Synthesis of New Isoxazolidine Derivatives Utilizing the Functionality of N-Carbonylpyrazol-Linked Isoxazolidines.

Using Ni(II) as the catalyst, electron-deficient 3,5-dimethylacryloylpyrazole olefin was reacted with C,N-diarylnitrones alone for 10 min to prepare novel five-member heterocyclic products, 4-3,5-dimethylacryloylpyrazole isoxazolidines with 100% regioselectivity and up to 99% yield. And then, taking these cycloadducts as substrates, six kinds of derivatization reactions, like ring-opening, nucleophilic substitution, addition-elimination and reduction, were studied. Experimental results showed that all kinds of transformations could obtain the target products at a high conversion rate under mild conditions, a finding which provided the basic methods for organic synthesis methodology research based on an isoxazolidine skeleton.

Identification of dual-target isoxazolidine-isatin hybrids with antidiabetic potential: Design, synthesis, in vitro and multiscale molecular modeling approaches.

In the development of novel antidiabetic agents, a novel series of isoxazolidine-isatin hybrids were designed, synthesized, and evaluated as dual α-amylase and α-glucosidase inhibitors. The precise structures of the synthesized scaffolds were characterized using different spectroscopic techniques and elemental analysis. The obtained results were compared to those of the reference drug, acarbose (IC50 = 296.6 ± 0.825 µM for α-amylase & IC50 = 780.4 ± 0.346 µM for α-glucosidase). Among the title compounds, 5d exhibited impressive α-amylase and α-glucosidase inhibitory activity with IC50 values of 30.39 ± 1.52 µM and 65.1 ± 3.11 µM, respectively, followed by 5h (IC50 = 46.65 ± 2.3 µM; IC50 = 85.16 ± 4.25 µM) and 5f (IC50 = 55.71 ± 2.78 µM; IC50 = 106.77 ± 5.31 µM). Mechanistic studies revealed that the most potent derivative 5d bearing the chloro substituent attached to the oxoindolin-3-ylidene core, and acarbose, are a competitive inhibitors of α-amylase and α-glucosidase, respectively. Structure activity relationship (SAR) was examined to guide further structural optimization of the most appropriate substituent(s). Moreover, drug-likeness qualities and ADMET prediction of the most active analogue, 5d was also performed. Subsequently, 5d was subjected to molecular docking and dynamic simulation during the progression of 120 ns analysis to check the essential ligand-receptor patterns, and to estimate its stability. In silico studies were found in good agreement with the in vitro enzymatic inhibitions results. In conclusion, we demonstrated that most potent compound 5d could be exploited as dual potential inhibitor of α-amylase and α-glucosidase for possible management of diabetes.

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.

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.

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.

Novel enantiopure isoxazolidine and C-alkyl imine oxide derivatives as potential hypoglycemic agents: Design, synthesis, dual inhibitors of α-amylase and α-glucosidase, ADMET and molecular docking study.

In an effort to explore a new class of antidiabetic inhibitors, a new series of isoxazolidine and C-alkyl imine oxide derivatives scaffolds were designed, synthesized and fully characterized. The newly synthesized analogues were evaluated for their human pancreatic α-amylase (HPA) and human lysosomal acid-α-glucosidase (HLAG) inhibitory activities and have shown a higher potency than acarbose. The compounds 7b (23.1 ± 1.1 µM) and 7a (36.3 ± 1.6 µM) were identified as the potent HPA and HLAG inhibitors with inhibitory effect up to 9 and 21-fold higher than acarbose, respectively. Antihyperglycemic activity results were supported by molecular docking approach of the most potent compounds 7b and 7a showing stronger interactions with the active site of HPA and HLAG as well as by in silico absorption, distribution, metabolism, excretion and toxicity (ADMET) profile suggesting their satisfactory oral druglikeness without toxic effect. Therefore, it can be concluded that both 7b and 7a can be used as effective lead molecules for the development of HPA and HLAG inhibitors for the management of T2DM.

Copper-Catalyzed Electrophilic Etherification of Arylboronic Esters with Isoxazolidines.

A copper-catalyzed electrophilic etherification of arylboronic esters is reported. Isoxazolidines are utilized as easily available and stable [RO]+ surrogates to give 1,3-amino aryl ethers. The O-selective arylation of isoxazolidines takes place without causing competitive N-arylation. In contrast to previously reported anionic conditions, our copper-catalyzed conditions are mild enough to achieve high functional group tolerance. Preliminary mechanistic studies and DFT calculations support that the reaction proceeds via a transmetalation/oxidative addition pathway, followed by a Lewis acid-promoted reductive elimination to induce the crucial O-selectivity.

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 ± 0.9 µM), HPA (10.1 ± 0.4 < IC50 < 26.8 ± 0.2 µM) and HLAG (65.4 ± 1.2 < IC50 < 274.8 ± 1.1 µM) when compared with the reference inhibitor, acarbose (IC50 = 284.6 ± 0.3 µM for PPA, 296.6 ± 0.8 µM for HPA, 780.4 ± 0.3 µM 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.

Semi-synthesis of a novel hybrid isoxazolidino withaferin via chemoselective and diastereoselective 1,3-dipolar nitrone cycloaddition reaction.

A facile, atom-economic synthesis of isoxazilidino withaferin, a novel hybrid of withaferin A, has been accomplished via two-step reaction of nitrone synthesis followed by nitrone 1,3-dipolar cycloaddition. The reaction is highly chemoselective (preferential reaction only on one of the two double bonds present on withaferin A) and diastereoselective affording exclusively the cis-fused products. The structure was determined by detailed analysis of 1D, 2D NMR and mass spectral data.

On the Nitrogen Inversion of Isoxazolidin-5-ones.

The nitrogen inversion energies of a series of N-substituted isoxazolidin-5-ones were studied by density functional theory. The transition state energy was found to strongly correlate with the s-character of the lone pair of electrons on the nitrogen in the ground state. Although the activation energy trends for isxazolidin-5-ones and isoxazolidines are similar, their conformational equilibria are slightly different and the isoxazolidin-5-one inversion energies are generally higher.

Advancement in the development of heterocyclic nucleosides for the treatment of cancer - A review.

Cancer diseases are widely recognised as an important medical problem and killing millions of people in a year. Chemotherapeutic drugs are successful against cancer in many cases and different compounds, including the analogues of natural substances, may be used for anticancer agents. Nucleoside analogues also have become a necessity for the treatment of cancer diseases. Nucleoside, nucleotide and base analogues have been utilised for decades for the treatment of viral pathogens, neoplasms and in anticancer chemotherapy. This review focuses on the different types of nucleosides and their potential role as anticancer agents. It also discusses the nucleoside analogues approved by FDA and in process of approval. The effect of the substitution on the nucleoside analogues and their pharmacological role is also discussed in the review. Owing to the advances in computational chemistry, it concludes with the future advancement and possible outcome of the nucleoside analogues. Also, it depicts the development of heterocyclic nucleoside analogues, explores the QSAR of the synthesised compounds and discusses the 3 D QSAR pharmacophore modelling in order to examine their potential anti-cancer activities.

A Pseudouridine Isoxazolidinyl Nucleoside Analogue Structural Analysis: A Morphological Approach.

An in silico study has been conducted upon (3'RS,5'SR)-5-[2'-benzyl-5'-hydroxymethyl-1',2'-isoxazolidin-3'-yl]uracil through a molecular dynamics/docking approach that highlights its potential inhibitory activity upon the wild-type pseudouridine 5'-monophosphate glycosidase. The crystal structure of this compound has been solved by means of X-ray single crystal diffraction and the data inferred were used to predict its crystal morphology. These data were compared with optical microscopy images and confirmed the validity of the computed models. This robust approach, already used for several other different compounds, provides a fast and reliable tool to standardize a crystallization method in order to get similar and good quality crystals. As different crystal shapes could be associated with different polymorphic forms, this method could be considered a fast and cheap screening to choose among different and coexistent polymorphic forms. Furthermore, a match with the original crystal structure of pseudouridine 5'-monophosphate is provided.

Isoxazolidine Conjugates of N3-Substituted 6-Bromoquinazolinones-Synthesis, Anti-Varizella-Zoster Virus, and Anti-Cytomegalovirus Activity.

1,3-Dipolar cycloaddition of N-methyl C-(diethoxyphosphoryl) nitrone to N3-substituted 6-bromo-2-vinyl-3H-quinazolin-4-ones gave (3-diethoxyphosphoryl) isoxazolidines substituted at C5 with quinazolinones modified at N3. All isoxazolidine cycloadducts were screened for antiviral activity against a broad spectrum of DNA and RNA viruses. Several isoxazolidines inhibited the replication of both thymidine kinase wild-type and deficient (TK⁺ and TK-) varicella-zoster virus strains at EC50 in the 5.4⁻13.6 µΜ range, as well as human cytomegalovirus (EC50 = 8.9⁻12.5 µΜ). Isoxazolidines trans-11b, trans-11c, trans-11e, trans-11f/cis-11f, trans-11g, trans-11h, and trans-11i/cis-11i exhibited moderate cytostatic activity towards the human lymphocyte cell line CEM (IC50 = 9.6⁻17 µM).

α,ß-Unsaturated Amides as Dipolarophiles: Catalytic Asymmetric exo-Selective 1,3-Dipolar Cycloaddition with Nitrones.

1,3-Dipolar cycloaddition is a commonly exploited method to access 5-membered chemical entities with a variety of peripheral functionalities and their stereochemical arrangements. Nitrones are isolable 1,3-dipoles that exhibit sufficient reactivity toward electron-deficient olefins in the presence of Lewis acids to deliver highly substituted isoxazolidines. Herein we document that α,ß-unsaturated amides, generally regarded as barely reactive in a 1,3-dipolar reaction manifold, were effectively activated using the designed 7-azaindoline auxiliary in an In(OTf)3 /bishydroxamic acid catalytic system. The broad substrate scope and clean removal of the 7-azaindoline auxiliary from the product highlight the synthetic utility of the present catalysis.

Reprofiling of full-length phosphonated carbocyclic 2'-oxa-3'-aza-nucleosides toward antiproliferative agents: Synthesis, antiproliferative activity, and molecular docking study.

A series of phosphonated carbocyclic 2'-oxa-3'-aza-nucleosides were synthesized via 1,3 dipolar cycloaddition and evaluated for their in vitro antiproliferative activity against the growth of cancer cell lines (MCF-7, A2780, HCT116) and normal non-transformed fibroblast (MRC5) using MTT assay. Synthesized compounds exhibited antiproliferative activity in the micromolar range. Compounds 11b showed the highest activity against MCF-7 cells (IC50 of 0.2344 µm). Cell cycle analysis was performed for compound 11b on MCF7 cells showing arrest of cells in the S phase. Molecular docking of synthesized compounds confirmed high affinity of these compounds to two different receptors for anticancer nucleosides on dCK, namely the 1P5Z and 2ZIA, showing scores higher than the cognate ligand for all tested compounds. All synthesized compounds were evaluated according to the Lipinski, Veber, and Opera rules, and all of them passed the evaluation showing excellent features, superior to reference drugs. In addition, ADME for all the synthesized compounds was predicted through a theoretical kinetic study using the discovery studio 3.1 software.

Stereoselective Synthesis of Isoxazolidines via Copper-Catalyzed Alkene Diamination.

A convenient copper-catalyzed intramolecular/intermolecular alkene diamination reaction to synthesize 3-aminomethyl-functionalized isoxazolidines under mild reaction conditions and with generally high levels of diastereoselectivity was achieved. This reaction demonstrates that previously underutilized unsaturated carbamates are good [Cu]-catalyzed diamination substrates. Sulfonamides, anilines, benzamide, morpholine, and piperidine can serve as the external amine source. This relatively broad amine range is attributed to the mild reaction conditions. Reduction of the N-O bond could also be achieved, revealing the corresponding 3,4-diamino-1-alcohols efficiently.

Crystal structure of 2-isopropyl-5,7'-dimethyl-1',3',3a',6',8a',8b'-hexa-hydro-spiro-[cyclo-hexane-1,6'-furo[3,4-d]imidazo[1,5-b]isoxazol]-8'(7'H)-one.

In the title compound, C17H28N2O3, the isoxazolidine ring adopts an envelope conformation with the O atom deviating from the mean plane of the other four ring atoms by 0.617 (1) Å. In the crystal, mol-ecules are linked via weak C-H⋯O hydrogen bonds, forming chains which extend along the b-axis direction.

New Isoxazolidine-Conjugates of Quinazolinones-Synthesis, Antiviral and Cytostatic Activity.

A novel series of (3-diethoxyphosphoryl)isoxazolidines substituted at C5 with various quinazolinones have been synthesized by the 1,3-dipolar cycloaddition of N-methyl-C-(diethoxyphosphoryl)nitrone with N3-substitued 2-vinyl-3H-quinazolin-4-ones. All isoxazolidines were assessed for antiviral activity against a broad range of DNA and RNA viruses. Isoxazolidines trans-11f/cis-11f (90:10), trans-11h and trans-11i/cis-11i (97:3) showed weak activity (EC50 = 6.84, 15.29 and 9.44 µM) toward VZV (TK⁺ strain) which was only one order of magnitude lower than that of acyclovir used as a reference drug. Phosphonates trans-11b/cis-11b (90:10), trans-11c, trans-11e/cis-11e (90:10) and trans-11g appeared slightly active toward cytomegalovirus (EC50 = 27-45 µM). Compounds containing benzyl substituents at N3 in the quinazolinone skeleton exhibited slight antiproliferative activity towards the tested immortalized cells with IC50 in the 21-102 µM range.

Crystal structure of 5-chloro-methyl-N-methyl-4-[(4-phenyl-1,2,3-triazol-1-yl)meth-yl]isoxazolidine-3-carboxamide.

The title compound, C15H18ClN5O2, crystallizes with two independent mol-ecules (A and B) in the asymmetric unit. In both mol-ecules, the isoxazolidine rings have an envelope conformation with the O atoms at the flap positions. Each mol-ecule has three stereogenic centres with configurations 2(S), 3(S) and 4(R), confirmed by resonant scattering. Their conformations are significantly different, for example in mol-ecule A the phenyl ring is inclined to the triazole ring by 32.5 (2)°, while in mol-ecule B the corresponding dihedral angle is 10.7 (2)°. In the crystal, the A and B mol-ecules are linked via an N-H⋯O and a C-H⋯O hydrogen bond. These units are linked by C-H⋯O and C-H⋯N hydrogen bonds, forming slabs parallel to the ab plane. There are C-H⋯π inter-actions present within the slabs.

Spiro sugar-isoxazolidine scaffold as useful polyfunctional building block for peptidomimetics design.

Spiro sugar-isoxazolidines obtained by 1,3-dipolar cycloaddition of activated exo-glycals and nitrones were efficiently functionalized at two sites, i.e. C-4 and C-7, with arginine, arginine mimetics and guanidylated appendages. Two bicyclic sugar derivatives differing by the configuration at C-7 were chosen as model compounds. The small library of peptidomimetics was evaluated toward inhibition of VEGF-A165/neuropilin-1 binding. Unexpected cleavage of C3-C4 bond of isoxazolidine moiety was observed during hydrogenolysis and opened thus a new way toward hemiketal structures which could also find interesting applications as less constrained scaffold.