B3LYP/6–311 level. In addition, after evaluation with MTT method of compounds 8a-8k against A549 cells, it was found that some compounds performed well antitumor activities.

Synthesis, optical properties, DNA, β-cyclodextrin interaction, hydrogen isotope sensor and computational study of new enantiopure isoxazolidine derivative (ISoXD)

A novel isoxazolidine derivative (ISoXD) dye was successfully synthesized and comprehensively characterized. In this study, we conducted a thorough examination of its various properties, including optical characteristics, interactions with DNA and β-cyclodextrin (β-CD), molecular docking, molecular dynamic simulation, and density functional theory (DFT) calculations. Our investigation encompassed a systematic analysis of the absorption and emission spectra of ISoXD in diverse solvents. The observed variations in the spectroscopic data were attributed to the specific solvent's capacity to engage in hydrogen bonding interactions. Remarkably, the most pronounced intensities were observed in glycol, which can establish many hydrogen bonds with ISoXD.Furthermore, our study revealed a significant distinction in the fluorescence behavior of ISoXD when subjected to different solvents, particularly between CHCl3 and CDCl3. Moreover, we explored the fluorescence intensity of the ISoXD complex in the presence of various metals, both in ethanol and water. The ISoXD complex exhibited a substantial increase of fluorescence upon interaction with different metal ions. The utilization of DFT calculations allowed us to propose an intramolecular charge transfer (ICT) mechanism as a plausible explanation for this quenching phenomenon. The interaction of ISoXD with DNA and β-CD was studied using absorption spectra. The binding constant (K) and the standard Gibbs free energy change (ΔGo) for the interaction between DNA and β-CD with ISoXD were determined. In docking study, ISoXD exhibited significant docking scores (−6.511) and MM-GBSA binding free energies (−66.27 kcal/mol) within the PARP-1 binding cavity. Its binding pattern closely resembles to the co-crystal ligand veliparib, and during a 100ns MD simulation, ISoXD displayed strong stability and formed robust hydrogen bonds with key amino acids. These findings suggest ISoXD's potential as a PARP-1 inhibitor for further investigation in therapeutic development.

In Silico Design, Synthesis, and Evaluation of Novel Enantiopure Isoxazolidines as Promising Dual Inhibitors of α-Amylase and α-Glucosidase.

Isoxazolidine derivatives were designed, synthesized, and characterized using different spectroscopic techniques and elemental analysis and then evaluated for their ability to inhibit both α-amylase and α-glucosidase enzymes to treat diabetes. All synthesized derivatives demonstrated a varying range of activity, with IC50 values ranging from 53.03 ± 0.106 to 232.8 ± 0.517 μM (α-amylase) and from 94.33 ± 0.282 to 258.7 ± 0.521 μM (α-glucosidase), revealing their high potency compared to the reference drug, acarbose (IC50 = 296.6 ± 0.825 µM and 780.4 ± 0.346 µM), respectively. Specifically, in vitro results revealed that compound 5d achieved the most inhibitory activity with IC50 values of 5.59-fold and 8.27-fold, respectively, toward both enzymes, followed by 5b. Kinetic studies revealed that compound 5d inhibits both enzymes in a competitive mode. Based on the structure-activity relationship (SAR) study, it was concluded that various substitution patterns of the substituent(s) influenced the inhibitory activities of both enzymes. The server pkCSM was used to predict the pharmacokinetics and drug-likeness properties for 5d, which afforded good oral bioavailability. Additionally, compound 5d was subjected to molecular docking to gain insights into its binding mode interactions with the target enzymes. Moreover, via molecular dynamics (MD) simulation analysis, it maintained stability throughout 100 ns. This suggests that 5d possesses the potential to simultaneously target both enzymes effectively, making it advantageous for the development of antidiabetic medications.

A Convenient Synthesis of Novel Isoxazolidine and Isoxazole Isoquinolinones Fused Hybrids.

Isoxazolidine, isoxazole, and isoquinolinone rings are present in the structure of several natural products and/or pharmaceutically interesting compounds. In this work, facile and efficient pathways have been developed for the preparation of fused frameworks bearing those heterocycles. The successful approaches for both isoxazolidine/isoquinolinone and isoxazole/isoquinolinone hybrid syntheses relied initially on 1,3-dipolar cycloadditions of nitrones and nitrile oxides to indenone and 2-propargylbenzamide, respectively. The construction of the isoquinolinone lactam system followed by performing a selective Schmidt reaction for isoxazolidine derivatives (two steps overall), whereas the isoxazole lactams were reached via an Ullmann-type cyclisation (three steps overall). Key observations were made regarding the stereo- and regioselectivities of the reactions employed, and small libraries of the targeted hybrids were prepared, demonstrating the general applicability of these strategies.

Dual docking of some synthesized isoxazolidine derivatives against Cathepsin L and main protease as a novel treatment strategy for COVID-19

Coronavirus disease 19 (COVID-19) continues to form a stressful threat to various sectors worldwide. With the advent of a new wave of Omicron sub-variant, exploration of novel drugs and strategies to cure COVID-19 patients are highly demanded. The current study evaluates the druggability of synthesized isoxazolidine derivatives(a, b) which are characterized by FT-IR, 13C NMR, and 1H NMR spectroscopy against cathepsin L and main protease (Mpro) using molecular docking. Procathepsin L 3D structure was predicted using SwissModel and then refined utilizing Galaxyrefine server. The refined structure in addition to MPpro retrieved from PDB served as receptors for docking by isoxazolidine derivatives using CB-Dock 2 and SwissDock platforms. Besides, drug-likeness and toxicity issues of the tested ligands were predicted using ADMET lab 2 and ProTox-II web servers. Molecular dynamics was conducted through Visual Dynamics server. Isoxazolidine derivatives exhibited strong dual inhibitory activity toward both receptors as well as good pharmacokinetics parameters. The tested ligands are a superior therapy option toward COVID-19.

Isoxazolidine Derivatives Exhibit Selective Antitumor Activity Against Breast Cancer Cells

Breast cancer, a leading cause of cancer-related mortality in women, necessitates effective therapeutic interventions. Heterocyclic compounds, prevalent in FDA-approved pharmaceuticals, play a pivotal role in drug development. This study focuses on isoxazolidine derivatives, a subgroup of nitrogen and oxygen-containing heterocycles, known for their potential in antitumor applications. A series of novel isoxazolidine compounds were synthesized and evaluated for their anticancer efficacy using MTT assays against MCF-7 and HdFn cell lines, alongside normal cells. Structural elucidation employed FT-IR, 13C-NMR, 1H-NMR, and E-I mass spectroscopy. Results revealed compound (IZ3) with an IC50 value of 32.49 µg/ml, demonstrating notable antitumor activity in MCF-7 cells compared to HdFn. Notably, compounds (IZ1 and IZ2) exhibited IC50 values of 64 µg/ml and 128 µg/ml, respectively. These findings underscore the potential of isoxazolidine derivatives as promising candidates for targeted breast cancer therapies, warranting further investigation in preclinical models and clinical trials.
 Highlight:
 
 Novel Isoxazolidine Compounds: Synthesized and Evaluated
 Selective Antitumor Activity: Demonstrated in MCF-7 Breast Cancer Cells
 Promising Therapeutic Candidates: Isoxazolidine Derivatives for Targeted Breast Cancer Therapy
 
 Keyword: Breast cancer, Isoxazolidine Derivatives, Antitumor Activity, Heterocyclic Compounds, Drug Development

In Vitro and In Silico Evaluation of Antiproliferative Activity of New Isoxazolidine Derivatives Targeting EGFR: Design, Synthesis, Cell Cycle Analysis, and Apoptotic Inducers.

A series of novel enantiopure isoxazolidine derivatives were synthesized and evaluated for their anticancer activities against three human cancer cell lines such as human breast carcinoma (MCF-7), human lung adenocarcinoma (A-549), and human ovarian carcinoma (SKOV3) by employing MTT assay. The synthesized compounds were characterized by NMR and elemental analysis. Results revealed that all the synthesized compounds displayed significant inhibition towards the tested cell lines. Among them, 2g and 2f, which differ only by the presence of an ester group at the C-3 position and small EDG (methyl) at the C-5 position of the phenyl ring (2g), were the most active derivatives in attenuating the growth of the three cells in a dose-dependent manner. The IC50 for 2g were 17.7 ± 1 µM (MCF-7), 12.1 ± 1.1 µM (A-549), and 13.9 ± 0.7 µM (SKOV3), and for 2f were 9.7 ± 1.3µM (MCF-7), 9.7 ± 0.7µM (A-549), and 6.5 ± 0.9µM (SKOV3), respectively, which were comparable to the standard drug, doxorubicin. The enzymatic inhibition of 2f and 2g against EGFR afforded good inhibitory activity with IC50 of 0.298 ± 0.007 μM and 0.484 ± 0.01 µM, respectively, close to the positive control, Afatinib. Compound 2f arrested the cell cycle in the S phase in MCF-7 and SKOV3 cells, and in the G2/M phase in the A549 cell; however, 2g induced G0/G1 phase cell cycle arrest, and inhibited the progression of the three cancer cells, together with significant apoptotic effects. The docking study of compounds 2f and 2g into EGFR ATP-active site revealed that it fits nicely with good binding affinity. The pharmacokinetic and drug-likeness scores revealed notable lead-like properties. At 100 ns, the dynamic simulation investigation revealed high conformational stability in the EGFR binding cavity.

Lewis-Acid-Catalyzed Reductive Hydroalkoxylation of Propargylic N-Hydroxylamines Gives Stereoselective Access to Isoxazolidines.

Lewis-acid-catalyzed 5-endo-dig reductive hydroalkoxylation cascade on propargylic N-hydroxylamine gave expedient, stereoselective access to isoxazolidine derivatives. The developed method provides a new approach toward the synthesis of isoxazolidine, a biologically privileged scaffold. The synthetic potential of the developed methodology was demonstrated by synthesizing 1,3-aminoalcohol, 4-aminotetrahydropyran, and sedamine natural products.

Photo-induced redox cascade reaction of nitroarenes and amines

A photo-induced redox cascade reaction has been developed for the chemoselective construction of isoxazolidine derivatives from stable and easily available nitroarenes and amines.

A Reversible Optical Sensor Film for Mercury Ions Discrimination Based on Isoxazolidine Derivative and Exhibiting pH Sensing.

We developed a new optical sensor for tracing Hg(II) ions. The detection affinity examines within a concentration range of 0-4.0 µM Hg(II). The sensor film is based on Methyl 2-hydroxy-3-(((2S,2'R,3a'S,5R)-2-isopropyl-5,5'-dimethyl-4'-oxotetrahydro-2'H-spiro[cy-clohexane-1,6'-im-idazo[1,5-b]isoxazol]-2'-yl)methyl)-5-methylbenzoate (IXZD). The novel synthesized compound could be utilized as an optical turn-on chemosensor for pH. The emission intensity is highly enhanced for the deprotonated form concerning the protonated form. IXZD probe has a characteristic fluorescence peak at 481 nm under excitation of 351 nm with large Stocks shift of approximately 130 nm. In addition, the binding process of IXZD:Hg(II) presents a 1:1 molar ratio which is proved by the large quench of the 481 nm emission peak of IXZD and the growth of a new emission peak at 399 nm (blue shift). The binding configurations with one Hg(II) cation and its electronic characteristics were investigated by applying the Density Functional Theory (DFT) and the time-dependent DFT (TDDFT) calculations. Density functional theory (DFT) and the time-dependent DFT (TDDFT) theoretical results were provided to examine Hg(II)-IXZD structures and their electronic properties in solution. The developed chemical sensor was offered based on the intramolecular charge transfer (ICT) mechanism. The sensor film has a significantly low limit of detection (LOD) for Hg(II) of 0.025 μM in pH 7.4, with a relative standard deviation RSDr (1%, n = 3). Lastly, the IXZD shows effective binding affinity to mercury ions, and the binding constant Kb was estimated to be 5.80 × 105 M-1. Hence, this developed optical sensor film has a significant efficiency for tracing mercury ions based on IXZD molecule-doped sensor film.

Heterocyclic Synthesis of Some New Isoxazolidine Derivatives via 1,3-Dipolar Cycloaddition of Nitrones to Styrene

A number of nitrones have been synthesized in three different procedures, starting with N-phenyl hydroxylamine, followed by the condensation reaction with some selected aldehydes. Furthermore, these nitrones were employed in the preparation of a number of new isoxazolidines. Cycloaddition reaction of nitrones to styrene produced the desired products.

Microwave-assisted synthesis and odor characteristics of some new isoxazolidines

We describe herein the design and synthesis of new isoxazolidin-5-carboxylates by microwave-assisted 1,3-dipolar cycloadditions of aldonitrones, derived from five fragrant aldehydes, with methacrylate esters. The reaction proceeded regioselectively providing mostly endo- diastereomers and in some cases an inseparable mixture of endo-exo products. The structures of target compounds were identified on the basis of IR, NMR, and TOF-MS measurements. Besides, both aldonitrone and isoxazolidine derivatives were subjected to olfactory evaluation by an expert nose. Diverse fragrance notes were observed in each series of isoxazolidines bearing different groups from aldonitrones. However, their odor ranges were found as animalic, medical, waxy, and ozonic undertones in common.

Synthesis of novel isoxazoline and isoxazolidine derivatives: carboxylic acids and delta bicyclic lactones via the nucleophilic addition of bis(trimethylsilyl)ketene acetals to isoxazoles

Synthesis of novel isoxazoline and isoxazolidine derivatives: carboxylic acids and delta bicyclic lactones via the nucleophilic addition of bis(trimethylsilyl)ketene acetals to isoxazoles

Computational exploration of the 1,3‐dipolar cycloaddition reaction of 7‐isopropylidenebenzonorbornadiene with nitrile oxide and cyclic nitrone derivatives

AbstractThe synthesis of isoxazolidine and isoxazole derivatives, versatile building blocks for the construction of a wide range of complex heterocyclic architectures in synthetic organic and medicinal chemistry, is efficiently achieved via the 1,3‐dipolar cycloaddition reaction (1,3‐DC). Herein, we report an extensive theoretical study on the peri‐, regio‐, stereo, and enantio‐selectivities of 1,3‐DC of 7‐isopropylidenebenzonorbornadiene with nitrile oxide and cyclic nitrone derivatives using density functional theory calculations. Acetophenone‐substituted nitrile oxide periselectively adds across the endocyclic olefinic bond of the dipolarophile to furnish the exo‐cycloadduct as the major product, a reaction that has a rate constant of 1.88 × 109 s−1. The endo approach of this periselective path is the closest competing pathway with a rate constant of 4.59 × 107 s−1. Different substituents on the nitrile oxide do not affect the peri‐ and stereo‐selectivity of the reaction. Diethyl ether solvation has no substantial effect on the energetic patterns observed in the gas phase computation. Also, we report a novel 1,3‐DC between cyclic nitrone derivatives and 7‐isopropylidenebenzonorbornadiene as an efficient way to generate isoxazolidine derivatives. Even though the reactions of the cyclic nitrone derivatives have slightly higher activation barriers than the acyclic nitrile oxide derivatives, the former is more enantioselective than the latter. Whereas electron‐donating groups (EDGs) on the cyclic nitrone favor the formation of the exo‐cycloadduct, electron‐withdrawing groups (EWGs) favor the formation of the endo‐cycloadduct. Both 1,3‐dipoles add across the dipolarophile via a concerted asynchronous mechanism.

Investigating the regio-, stereo-, and enantio-selectivities of the 1,3-dipolar cycloaddition reaction of C-cyclopropyl-N-phenylnitrone derivatives and benzylidenecyclopropane derivatives: A DFT study

The biomedical importance of spirocyclopropane isoxazolidine derivatives is widely known. The 1,3-dipolar cycloaddition (1,3-DC) of C-cyclopropyl-N-phenylnitrone derivative and benzylidenecyclopropane derivatives leading to the formation of 5- and 4-spirocyclopropane isoxazolidines derivatives have been studied using density functional theory (DFT) at M06–2X/6-311G (d,p) level of theory. An extensive exploration of the potential energy surface shows that the 1,3-dipole adds across the dipolarophile via an asynchronous concerted mechanism. While electron-donating groups (EDGs) on the benzylidenecyclopropane favor the formation of the 4-spirocyclopropane isomer, electron-withdrawing groups (EWGs) favor the reaction channels that furnish the 5-spirocyclopropane isoxazolidine isomer. Both EWDs and EDGs on the 1,3-dipole favor the formation of the 5-spirocyclopropane isoxazolidine isomer. Irrespective of the electronic nature of substituents on the C-cyclopropyl-N-phenylnitrone, the reaction channels that regioselectively lead to the formation of the 5-spirocyclopropane isoxazolidine isomer are favored. In all reactions considered, the channels that selectively lead to the formation of the cis-diastereoisomers proceed with lower activation barriers than the trans-diastereoisomers. In all cases, the observed selectivities in the title reaction are kinetically controlled.

Multifunctional isoxazolidine derivatives as α-amylase and α-glucosidase inhibitors.

A series of novel isoxazolidines based on benzaldehyde derivatives have been synthesized from the cycloaddition of chiral menthone-based nitrone and allyl phenyl ethers. All synthetic compounds were assessed for their in vitro PPA, HPA and HLAG inhibitory activity. The results revealed that all targets exhibited better inhibitory effect against PPA (12.3±0.4<IC50<38.2±0.9μM), HPA (10.1±0.4<IC50<26.8±0.2μM) and HLAG (65.4±1.2<IC50<274.8±1.1μM) when compared with the reference inhibitor, acarbose (IC50=284.6±0.3μM for PPA, 296.6±0.8μM for HPA, 780.4±0.3μM for HLAG) with the highest PPA inhibitory activity was ascribed to compound 3g against both PPA and HPA, and 3b against HLAG enzymes, respectively. Structural activity relationships (SARs) were also established for all synthesized compounds and the interaction modes of the most potent inhibitors (3g for PPA and HPA, 3b for HLAG) and the active site with residues of three enzymes were confirmed through molecular docking studies. Furthermore, a combination of molecular docking analysis with the in vitro activities can help to improve prediction success and encourages the uses of some of these molecules as potential alternatives toward the modulation of T2D.

Organocatalytic synthesis of 5-hydroxyisoxazolidine catalyzed by camphor sulfonyl hydrazines through aza-Michael addition/cyclization.

A series of chiral 5-hydroxy isoxazolidines has been successfully synthesized through camphor sulfonyl hydrazine-catalyzed asymmetric aza-Michael addition reaction between N,O-protected hydroxyamines and enals. Moderate yields with moderate to good enantioselectivities (up to 96% enantiomeric excess [ee]) were achieved. It provides an alternative asymmetric approach to preparing isoxazolidine derivatives.

Asymmetric organocatalytic multicomponent reactions for efficient construction of bicyclic compounds bearing bisacetal and isoxazolidine moieties.

An organocatalytic multicomponent reaction of N-protected hydroxylamines, acrylaldehyde and acetal-containing enones was developed. Bisacetal-containing bicyclic isoxazolidine derivatives bearing four continuous stereocenters were formed with excellent stereoselectivities. A plausible reaction pathway was proposed based on 18O-labeling control experiments.