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Non-steroidal anti-inflammatory drugs (NSAIDs) are considered one of the most commonly used medications globally. Seventeen isoxazole-containing compounds with various functional groups were evaluated in this work to identify which one was the most potent and which group was most selective toward COX-1 and COX-2 by using an in vitro COX inhibition assay kit. Their cytotoxicity was evaluated on the normal hepatic cell line (LX-2) utilizing the MTS assay. Moreover, these molecules' antibacterial and antifungal activities were evaluated using a microdilution assay against several bacterial and fungal species. In addition, molecular docking studies were conducted to identify the possible binding interactions between these compounds and their biological targets by using the X-ray crystal structure of the human COX enzyme and different proteins of bacterial and fungal strains. At the same time, the QiKProp module was used for ADME-T analysis. The results showed that all evaluated isoxazole derivatives showed moderate to potent activities against COX enzymes. The most potent compound against COX-1 and COX-2 enzymes was A13, with IC50 values of 64 and 13 nM, respectively, and a significant selectivity ratio of 4.63. It was clear that the 3,4-dimethoxy substitution on the first phenyl ring and the Cl atom on the other phenyl pushed the 5-methyl-isoxazole ring toward the secondary binding pocket and created the ideal binding interactions with the COX-2 enzyme in comparison with the other compounds. Compound A8 showed antibacterial and antifungal activities against Pseudomonas aeruginosa, Klebsiella pneumonia, and Candida albicans with MIC values of 2 mg/ml. In fact, this compound showed possible binding interactions with the elastase in P. aeruginosa and KPC-2 carbapenemase in K. pneumonia. Furthermore, for better understanding, molecular dynamics simulations were undertaken to study the change in dynamicity of the protein backbone and ligand after the ligand binds to the protein and to ensure the stability of ligand–protein complexes. [ABSTRACT FROM AUTHOR]

We developed a DOS approach to the synthesis of hydroxysulfanylazole derivatives (12 examples) using diversification with various N,N‐ and N,O‐binucleophilic reagents of the carbonyl groups of hydroxysulfanyl diketones (6 examples) obtained by the piperidine‐catalyzed thiomethylation reaction involving the С(α)‐Н position of 2,4‐pentanedione with aromatic aldehydes and 2‐mercaptoethanol. X‐ray diffraction analysis was used to determine the structures and crystal packing for three hydroxysulfanylpyrazoles. The calculation of the intermolecular interactions in the crystals (analysis of Hirshfeld surfaces) demonstrated the influence of the substituent nature on the contribution of the H...O/O...H contacts. Using molecular docking studies, justified assumptions were made about the complementarity of the obtained series of compounds to the active sites of COX isoforms. [ABSTRACT FROM AUTHOR]

A series of N-acyl derivatives of anabasine and cytisine were prepared, to discover novel, natural product-based medicinal agents. All synthesized compounds were tested for antimicrobial, antifungal, antiviral and analgesic activity. The most pronounced antibacterial activity was shown by the compounds with isoxazole fragments, while the adamantane derivatives showed the greatest antiviral effect. It was found that the majority of anabasine derivatives showed significant analgesic activity, reducing the pain response of animals to the irritating effect of acetic acid. The presence of a high level of antimicrobial and antiviral activity in newly synthesized compounds makes it possible to consider them promising for further study of their pharmacological properties. [ABSTRACT FROM AUTHOR]

Our previous work identified various novel Chalcones (I-III) produced by mixing the equimolar amount of Ferrocene aldehyde and different substituted acetophenones which has a strong base. Hence, in the present study, novel various Chalcones (I-III) were treated with hydroxylamine hydrochloride to form various Isoxazoles (Ic-IIIc). The synthesized novel chalcone-based Isoxazole derivatives were determined by spectroscopic techniques such as¹H,13C-NMR, FT-IR,and UV. Further, these products were evaluated for antimicrobial studies and antioxidant susceptibilities through DPPH radical scavenging method. The synthesized isoxazole (Ic) was subjected to a study of their anti-inflammatory activity(COX and LOX) assay. [ABSTRACT FROM AUTHOR]

Cancer is a large group of diseases in which the rapid proliferation of abnormal cells generally leads to metastasis to surrounding tissues or more distant ones through the lymphatic and blood vessels, making it the second leading cause of death worldwide. The main challenge in designing a modern anticancer therapy is to develop selective compounds that exploit specific molecular targets. In this work, novel oxazolo[5,4-d]pyrimidine derivatives were designed, synthesized, and evaluated in vitro for their cytotoxic activity against a panel of four human cancer cell lines (lung carcinoma: A549, breast adenocarcinoma: MCF7, metastatic colon adenocarcinoma: LoVo, primary colon adenocarcinoma: HT29), along with their P-glycoprotein-inhibitory ability and pro-apoptotic activity. These oxazolo[5,4-d]pyrimidine derivatives, which are structurally similar to nucleic purine bases in general, are characterized by the presence of a pharmacologically favorable isoxazole substituent at position 2 and aliphatic amino chains at position 7 of the condensed heterocyclic system. In silico analysis of the obtained compounds identified their potent inhibitory activity towards human vascular endothelial growth factor receptor-2 (VEGFR-2). Molecular docking was performed to assess the binding mode of new derivatives to the VEGFR-2 active site. Then, their physicochemical, pharmacokinetic, and pharmacological properties (i.e., ADME—administration, distribution, metabolism, and excretion) were also predicted to assess their druglikeness. In particular, compound 3g (with a 3-(N,N-dimethylamino)propyl substituent) was found to be the most potent against the HT29 cell line, with a 50% cytotoxic concentration (CC50) of 58.4 µM, exceeding the activity of fluorouracil (CC50 = 381.2 μM) and equaling the activity of cisplatin (CC50 = 47.2 µM), while being less toxic to healthy human cells (such as normal human dermal fibroblasts (NHDFs)) than these reference drugs. The results suggest that compound 3g is a potentially promising candidate for the treatment of primary colorectal cancer. [ABSTRACT FROM AUTHOR]

Here, we have developed an expeditious and efficient protocol for the synthesis of isoxazole-5(4H)-ones derivatives using guanidine hydrochloride as a catalyst using water as a solvent. The one-pot multicomponent reaction of aldehydes, ethyl acetoacetate, and hydroxylamine hydrochloride at room temperature to give a 3-methyl-4-(hetero)arylmethylene isoxazole-5(4H)-ones derivatives in an excellent yield. The key advantages of the reported method are shorter reaction time, energy-efficient, easy work-up procedure, wide substrate scope tolerance, economical, etc. further the catalyst was recycled up to 5 times along with high product yield without significant loss of its catalytic activity. [ABSTRACT FROM AUTHOR]

This study described the reactions of 5-methylisoxazol-3-amine with activated enol ethers in the reflux of xylene. When enol ethers are diethyl ethoxymethylenemalonates, the intermediates isoxazolyl enamines were converted to the corresponding isoxazolopyrimidinones. The products of these reactions are isoxazolylenamines when enol ethers are ethoxymethylenecyanoacetate, or ethoxymethylenemalononitrile. All the synthesized compounds were characterized by, MS, IR and NMR spectroscopy. [ABSTRACT FROM AUTHOR]

An efficient approach has been developed for the trapping in situ generated benzopyrone-based ortho-quinone methide intermediates by 3- and 5-amino pyrazoles or isoxazoles. In cases of naturally occurring phenolic Mannich bases, hybrid compounds between the azole and flavonoid, namely, coumarin, chromone, isoflavone, and aurone were synthesized in moderate to good yields. It is remarkable that depending on 3- or 5-position of the amino group, the reaction led to the formation of C-4 or 3-NH substituted azole derivatives, respectively. In vitro studies showed that some of the obtained compounds bearing 5-aminoisoxazole part exhibit inhibitory activity towards α-glucosidase with IC 50 values in the micromolar range., (© 2024 Wiley-VCH GmbH.)

Abstract Background Liver cancer is predicted to be the sixth most diagnosed cancer globally and fourth leading cause of cancer deaths. In this study, a series of indole-3-isoxazole-5-carboxamide derivatives were designed, synthesized, and evaluated for their anticancer activities. The chemical structures of these of final compounds and intermediates were characterized by using IR, HRMS, 1H-NMR and 13C-NMR spectroscopy and element analysis. Results The cytotoxic activity was performed against Huh7, MCF7 and HCT116 cancer cell lines using sulforhodamine B assay. Some compounds showed potent anticancer activities and three of them were chosen for further evaluation on liver cancer cell lines based on SRB assay and real-time cell growth tracking analysis. Compounds were shown to cause arrest in the G0/G1 phase in Huh7 cells and caused a significant decrease in CDK4 levels. A good correlation was obtained between the theoretical predictions of bioavailability using Molinspiration calculation, Lipinski’s rule of five, and experimental verification. These investigations reveal that indole-isoxazole hybrid system have the potential for the development of novel anticancer agents. Conclusions This study has provided data that will form the basis of further studies that aim to optimize both the design and synthesis of novel compounds that have higher anticancer activities.

The present study aimed to design and synthesize a series of phenyl-isoxazole-carboxamide derivatives and investigate their antitumor and antioxidant activities. The in vitro cytotoxic evaluation was conducted using the MTS assay against four cancer cell lines: hepatocellular carcinoma (Hep3B and HepG2), cervical adenocarcinoma (HeLa), breast carcinoma (MCF-7), in addition to the normal cell line (Hek293T). Besides, the antioxidant activity was evaluated using a 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. All obtained compounds were found to have potent to moderate activities against Hep3B and MCF-7 cancer cells lines, except compound 2e. It was found that compound 2a has potent activity against HeLa and Hep3B cancer cell lines with IC50 values of 0.91 and 8.02 µM, respectively. The IC50 dose range of the tested compounds against Hep3B was 5.96–28.62 µM, except for 2e, compared with doxorubicin, which has an IC50 value of 2.23 µM. Also, the IC50 value range of the compounds against Hek293T was 112.78–266.66 µM, compared with doxorubicin, which has an IC50 dose of 0.581 µM. The antioxidant activity of the synthesized compounds was weak, and compound 2d showed moderate activity against the DPPH enzyme with an IC50 value of 138.50 µM in comparison with Trolox, which has an IC50 dose of 37.23 µM.

Isoxazolo[3,4-d] pyridazinones ([3,4-d]s) were previously shown to have selective positive modulation at the metabotropic glutamate receptor (mGluR) Subtypes 2 and 4, with no functional cross-reactivity at mGluR1a, mGluR5, or mGluR8. Additional analogs were prepared to access more of the allosteric pocket and achieve higher binding affinity, as suggested by homology modeling. Two different sets of analogs were generated. One uses the fully formed [3,4-d] with an N6-aryl with and without halogens. These underwent successful selective lateral metalation and electrophilic quenching (LM&EQ) at the C3 of the isoxazole. In a second set of analogs, a phenyl group was introduced at the C4 position of the [3,4-d] ring via a condensation of 4-phenylacetyl-3-ethoxcarbonyl-5-methyl isoxazole with the corresponding hydrazine to generate the 3,4-ds 2b and 2j to 2n.

Histone deacetylases (HDACs) are an attractive drug target for the treatment of human breast cancer (BC), and therefore, HDAC inhibitors (HDACis) are being used in preclinical and clinical studies. The need to understand the scope of the mode of action of HDACis, as well as the report of the co-crystal structure of HDAC6/SS-208 at the catalytic site, provoked us to develop an isoxazole-based lead structure called 4-(2-(((1-(3,4-dichlorophenyl)-1H-1,2,3-triazol-4-yl)methyl)thio) pyrimidin-4-yl) morpholine (5h) and 1-(2-(((3-(p-tolyl) isoxazol-5-yl)methyl)thio) pyrimidin-4-yl) piperidin-4-one (6l) that targets HDACs in human BC cells. We found that the compound 5h or 6l could inhibit the proliferation of BC cells with an IC50 value of 8.754 and 11.71 µM, respectively. Our detailed in silico analysis showed that 5h or 6l compounds could target HDAC in MCF-7 cells. In conclusion, we identified a new structure bearing triazole, isoxazole, and thiouracil moiety, which could target HDAC in MCF-7 cells and serve as a base to make new drugs against cancer.

[Display omitted] The Baeyer–Villiger oxidation of apiolaldehyde bearing o -(3- p -anisylisoxazolin-5-yl)methyl substituent proceeds first with the formation of the anticipated phenol. The subsequent oxidation of phenol with destruction of methylenedioxy ring leads to p -quinone derivative which would undergo opening of the benzene ring to finally produce maleic anhydride moiety. The structure of new compounds was proved by X-ray diffraction analysis. [ABSTRACT FROM AUTHOR]

Reactions of ethyl 3-(4-oxo-4H-chromen-3-yl)prop-2-enoates with 1,2-binucleophilic agents (hydrazine, phenylhydrazine, hydroxylamine) leads to the formation of some new pyrazole and isoxazole derivatives. The reactions proceed under mild conditions (ethanol, room temperature) to form the title products with high yields (71–99%). [ABSTRACT FROM AUTHOR]

The hybrid peptides consisting of α and β-amino acids show great promise as peptidomimetics that can be used as therapeutic agents. Therefore, the development of new unnatural amino acids and the methods of their incorporation into the peptide chain is an important task. Here, we described our investigation of the possibility of 5-amino-3-methyl-isoxazole-4-carboxylic acid (AMIA) application in the solid phase peptide synthesis. This new unnatural β-amino acid, presenting various biological activities, was successfully coupled to a resin-bound peptide using different reaction conditions, including classical and ultrasonic agitated solid-phase synthesis. All the synthesized compounds were characterized by tandem mass spectrometry. The obtained results present the possibility of the application of this β-amino acid in the synthesis of a new class of bioactive peptides. [ABSTRACT FROM AUTHOR]

Isoxazole derivatives are significant enough due to their wide range of pharmacological and therapeutic activities. The purpose of the current study is to use computational, in vitro, in vivo, and extensive molecular approaches to examine the possible anti-ulcer activity of 4-benzylidene-3 methyl-1,2-isoxazol-5(4H)-one (MBO). Biovia Discovery Studio visualizer (DSV) was utilized for virtual screening. A tissue antioxidant investigation, H+/K+-ATPase test, and anti-H. pylori activities were carried out. ELISA, immunohistochemistry, and PCR methods were employed for the proteome analysis. An ethanol-induced stomach ulcer model was used to examine the anti-ulcer potential in rats. The binding affinities for MBO ranged from −5.4 to −8.2 Kcal/mol. In vitro findings revealed inhibitory activity against H. pylori and the H+/K+-ATPase pump. It also enhanced levels of glutathione, catalase, and glutathione-S-transferase and reduced lipid peroxidation levels in gastric tissues of rats. In vivo results showed the gastro-protective effect of MBO (30 mg/kg) in ulcerative rat stomachs. The proteomic study revealed decreased expression of inflammatory markers (cyclooxygenase-2, p-NFkB, and TNF-α). In RT-PCR analysis, the expression levels of H+/K+-ATPase were reduced. Furthermore, ADMET (absorption, distribution, metabolism, excretion and toxicity) studies revealed that MBO has high GIT solubility and has a safer profile for cardiac toxicity. This study suggests that MBO displayed anti-ulcer potential, which may have been mediated through the inhibition of the H+/K+-ATPase pump, as well as antioxidant and anti-inflammatory pathways. It has the potential to be a lead molecule in the treatment of peptic ulcers with fewer adverse effects. [ABSTRACT FROM AUTHOR]

The synthesis of substituted 3‐isoxazolethioethers and their bioevaluation as anti‐leishmanial and anti‐bacterial agents are described. The DBU‐catalyzed thioetherification of substituted 3‐nitroisoxazoles via nucleophilic aromatic substitution (SNAr) reaction using aromatic, aliphatic and heteroaromatic thiols gave the title compounds in good yields. These 3‐thioisoxazole derivatives were synthetically modified to prepare new compounds including 3‐phenylbenzo[b]isoxazolo[4,3‐f][1,4]thiazepin‐4(5H)‐ones. Four compounds displayed promising activity against amastigote stage of L. donovani whereas two compounds displayed good antibacterial effect. [ABSTRACT FROM AUTHOR]

Green synthetic tools involve the design, synthesis and use of chemical substances by eliminating the generation of chemical hazards. This technique is advantageous in terms of atom economy, use of safer chemicals, energy efficient and decomposition of the waste materials to nontoxic substances which are eco-friendly. So, microwave irradiated heating method is applied for the generation of novel isoxazole derivatives. The structure of isoxazoles moiety contains three carbon atoms, one oxygen atom and one nitrogen atom in the five membered ring. Isoxazole scaffold exhibits diverse pharmacological activities such as anti-viral, antitubercular, anti-diabetic, anticancer, anthelmintic, antimicrobial, antifungal, antioxidant, antiepileptic, antipsychotic etc. A series of novel isoxazole derivatives are synthesized under microwave irradiation. By the help of microwave, the rate of the reaction is enhanced which leads to high selectivity with better product yield as compared to the conventional heating methods. The titled compounds are evaluated for their antiepileptic activity by using maximal electroshock (MES) method. The screening results revealed that some of the compounds exhibited promising antiepileptic activity as compared to the standard drug. [ABSTRACT FROM AUTHOR]

The current study aimed to design and synthesize a novel series of fluorophenyl-isoxazole-carboxamide derivatives and evaluate their antiproliferative activities. Anticancer activities of the novel compounds were evaluated by MTS assay against four cancer cell lines, including liver (Hep3B, HepG2), cervical (HeLa), and breast (MCF-7), and α-fetoprotein tumor marker, cell cycle analysis, and annexin V tests. Chemo-informatics analysis showed that all synthesized derivatives 2a–2f obeyed Lipinski’s rule. Compound 2f was the most potent compound against Hep3B and Hep-G2 cancer cell lines with IC50 values of 5.76 and 34.64 µg/mL, respectively. Moreover, compounds 2a–2c and 2e showed potent inhibitory activity against Hep3B with an IC50 value range of 7.66–11.60 µg/mL. Hep3B secretions of α-fetoprotein (α-FP) results showed that compound 2f reduced the secretion of Hep3B to 168.33 ng/mL and compound 2d reduced the secretion to value approximately 598.33 ng/mL, in comparison with untreated cells’ value of 1116.67 ng/mL. Furthermore, cell cycle analysis showed that the 2f compound induced arrest in the G2-M phase in 6.73% of the total cells and that was lower than the activity of the positive control doxorubicin (7.4%). Moreover, 2b and 2f compounds reduced the necrosis rate of Hep3B to 4-folds and shifted the cells to apoptosis.

• A series of 3,5-disubstituted Isoxazole-linked benzimidazolone derivatives was synthesized. • The synthesized isoxazoles were characterized using1H and 13C NMR, HRMS and single-crystal XRD. • All synthesized compounds were evaluated for their antioxidant activities and acute toxicity. • DFT calculations and Hirshfeld surface analysis were performed. A series of new isoxazole derivatives containing a benzimidazolone has been synthesized by cycloaddition reaction using various nitrile oxides. In all cases, these cycloadditions are completely chemo and regioselective. The structures of the new cycloadducts were characterized by 1H, 13C NMR spectroscopy, HRMS and confirmed in one case by a single crystal structure determination. The isoxazole compounds were evaluated for in vitro antioxidant activity using the DPPH and ABTS methods. As a result, compound 5a showed good antioxidant activity. The results of the acute toxicity study of the heterocycles studied by the oral route showed no deaths and no clinical signs of toxicity. Additionally, the Hirshfeld surface analysis and the molecular electrostatic potential using density functional theory (DFT) modeling at the B3LYP/6–31G(d,p) level. Hirshfeld surface analysis (d norm surface and 2D-fingerprint plots) revealed the nature of intermolecular contacts. H⋯H interactions make the most significant contribution to crystal packing. The optimized structural parameters obtained through DFT calculations closely matched those determined via X-ray analysis, demonstrating strong agreement between theoretical predictions and experimental observations. [Display omitted] [ABSTRACT FROM AUTHOR]

The title compound, C17H13NO3, adopts a Z configuration about the C=C bond. The isoxazole and methoxybenzylidene rings are almost coplanar with a dihedral angle of 9.63 (7)° between them. In contrast, the phenyl substituent is twisted significantly out of the plane of the oxazole ring, with the two rings inclined to each other by 46.22 (4)°. The crystal structure features C—H...O, C—H...N and C—H...π hydrogen bonds and π–π contacts. An analysis of the Hirshfeld surfaces points to the importance of H...H, H...C/C...H and H...O/O...H contacts. The included surface areas of the title compound were compared to those of the isomeric structure (Z)-4-(4-methoxybenzylidene)-3-phenylisoxazol-5(4H)-one [Zhang et al. (2015). CrystEngComm, 17, 7316–7322].

The title compound, C9H7NO2S crystallizes with two independent molecules (A and B) in the asymmetric unit with Z = 8. Both molecules are almost planar with a dihedral angle between the isoxazole and thiophen rings of 3.67 (2)° in molecule A and 10.00 (1) ° in molecule B. The packing of molecules A and B is of an ABAB... type along the b-axis direction, the configuration about the C=C bond is Z. In the crystal, the presence of C—H...O, C—H... N and π–π interactions [centroid–centroid distances of 3.701 (2) and 3.766 (2) Å] link the molecules into a three-dimensional architecture. An analysis of Hirshfeld surfaces shows the importance of C—H...O and C—H...N hydrogen bonds in the packing mechanism of the crystalline structure.

The identification of chemically different inhibitors that target the colchicine site of tubulin is still of great value for cancer treatment. Combretastatin A-4(CA-4), a naturally occurring colchicine-site binder characterized by its structural simplicity and biological activity, has served as a structural blueprint for the development of novel analogues with improved safety and therapeutic efficacy. In this study, a library of forty-eight 4-phenyl-5-quinolinyl substituted triazole, pyrazole or isoxazole analouges of CA-4, were synthesized and evaluated for their cytotoxicity against Esophageal Squamous Cell Carcinoma (ESCC) cell lines. Compound C11 , which features a 2-methyl substitution at the quinoline and carries an isoxazole ring, emerged as the most promising, with 48 h IC 50 s of less than 20 nmol/L against two ESCC cell lines. The findings from EBI competitive assay, CETA, and in vitro tubulin polymerization assay of C11 are consistent with those of the positive control colchicine, demonstrating the clear affinity of compound C11 to the colchicine binding site. The subsequent cellular-based mechanism studies revealed that C11 significantly inhibited ESCC cell proliferation, arrested cell cycle at the M phase, induced apoptosis, and impeded migration. Experiments conducted in vivo further confirmed that C11 effectively suppressed the growth of ESCC without showing any toxicity towards the selected animal species. Overall, our research suggests that the tubulin polymerization inhibitor incorporating quinoline and the isoxazole ring may deserve consideration for cancer therapy. [Display omitted] • A library of forty-eight 4-phenyl-5-quinolinyl substituted triazole, pyrazole or isoxazole, analouges of CA-4, was synthesized. • Compound C11 showed low nanomolar IC 50 values of less than 20 nmol/L against two ESCC cell lines. • Compound C11 inhibited tubulin polymerization by binding to the colchicine site. • Compound C11 effectively suppressed ESCC cells in vitro and in vivo. [ABSTRACT FROM AUTHOR]

The biological significance of benzopyran-4-ones as cytotoxic agents against multi-drug resistant cancer cell lines and isoxazoles as anti-inflammatory agents in cellular assays prompted us to design and synthesize their hybrid compounds and explore their antiproliferative activity against a panel of six cancer cell lines and two normal cell lines. Compounds 5a–d displayed significant antiproliferative activities against all the cancer cell lines tested, and IC50 values were in the range of 5.2–22.2 μM against MDA-MB-231 cancer cells, while they were minimally cytotoxic to the HEK-293 and LLC-PK1 normal cell lines. The IC50 values of 5a–d against normal HEK-293 cells were in the range of 102.4–293.2 μM. Compound 5a was screened for kinase inhibitory activity, proteolytic human serum stability, and apoptotic activity. The compound was found inactive towards different kinases, while it completely degraded after 2 h of incubation with human serum. At 5 μM concentration, it induced apoptosis in MDA-MB-231 by 50.8%. Overall, these findings suggest that new benzopyran-4-one-isoxazole hybrid compounds, particularly 5a–d, are selective anticancer agents, potentially safe for human cells, and could be synthesized at low cost. Additionally, Compound 5a exhibits potential anticancer activity mediated via inhibition of cancer cell proliferation and induction of apoptosis.

New fluorescent dyes containing an assembled 1,4-dihydroazolo[5,1-c][1,2,4]triazine (DAT) core and an isoxazole ring were synthesized through a reaction between diazopyrazole or diazoimidazoles and isoxazolyl-derived enamines in mild conditions. The photophysical characteristics (maxima absorption and emission, Stokes shifts, fluorescent quantum yields, and fluorescence lifetimes) of the new fluorophores were obtained. The prepared DATs demonstrated emission maxima ranging within 433–487 nm, quantum yields within 6.1–33.3%, and a large Stokes shift. The photophysical characteristics of representative DAT examples were studied in ten different solvents. Specific (hydrogen bonds) and non-specific (dipole–dipole) intermolecular and intramolecular interactions were analyzed using XRD data and spectral experiments. Solvatochromism was analyzed using Lippert–Mataga and Dimroth–Reichardt plots, revealing the relationship between the DAT structure and the nature of solute–solvent interactions. The significant advantages of DATs are the fluorescence of their powders (QY up to 98.7%). DAT-NMe2 10 expressed bright aggregation-induced emission (AIE) behavior in DMSO and THF as the water content increased. The numerous possible variations of the structures of the heterocycles included in the DATs, as well as substituents, create excellent prospects for adjusting their photophysical and physicochemical properties.

Background: Cancer is one of the most dangerous and widespread diseases in the world today and it has risen to the position of the leading cause of death around the globe in the last few decades. Due to the inherent resistance of many types of cancer to conventional radiotherapy and chemotherapy, it is vital to develop innovative anticancer medications. Recently, a strategy based on nanotechnology has been used to improve the effectiveness of both old and new cancer drugs. Objectives: The present study aimed to design and synthesize a series of phenyl-isoxazole–Carboxamide derivatives, evaluate their anticancer properties, and improve the permeability of potent compounds into cancer cells by using a nano-emulgel strategy. Methods: The coupling reaction of aniline derivatives and isoxazole–Carboxylic acid was used to synthesize a series of isoxazole–Carboxamide derivatives. IR, HRMS, 1H-NMR, and 13C-NMR spectroscopy techniques, characterized all the synthesized compounds. The in-vitro cytotoxic evaluation was performed by using the MTS assay against seven cancer cell lines, including hepatocellular carcinoma (Hep3B and HepG2), cervical adenocarcinoma (HeLa), breast carcinoma (MCF-7), melanoma (B16F1), colorectal adenocarcinoma (Caco-2), and colon adenocarcinoma (Colo205), as well as human hepatic stellate (LX-2) in addition to the normal cell line (Hek293T). A nano-emulgel was developed for the most potent compound, using a self-emulsifying technique. Results: All synthesized compounds were found to have potent to moderate activities against B16F1, Colo205, and HepG2 cancer cell lines. The results revealed that the 2a compound has broad spectrum activity against B16F1, Colo205, HepG2, and HeLa cancer cell lines with an IC50 range of 7.55–40.85 µM. Moreover, compound 2e was the most active compound against B16F1 with an IC50 of 0.079 µM compared with Dox (IC50 = 0.056 µM). Nanoemulgel was used to increase the potency of the 2e molecule against this cancer cell line, and the IC50 was reduced to 0.039 µM. The antifibrotic activities were investigated against the LX-2 cell line, and it was found that our synthesized molecules showed better antifibrotic activities at 1 µM than 5-FU, and the cell viability values were 67 and 95%, respectively. Conclusion: This study suggests that a 2e nano-formalized compound is a potential and promising anti-melanoma agent. [ABSTRACT FROM AUTHOR]

An efficient method of producing quinine derivatives via reaction of acylation with 4,5-dichloroisothiazole-3-, 5-arylisoxazole-3-, adamantane- and hydrochlorides of pyridine-3- and pyridine-4-carbonyl chlorides was developed. All synthesized compounds were tested for antiviral, antimicrobial and analgesic activity. The most pronounced antibacterial activity was shown by the compounds 2e, 3b, 3c and 3e with isoxazole and pyridine fragments. It was found that most of the tested compounds showed significant analgesic activity reducing the pain response of animals to the irritating effect of acetic acid. [ABSTRACT FROM AUTHOR]

In the present study, a novel series of isoxazole derivatives containing phenothiazine-sulfonamide (IIIa–k) were synthesized by the Cu(I) catalyzed reaction of nitrile oxides generated in situ with 1-nitro-N- (prop-2-yn-1-yl)-10H-phenothiazin-3-sulfonamide with good yields. Newly synthesized compounds were screened for their antibacterial activity. Among all the compounds synthesized, (IIIk) and (IIIh) showed excellent inhibition against all the bacterial strains tested with MICs ranging from 1.56 ± 0.21 to 6.25 ± 0.49 µg/mL. While the rest of the compounds showed moderate to low activity against all strains tested compared to standard streptomycin. [ABSTRACT FROM AUTHOR]

A method for the synthesis of 5-arylisoxazole- and 4,5-dichloroisothiazole-3-carboxylic acids derivatives based on 4-acetyl- and 4-benzoylpyridine has been developed. Esters and amides were prepared by acylation of (pyridin-4-yl)methanols and (pyridin-4-yl)methanamines with acid chlorides of substituted 1,2-azole-3-carboxylic acids in ether or methylene chloride in the presence of triethylamine. Quaternary ammonium salts of synthesized pyridine derivatives were also obtained. [ABSTRACT FROM AUTHOR]

In this study, 7 new isoxazole compounds (8-14) were synthesized from the cyclization of chalcone compounds (1-7) containing different functional groups with hydroxylamine hydrochloride in alkaline medium. Tyrosinase and antioxidant properties of 8-14 were investigated. IC50 values for the tyrosinase enzyme inhibition of compounds 8, 11, 12, and 13 were varied between 61.47 ± 3.46 and 188.52 ± 5.85, while compounds 9, 10 and 14 did not show any inhibition effect. The antioxidant properties of 8-14 were investigated by DPPH and CUPRAC methods. Compound 12 showed the best DPPH radical scavenging activity (SC50: 40.21 ± 2.71), while 12 and 13 had shown the greatest Cupric ion reducing effect as 1.233 ± 0.015 and 1.245 ± 0.019 mg TEAC/mg, respectively. As a result, the change of functional groups in the synthesized compounds caused a significant difference in the biological properties of 8-14. [ABSTRACT FROM AUTHOR]

A series of novel benzo[1,2,3]selenadiazole–isoxazole hybrid compounds were designed and synthesized from natural (R)-carvone. These derivatives were synthesized from the selenation reaction between the corresponding semicarbazones and selenium dioxide (SeO2) in the presence of glacial acetic acid as a solvent. The structures of the newly synthesized products were fully characterized by spectroscopic analysis (1H, 13C NMR) and HRMS. All the synthesized compounds were tested in vitro against four human cancer cell lines, fibrosarcoma (HT-1080), lung (A-549) and breast (MCF-7 and MDA-MB-231) carcinoma to evaluate their anticancer activity. Most of the semicarbazones and some of the benzo[1,2,3]selenadiazole–isoxazole hybrids showed interesting cell growth inhibitory activity with IC50 values ranging from 10 to 20 µM. Furthermore, semicarbazone bearing 3-phenylisoxazole nucleus and the benzo[1,2,3]selenadiazole-3-p-chlorophenylisoxazole hybrid exhibited significant antiproliferative activity against HT-1080 cells with IC50 values close to 10.9 ± 1.2 and 18.6 ± 2.6 μM, respectively. Furthermore, the semicarbazone bearing a phenyl group on C3 position of the isoxazole nucleus and the 3-(4-chlorophenyl)-benzo[1,2,3]selenadiazole–isoxazole hybrid had a quite good survival performance against MRC5 cells. The mechanism of action of this latter suggested that it induces apoptosis through caspase-3/7 activation. [ABSTRACT FROM AUTHOR]

Herein, we report a multi-component reaction (MCRs) to synthesise a range of 3-phenyl-5-(bromomethyl)isoxazoles analogues using DMF/water mixture as solvent, providing desired products in good to excellent yields. The reaction efficiently involves the 1,3-dipolar cycloaddition reaction between propargyl bromide and in situ-generated α-chloro aldoximes. The protocol proceeded well under mild metal-free conditions and showed a tolerance for a wide range of substituents. [ABSTRACT FROM AUTHOR]

In the present work a series of heterocyclization reactions were adopted using cyclohexan-1,3-dione through its reaction with either furan-2-carbaldehyde or thiophene-2-carbaldehyde to give the corresponding ylidene derivatives 3a,b. The latter compounds underwent heterocyclization reactions to give thiophene and pyran derivatives 5a–d and 6a–d, respectively. Moreover, compounds 3a,b reacted with elemental sulfur and phenyl isothiocyanate to give the fused thiazole derivatives 8a,b. In addition, the reaction with either of hydrazine hydrate or phenylhydrazine has given the 4-hydrazono-4,5,6,7-tetrahydro-2H-indazole derivatives 10a–d, respectively. Similarly, the reaction of either 3a or 3b with hydroxylamine hydrochloride gave the 6,7-dihydrobenzo[c]isoxazol-4(5H)-one oxime derivatives 12a and 12b, respectively. Other fused heterocyclic compounds were produced and their structures were elucidated. Evaluation of the synthesized compounds against selected cancer cell lines was performed. The most active compounds were further evaluated against tyrosine kinases and Pim-1 kinase inhibitions.

Herein, synthesis of new 4-azaindole-1,2,4-isoxazoles by Cu(I)-catalyzed 1,3-dipolar cycloaddition reaction of [4-(prop-2-yn-1-yl)piperazin-1-yl](1H-pyrrolo[3,2-b]pyridin-3-yl)methanone with several aromatic aldehydes is presented. All products have been tested for their in vitro anticancer activity against three human cancer cell lines including A549 (lung), A375 (melanoma) and MCF7 (breast). The results of the tests indicate that two products are highly active against all cell lines with the activity superior to that of the standard doxorubicin. Also two products demonstrate inhibitory activity against tyrosine kinase EGFR higher than that of Erlotinib. [ABSTRACT FROM AUTHOR]

Base-free reaction of dichloroglyoxime with copper(i) acetylides gave 3,3′-biisoxazoles via a nucleophilic substitution of the chlorine atom of dichloroglyoxime with the acetylene moiety followed by cyclization of the intermediate formed. The effects of the solvent on the product yields were studied. In the case of substituted copper acetylides, 5,5′-disubstituted 3,3′-biisoxazoles were obtained in the yields from moderate to high and high regioselectivity. [ABSTRACT FROM AUTHOR]

The title compounds, C11H11N3O3, (I), and C10H10N2O2, (II), are commercially available and were crystallized from ethyl acetate solution. The dihedral angle between the pyrazole and phenyl rings in (I) is 52.34 (7)° and the equivalent angle between the isoxazole and phenyl rings in (II) is 7.30 (13)°. In the crystal of (I), the mol­ecules form carb­oxy­lic acid inversion dimers with an R(8) ring motif via pairwise O--H···O hydrogen bonds. In the crystal of (II), the mol­ecules are linked via N--H···N hydrogen bonds forming chains propagating along [010] with a C(5) motif. A weak N--H···π inter­action also features in the packing of (II). Hirshfeld surface analysis was used to explore the inter­molecular contacts in the crystals of both title compounds: the most important contacts for (I) are H···H (41.5%) and O···H/H···O (22.4%). For (II), the most significant contact percentages are H···H (36.1%) followed by C···H/H···C (31.3%). [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is now ranked as the third leading cause of death after heart disease and cancer. There is no definite cure for AD due to the multi-factorial nature of the disease, hence, multi-target-directed ligands (MTDLs) have attracted lots of attention. In this work, focusing on the efficient cholinesterase inhibitory activity of tacrine, design and synthesis of novel arylisoxazole-tacrine analogues was developed. In vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition assay confirmed high potency of the title compounds. Among them, compounds 7l and 7b demonstrated high activity toward AChE and BChE with IC50 values of 0.050 and 0.039 μM, respectively. Both compounds showed very good self-induced Aβ aggregation and AChE-induced inhibitory activity (79.4 and 71.4% for compound 7l and 61.8 and 58.6% for compound 7b, respectively). Also, 7l showed good anti-BACE1 activity with IC50 value of 1.65 µM. The metal chelation test indicated the ability of compounds 7l and 7b to chelate biometals (Zn2+, Cu2+, and Fe2+). However, they showed no significant neuroprotectivity against Aβ-induced damage in PC12 cells. Evaluation of in vitro hepatotoxicity revealed comparable toxicity of compounds 7l and 7b with tacrine. In vivo studies by Morris water maze (MWM) task demonstrated that compound 7l significantly reversed scopolamine-induced memory deficit in rats. Finally, molecular docking studies of compounds 7l and 7b confirmed establishment of desired interactions with the AChE, BChE, and BACE1 active sites. [ABSTRACT FROM AUTHOR]

A series of amino derivatives of 5-arylisoxazoles and 4,5-dichloroisothiazole with primary and secondary amino groups was synthesized. 3-Aminomethyl-5-arylisoxazol-3-ylmethanamines were obtained on the basis of 5-aryl-3-(chloromethyl)isoxazoles using the Gabriel phthalimide method. 5-Arylisoxazol-3-yl- and 4,5-dichloroisothiazol-3-ylallylamines were synthesized in two ways: reduction of azomethines obtained by condensation of 5-arylisoxazolyl- and 4,5-dichloroisothiazolyl-3-carbaldehydes with allylamine, and by nucleophilic substitution of the chlorine atom in 3-chloromethyl derivatives of the corresponding azoles by reaction with allylamine. Amides and sulfonamides of azolylallylamines were synthesized. Some of the compounds obtained showed antibacterial and fungicidal activity. [ABSTRACT FROM AUTHOR]

A set of new heterocyclic substituted thiazole derivatives were synthesized as powerful analgesic and antiinflammatory agents with minimal ulcer index. Spectroscopic and elemental analyses were employed to confirm the chemical structures of the prepared compounds. Molecular properties, ADME properties, drug-likeness scores, and toxicities of title compounds were predicted using insilico studies. In addition, title compounds were docked against two proteins namely, 3KK6 and 3LN1 using AutoDock 4.2. Tail-flick method and carrageenan-induced foot paw oedema methods were used to screen in vitro analgesic and anti-inflammatory activities of title compounds, respectively. Moreover, the ulcerogenicity of potent compounds of the series was also determined. Most of the novel heterocyclic substituted thiazoles produced, mild-to-good analgesic and anti-inflammatory activity with a low-toreasonable ulcer index. Out of thirteen tested derivatives the most potent compound was found to be 1-(4-chlorophenyl)-4-(2-(4-(4-methoxyphenyl)thiazol-2-yl)hydrazono)-3-methyl-1H-pyrazol-5(4H)-one. [ABSTRACT FROM AUTHOR]

In this study, a novel series of isoxazole-naphthalene derivatives as tubulin polymerization inhibitors were designed, synthesized and evaluated for their anti-proliferative activities against human breast cancer cell line MCF-7. Most of the synthesized compounds exhibited moderate to potent antiproliferative activity (IC50

Sixteen new isoxazole tagged indole compounds have been synthesized via copper (I) catalyzed click chemistry of the aryl hydroxamoyl chloride and an indole containing alkyne moiety. The chemical structure of the synthesized compounds has been established using various physicochemical techniques. X-ray single crystal analysis of Ethyl 1-((3-phenylisoxazol-5-yl) methyl)-1H-indole-2-carboxylate (8a) has been analyzed. All compounds were tested for their antibacterial and anticancer activities. The activities for the new compounds were weak against both bacterial strains and the cancer cell lines.

The reaction of dimedone with arylaldehydes gave the benzylidene derivatives 3a–c, the latter underwent a series of heterocyclization reactions to give fused thiophene, pyrazole isoxazole and pyridazine derivatives. The synthesized compounds were evaluated against different kinds of cancer cell lines together tyrosine kinases and Pim-1 kinase inhibitions. All the synthesized compounds were assessed for the inhibitory activities against A549 (non-small cell lung cancer), H460 (human lung cancer), HT-29 (human colon cancer) and MKN-45 (human gastric cancer) cancer cell lines together with foretinib as the positive control by a MTT assay. The promising compounds were 3c, 5b, 5e, 5f, 7c, 7f, 9c, 11b, 12c, 12d, 13b, 13d, 14b, 16c and 16d among the tested compounds. On the other hand, compounds 5b, 5e, 5f, 7c, 11b, 12c, 12d, 13d, 14b, 16c and 16d were the most effective inhibitors against tyrosine kinases and compounds 5b, 11b, 12d, 13d, 14b and 16c were the most potent against Pim-1 kinase.

A series of novel thiourea and amide liquid crystals containing 5-membered isoxazoline and isoxazole rings were synthetized and the liquid crystal properties studied. Thioureas were obtained using a condensation reaction of benzoyl chlorides, arylamines and ammonium thiocyanate. The amides, on the other hand, were the byproduct of a quantitative reaction which used potassium cyanate as the starting material. Thiourea and amide derivatives were predominantly SmA mesophase inductors. A nematic mesophase was observed only for thioureas and amides containing an isoxazole ring. Additionaly, the liquid crystal behavior was also dependent on the relative position of nitrogen and oxygen atoms on the 5-membered heterocycle.

In search of synthetically accessible open-ring analogs of PD144418 or 5-(1-propyl-1,2,5,6-tetrahydropyridin-3-yl)-3-(p-tolyl)isoxazole, a highly potent sigma-1 receptor (σ1R) ligand, we herein report the design and synthesis of sixteen arylated acyl urea derivatives. Design aspects included modeling the target compounds for drug-likeness, docking at σ1R crystal structure 5HK1, and contrasting the lower energy molecular conformers with that of the receptor-embedded PD144418—a molecule we opined that our compounds could mimic pharmacologically. Synthesis of our acyl urea target compounds was achieved in two facile steps which involved first generating the N-(phenoxycarbonyl) benzamide intermediate and then coupling it with the appropriate amines weakly to strongly nucleophilic amines. Two potential leads (compounds 10 and 12, with respective in vitro σ1R binding affinities of 2.18 and 9.54 μM) emerged from this series. These leads will undergo further structure optimization with the ultimate goal of developing novel σ1R ligands for testing in neurodegeneration models of Alzheimer’s disease (AD).

A practical method was developed for the convenient synthesis of isoxazole-fused tricyclic quinazoline alkaloids. This procedure accesses diverse isoxazole-fused tricyclic quinazoline alkaloids and their derivatives via intramolecular cycloaddition of methyl azaarenes with tert-butyl nitrite (TBN). In this method, TBN acts as the radical initiator and the source of N–O. Moreover, this protocol forms new C–N, C–C, and C–O bonds via sequence nitration and annulation in a one-pot process with broad substrate scope and functionalization of natural products.

Isoxazoles and isoxazolines are five-membered heterocyclic molecules containing nitrogen and oxygen. Isoxazole and isoxazoline are the most popular heterocyclic compounds for developing novel drug candidates. Over 80 molecules with a broad range of bioactivities, including antitumor, antibacterial, anti-inflammatory, antidiabetic, cardiovascular, and other activities, were reviewed. A review of recent studies on the use of isoxazoles and isoxazolines moiety derivative activities for natural products is presented here, focusing on the parameters that affect the bioactivity of these compounds.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects the elderly population globally and there is an urgent demand for developing novel anti-AD agents. In this study, a new series of indole-isoxazole carbohydrazides were designed and synthesized. The structure of all compounds was elucidated using spectroscopic methods including FTIR, 1 H NMR, and 13 C NMR as well as mass spectrometry and elemental analysis. All derivatives were screened for their acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activity. Out of all synthesized compounds, compound 5d exhibited the highest potency as AChE inhibitor with an IC 50 value of 29.46 ± 0.31 µM. It showed significant selectivity towards AChE, with no notable inhibition against BuChE. A kinetic study on AChE for compound 5d indicated a competitive inhibition pattern. Also, 5d exhibited promising BACE1 inhibitory potential with an IC 50 value of 2.85 ± 0.09 µM and in vitro metal chelating ability against Fe 3+ . The molecular dynamic studies of 5d against both AChE and BACE1 were executed to evaluate the behavior of this derivative in the binding site. The results showed that the new compounds deserve further chemical optimization to be considered potential anti-AD agents., (© 2024. The Author(s).)

Alkaloid-based urea derivatives were produced with high yield through the reaction of anabasine and cytisine with isoxazolylphenylcarbamates in boiling benzene. Their antitumor activity, in combination with the commonly used five anticancer drugs, namely cyclophosphane, fluorouracil, etoposide, cisplatin, ribomustine with different mechanisms of action, was investigated. Based on the quantum chemical calculations data and molecular docking, hypotheses have been put forward to explain their mutual influence when affecting C6 rat glioma model cells.