Isoxazole Derivatives Research Articles

Synthesis, crystal structure, DFT studies and Hirshfeld surface analysis of novel isoxazole derivatives

This article describes firstly the synthesis of a new series of isoxazole 5a-e from p-methoxythymol, extracted from Tetraclinis Articulata, as starting material involving 1,3-dipolar cycloaddition reaction and secondly a detailed study of the molecular packing and intermolecular interactions in crystals of five related 5-((2-isopropyl-4-‑methoxy‑5-methylphenoxy)methyl)-3-phenylisoxazole derivatives. All compounds were synthesized and subjected to solid state characterization by single-crystal X-ray diffraction analysis, and to studies with the use of NMR and Hirshfeld surface analysis. All structures display intermolecular C—H···O hydrogen bonding and C—H···π interactions, forming layers in the crystal lattice. The crystal structures of compounds 5a; 5c and 5d are consolidated by π—π interactions. Hirshfeld surface analysis, the dnorm surfaces, electrostatic potential and two-dimensional fingerprint plots were examined to verify the contributions of the different intermolecular contacts within the supramolecular structure. The most important contributions for the crystal packing are from H···H, H···C/C···H and O···H/H···O interactions. Additionally, DFT calculations have been used to analyze the electronic and geometric frontier molecular orbital and Molecular Electrostatic Potential map analyses of the compounds were produced using the optimized structures.

Design, Synthesis, Characterisation & Anticonvulsant Activities of Novel Heterocyclic Substituted Isatin Derivatives

Twelve new isoxazole/pyrazole/pyrimidine substituted 5-nitrosation analogues were designed according to the requirements of the anticonvulsant drugs pharmacophore model and synthesised from indole-2,3-dione. Entire prepared compounds chemical structures were established from its IR, proton-NMR, Mass spectrum & microanalysis data. Anticonvulsant potency of final isatin analogues was assessed by MES technique & sc PTZ technique. Besides rotarod test was used to assess the neurotoxicity of all potent title analogues. Title compounds exhibited a varying degree of anticonvulsant potency ranging from mild to good. In the present study, it was concluded that pyrazole derivatives exhibited higher anti-epileptic activity than isoxazole derivatives. However, pyrimidine analogues displayed inferior activity than isoxazole analogues. 4-(2-(4-(1-((Dimethylamino)methyl)-5-nitro-2-oxindole-3-ylideneamino)phenyl) hydrazone)-1-(4-chlorophenyl)-3-amino-1H-pyrazole-5(4H)-one 7c was established as the most active analog of this series. Hence this derivative can act as a pilot molecule for further progress of new effective anticonvulsant drugs.

Синтез 3-арилизоксазолов и их сульфамидных производных

Great interest in binuclear aromatic systems containing an isoxazole ring and a sulfamide group is due to the effect of two pharmacophore groups at once on the biological activity of these compounds. This article is devoted to the development of a method for the synthesis of 3-arylisoxazole-containing compounds and their sulfamide derivatives from simple and accessible products of organic synthesis. The target products of the developed multistage schemes are derivatives of various bicyclic systems containing an isoxazole ring and a second aromatic ring associated with a sulfofragment. The synthesis of 3-aryl-5-acylaminoisoxazoles was carried out by sequential conversion of methyl esters of aromatic carboxylic acids into the corresponding nitriles by reaction with acetonitrile in the presence of sodium hydride in dioxane. At the next stage, the nitriles reacted with hydroxylamine in an aqueous solution of sodium hydroxide to form the corresponding bicyclic amines, which were then acylated in acetonitrile with acetic acid chloride in the presence of pyridine. The total yields of 3-aryl-5-N-acylaminoisoxazoles were at least 60%. It was found that the sulfonylchlorination of 3-aryl-5-N-acylamino derivatives of isoxazole, depending on the experimental conditions and the structure of the starting substrates, forms both mono- and disulfochlorides. The regioselectivity of the sulfochlorination reaction of the synthesized bicyclic systems was proved by 1H NMR spectroscopy. The influence of various factors on the course of the sulfochlorination reaction of the synthesized bicyclic systems was studied. The dependence of the direction of the electrophilic attack on the structure of the compounds and on the conditions of the experiment was established. As a result of the performed research, both mono and disulfochlorination products were obtained. With an increase in the reaction time, the disulfonylchlorination product accumulates and the deacylation reaction proceeds in parallel. Convincing proof of the structure of all synthesized compounds has been carried out using a complex of modern methods of physical and chemical analysis.

Dynamic and static fluorescence quenching on the inclusion complex formed by [3-(4-methylphenyl)-4,5-dihydro-1,2-oxazole-4,5-diyl] bis (methylene) diacetate and methyl-beta-cyclodextrin in aqueous media

An inclusion complex was formed between [3-(4-methylphenyl)-4,5-dihydro-1,2-oxazole-4,5-diyl] bis (methylene) diacetate compound, an isoxazole derivative and methyl-beta-cyclodextrin, the smallest unit of the macrocyclic family. With this newly formed fluorescent probe, the induced photophysical properties of heavy metals were investigated. The complex was thermally analyzed by differential scanning calorimetry – thermogravimetry, Fourier transform infrared, proton nuclear magnetic resonance and two dimensional correlated spectroscopy techniques were used for spectral characterization. Complex formation constant, Gibbs free energy and approximate quenching activation energy values were calculated. Lifetime, bimolecular quenching rate constant values and diffusion rate constant calculations were made and the mechanism of the quenching event with heavy metal effect was trying to be clarified. Whether quenching with Zn is dynamic, and whether or not quenching with Fe is static and diffusion controlled were investigated by the sphere of action static quenching, and by the finite sink approximation models. Highlights A new inclusion complex between OXA and Me-β-CD was obtained. The static action and finite approximation models were used for iron. A dynamic and static quenching mechanism was observed for Zn and Fe, respectively. A weak bound encounter complex formation for iron was suggested.

Gravimetric, electrochemical, and morphological studies of an isoxazole derivative as corrosion inhibitor for mild steel in 1M HCl

In present study, an isoxazole derivative, namely, (Z)-4-(4-hydroxy-3-methoxybenzylidene)-3-methylisoxazol-5(4H)-one referred here as (IOD) has been studied as an environment-friendly corrosion inhibitor for mild steel (MS) in acidic medium (1 M HCl). The present work was investigated by gravimetric, electrochemical impedance spectroscopy (EIS), potentiodynamic polarization (PDP), fourier-transform infrared (FT-IR) spectroscopy techniques. Atomic force microscopy (AFM), scanning electron microscopy (SEM), and energy-dispersive X-ray spectroscopy (EDS) confirmed the surface morphologies of the MS surface with and without IOD in the acid medium. The inhibition efficiency (I.E.) of IOD was increased by rising its concentration attaining maximum value (96.6%) at 300 ppm at 30 °C and decreases with increasing temperature from 30 °C to 60 °C. The adsorption of studied inhibitor followed Langmuir adsorption isotherm model. The PDP study revealed that the IOD acts as a mixed-type inhibitor with predominating anodic effect. The EIS study confirmed that increasing IOD concentration enhances the charge transfer resistance (Rct) and then reduces the double layer capacitance (Cdl) owing to the development of a protective layer on the MS surface.

One-pot three-component synthesis of isoxazole using ZSM-5 as a heterogeneous catalyst

A mild and convenient route for the synthesis of isoxazole derivatives has been developed using ZSM-5 as a heterogeneous catalyst. The reaction was carried out under a solvent-free condition to afford the desired products in good yields. A variety of functional groups was tolerated under the reaction conditions employed. Moreover, the heterogeneous catalyst (ZSM-5) was recovered and reused several times without significant loss of its catalytic activity.

Pro-apoptotic activity of novel synthetic isoxazole derivatives exhibiting inhibitory activity against tumor cell growth in vitro.

In order to develop potential anticancer agents stimulating apoptosis, novel 3,4-isoxazolediamide and 4,5,6,7-tetrahydro-isoxazolo-[4,5-c]-pyridine derivatives have been synthetized. The original structures of geldanamycin and radicicol, which are known natural heat shock protein (HSP) inhibitors, were deeply modified because both of them exhibit several drawbacks, such as poor solubility, hepatotoxicity, intrinsic chemical instability or deprivation of the in vivo activity. This novel class of synthetic compounds containing the isoxazole nucleus exhibited potent and selective inhibition of HSP90 in previous studies. Biological assays (focusing on in vitro antiproliferative effects and pro-apoptotic activity) in human erythroleukemic K562 cells (as a model system referring to tumor cells grown in suspension), glioblastoma U251-MG and glioblastoma temozolomide (TMZ)-resistant T98G cell lines (two model systems referring to tumor cells grown attached to the flask), were performed. Almost all isoxazole derivatives demonstrated significant antiproliferative and pro-apoptotic activities, showing induction of both early and late apoptosis of K562 cells. Different effects were observed on the glioma U251-MG and T98G cells, depending on the structure of the analogues. Antiproliferative and pro-apoptotic activities in K562 cells were associated with the activation of the erythroid differentiation program. The present study demonstrated that 3,4-isoxazolediamide and 4,5,6,7-tetrahydro-isoxazolo-[4,5-c]-pyridine derivatives should be considered for in vivo studies focusing on the development of anticancer drugs acting, at least partially, via activation of apoptosis.

Isoxazole derivatives of silatrane: synthesis, characterization, in silico ADME profile, prediction of potential pharmacological activity and evaluation of antimicrobial action

A new family of mono‐ (3a‐h) and bis‐ (4a‐g) isoxazole‐bridged silatranes has been synthesized by the reaction of 3‐aminopropylsilatrane (1) and 3‐substituted 5‐chloro‐methylisoxazoles (2a‐h). The structure of the isoxazole‐silatrane hybrids is characterized by elemental analysis, FT‐IR, UV, NMR (1H, 13C,29Si and 15N) spectroscopy, high‐resolution mass spectrometry, and X‐ray diffraction analysis. The in silico ADME (absorption, distribution, metabolism, excretion) assessment reveals that properties of mono‐adducts (3a‐h) are similar to those of drugs obeyed to the Lipinski's rule. The calculated screening of potential pharmacological activity profiles (in silico PASS program) of isoxazole‐silatranes shows that all synthesized compounds (both mono‐ and bis‐substituted) may have high antitumor action, unlike starting isoxazoles. The preliminary screening of the synthesized silatranes for antimicrobial activity against Enterococcus durans, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa indicates that all test samples are active only against gram‐positive microorganisms. Silatrane 3f displays minimal inhibitory concentration (MIC 12.5 and 6.2 μg ml−1) against E. durans and B. subtilis as compared with standard drug gentamicin (MIC 25 and 50 μg ml−1).

New series of isoxazole derivatives targeting EGFR-TK: Synthesis, molecular modeling and antitumor evaluation

New series of isoxazole derivatives were synthesized and evaluated for in vitro antitumor activity against HepG2, MCF-7 and HCT-116 cancer cells. Results showed that 4b and 25a are the most potent members against the three cancer cells (IC50 = 6.38–9.96 μM). Further, 4a, 8a and 16b showed strong activity against the three cancer cells, whereas 6b, 10a, 10b and 16a exhibited moderate activity against the three cancer cells. Moreover, 25a showed low cytotoxicity against WISH and WI38 normal cells (IC50 = 53.19 ± 3.1 and 38.64 ± 2.8 µM, respectively), and it might be used as a potent and safe antitumor agent. The nine active compounds 4a, 4b, 6b, 8a, 10a, 10b, 16a, 16b and 25a were studied for EGFR-TK inhibitory activity, where 10a, 10b and 25a showed the highest inhibitory activity (IC50 = 0.064 ± 0.001, 0.066 ± 0.001 and 0.054 ± 0.001 µM, respectively). Compound 25a was also assessed against other four target proteins, and it showed promising inhibitory activities against VEGFR-2, CK2α and topoisomerase IIβ, and acceptable inhibitory activity against tubulin polymerization. Cell cycle analysis of cancer cells treated with 25a proved that it induces cell cycle arrest at G2/M and pre-G1 phases. Furthermore, it was confirmed that 25a induces cancer cell death through apoptosis, supported by increased caspases 3/9 levels and increased Bax/Bcl-2 ratio in the three cancer cells. In addition, docking studies proved the exact fit of 25a into the active site of EGFR-TK, VEGFR-2, CK2α, topoisomerase IIβ and tubulin. Lipinski’s rule and Veber’s standards were also analyzed, and results illustrated that 25a is expected to be well absorbed orally.

Design, synthesis and biological evaluation of 3,5-diaryl isoxazole derivatives as potential anticancer agents

The present study was carried out in the attempt to synthesize a new class of potential anticancer agents comprising eleven compounds (24–34) sharing the 3,5-diarylisoxazole as a core. The chemical structure of the new synthesized compounds was established by IR, 1H NMR, 13C NMR and elemental analysis. Their biological potential towards prostate cancer was evaluated by using cancer PC3 cells and non-tumorigenic PNT1a cells. Interestingly, compound 26 distinguished from others with a quite high selectivity value that is comparable to 5-FU. The binding mode of 26 towards Ribosomal protein S6 kinase beta-1 (S6K1) was investigated at a molecular level of detail by employing docking simulations based on GLIDE standard precision as well as MM-GBSA calculations.

Efficient synthesis and characterization of novel isoxazole derivatives including dihdyropyrazole and methanoisoindole moieties

Efficient synthesis and characterization of novel isoxazole derivatives including dihdyropyrazole and methanoisoindole moieties

Uses of dimedone to synthesis pyrazole, isoxazole and thiophene derivatives with antiproliferative, tyrosine kinase and Pim-1 kinase inhibitions

We are aiming in this work to synthesize target molecules not only possess antitumor activities but also kinase inhibitors. The target molecules were obtained from dimedone, which reacted with triethoxymethane to produce a product that is capable for many heterocyclization reactions to give fused pyrazole, thiophene and isoxazole derivatives. Compounds 7b, 7c, 7d, 9b, 11, 12c, 12d, 14b, 16b, 17c, 17d, 18c, 18d, and 18e were the most cytotoxic compounds, their further tests toward the five tyrosine kinases c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR and Pim-1 kinase showed that compounds 7b, 7d, 11, 12c, 14b, 16b, 17d, 18d, and 18e were the most potent of the tested compounds toward the five tyrosine kinases and compounds 7b, 7d, 14b, 16b, and 18e were of the highest inhibitions toward Pim-1 kinase. PAINS the most cytotoxic compounds showed zero PAINS alert, therefore, these compounds can be used as useful drugs in the future.

Regio-isomeric isoxazole sulfonates: Synthesis, characterization, electrochemical studies and DNA binding activity

The transformation of 3,5-bis hydroxypheny-1,2-isoxazoles to their sulfonate ester derivatives is being described. The synthesis of the products was confirmed using FT-IR, NMR, and X-ray diffraction analysis. Subsequently the electrochemical and DNA binding studies of the synthesized compounds were executed. Electrochemical studies of compounds were carried out using cyclic voltammetry (CV). Results from cyclic voltammetry depicted that the synthesized compounds demonstrate one electron oxidation. CV titrations were employed to study interactions between synthesized isoxazole derivatives and DNA, which revealed intercalative interaction of the synthesized compounds with DNA. Compound 4 exhibited highest DNA interaction with the value of 9.03 × 104 M−1 for the binding constant (K).

Synthesis of isoxazole and isothiazole derivatives of curcumin

Curcumin is a chemical compound with antioxidant properties as well as strong anti-inflammatory, antiviral, analgesic, antimicrobial and antitumor effect, contained in the tuberous rhizomes of the turmeric plant (Curcuma longa). Curcumin derivatives are being intensively studied as potential drugs – antitumor drugs for the treatment of certain forms of cancer. The presence of reactive functional groups makes curcumin a convenient starting compound for the further chemical modification. The esters of curcumin and 5-phenylisoxazole-3-carboxylic acid, 5-(p-tolyl)isoxazole-3-carboxylic acid, 4,5- dichloroisothiazole-3-carboxylic acid and adduct of 5-(p-tolyl)isoxazol-3-carbaldehyde with curcumin were synthesized. Esters were obtained by acylation of curcumin with heterocycle-containing carboxylic acid chloride in diethyl ether in the presence of triethylamine. The IR and NMR spectra of the obtained compounds are described.

Uses of Cyclohexan-1,3-dione for the Synthesis of Thiazole, Pyrazole, Thiophene, Isoxazole and Pyran Derivatives with Antitumor Activities

Background: A wide range of thiazole, pyrazole and pyran derivatives gained special attention due to pharmacological activities especially therapeutic activities. Many pharmacological drugs containing the thiazole and pyrazole nuclei are known in the market. Methods: The 2-arylidencyclohexan-1,3-dione 3a-c were the key starting compounds for many heterocyclic reactions to produce substituted heterocyclic derivatives. Results: Antiproliferative activities of the produced compounds against six cancer cell lines A549, HT-29, MKN-45, U87MG, SMMC-7721 and H460 were measured in which the compounds showed high inhibition. The most promising compounds were tested against tyrosine kinases (c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR). Structure-Activity Relationship (SAR) was rationalized by assessing the varying structural features of the molecules. In addition, the most active compounds were selected for Pim-1 inhibition. Conclusion: Thirty compounds were synthesized. Ten of them (3a, 3c, 5a, 5c, 7a, 10f, 11a, 13c, 16a and 16c) were the most active compounds for selected cancer cell lines. Compounds 3c, 5c, 7a, 10f, 13c and 16c showed high inhibition toward the tyrosine kinases while compounds 3c, 5c and 10f were the most potent to inhibit Pim-1.

Synthesis and Cytotoxicity of 28-Oxo-Allobetulone Derivatives

28-Oxo-allobetulone derivatives that were newly synthesized or prepared earlier by modification of ring A (3- and 4-pyridylidene, furfurylidene, azepane, lactam, quinolone, spiroindole, pyrazole, isoxazole, and tetraoxane derivatives) and 3β,19β,28-oleantriol were tested in vitro for cytotoxicity against 60 cell lines of 9 human tumor types. Melanoma SK-MEL-5 and CNS SNB-75 cancer cells died in the presence of 3- or 4-pyridylidene derivatives of 28-oxo-allobetulone. 3β,19β,28-Oleantriol possessed selective cytotoxicity against CNS cancer cell line SNB-75.

Design, Synthesis, Molecular Docking Studies, and Biological Evaluation of Pyrazoline Incorporated Isoxazole Derivatives

A novel series of pyrazoline incorporated isoxazole derivatives were designed and synthesized. The synthesized compounds were characterized by 1H NMR, IR and ESI-MS spectra. In addition, all the synthesized compounds were docked with the target human DHFR (PDB ID: 1KMS). Among all the compounds, compound 5-(4-methoxyphenyl)-3-(5-methyl-3-(4-nitrophenyl)isoxazol-4-yl)-4,5-dihydro-1H-pyrazol-1-yl)(phenyl)methanone proved to be the most potent exhibiting the highest binding affinity with a docking score of 153.763. All the synthesized compounds were screened for anticancer activity against human breast cancer cell lines MCF-7 and MDA-MB-231 through MTT assay. Out of all the synthesized compounds (5-(4-methoxyphenyl)-3-(5-methyl-3-(4-nitrophenyl)isoxazol-4-yl)-4,5-dihydro-1H-pyrazol-1-yl)(phenyl)methanone posses good activity with IC50 values ranging from 3–4 μg/mL. Further all the compounds were screened for antitubercular assay against the strain H37Rv and multidrug resistant strain DKU 156, among all four compounds exhibited significant activity at 6.25 µg/mL concentrations. Thus the MIC value may be in between the range of 3.12 and 6.25 µg/mL.

Synthesis and Biological Activity of Some Novel Derivatives of 4-[5-(2,3-Dihydrobenzo[b][1,4]dioxin-7-yl)isoxazole-3-yl]benzoic Acid

Some novel isoxazole derivatives of 4-[5-(2,3-dihydrobenzo[b][1,4]dioxin-7-yl)isoxazole-3-yl]benzoic acid bearing biologically active pharmacophores like benzodioxane and peptide bond have been synthesized, and their structures are supported by FTIR,1H and 13C NMR, and mass spectra. The title compounds have been tested for antimicrobial and antioxidant activities. Molecular docking of the structures has also been carried out with protein Sortase A, according to which some compounds are characterized as potentially antimicrobial agents. Four products demonstrate strong antioxidant activity.

Design, Synthesis and Biological Evaluation of 3-(3,4,5-Trimethoxyphenyl)- 5-(2-(5-arylbenzo[b]thiophen-3-yl)oxazol-5-yl)isoxazole Derivatives as Anticancer Agents

A new series of 3-(3,4,5-trimethoxyphenyl)-5-(2-(5-arylbenzo[b]thiophen-3-yl)oxa zol-5- yl)isoxazole derivatives were designed and synthesized. All these derivatives were evaluated for their anticancer activity against various human cancer cell lines such as MCF-7 (breast cancer), A549 (lung cancer), DU-145 (prostate cancer) and MDA MB-231 (breast cancer)-four human cancer cell lines by using MTT assay. Here, etoposide was used as a standard reference drug and most of the compounds were exhibited good anticancer activity with respect to cell lines. Among all compounds, five compounds 11b, 11c, 11f, 11i and 11j showed more potent activity than standard drug, in which, compound 11f was the most promising compound.

Synthesis of Diimidazole Has Pyrazole, Isoxazole and Pyrimidine Derivatives and Evaluation as Antibacterial

New diimidazole contains pyrazole , isoxazole and thiopyrimidine were synthesized by using simple methods . All compounds were synthesized by using hippuric acid (1) as stating material which was obtained from benzoyl and glycine with. pyrazole derivatives (6a – b ) was obtained from reaction (5a – b) with hydrazine hydrate while reaction of (5a – b )with hydroxyl amine isoxazole derivatives (7a – b) were obtained ,finally reaction of thiourea was reacted with 5a – b thiopyrimidine derivatives were get (8a –b ) . FTIR and 1HNMR spectra were used to characterized derivatives several bacterial species like Pseudomonas aeruginosa , Staphylococcus aureus, and Acinetobacter baumanii were used to tested antibacterial activity