Search Results (200)

The isoxazole-5-one ring system is a central structure in many synthetic bioactive molecules, showing a wide range of biological activities, including antibacterial, antitumor, anticorrosion, antifungal, antituberculosis, and antioxidant. They are also applied as agrochemicals with potential fungicidal effects. Given various applications, these pharmaceutically and biologically significant heterocyclic compounds have attracted the attention of chemistry researchers. This study aimed to investigate the application of glycerol as a reaction medium for the three-component synthesis of arylidenisoxazol-5(4H)-one derivatives. The results of the optimized investigations revealed that 3.0 mL of glycerol is the best reaction medium. Evaluation of the effect of reaction temperature showed that the best temperature for this strategy is 60 °C. In the present environmentally friendly study, the desired heterocyclic compounds were quickly synthesized via a one-pot three-component reaction of two keto-esters with hydroxylamine hydrochloride and a number of aryl/heteroaryl aldehydes. This synthetic approach has significant merits, such as cost-effectiveness of the reaction medium, rapid green synthesis, operational simplicity, easy workup, avoiding chromatographic purification, sustainability, acceptable yields, and relatively inexpensive as well as commercially available starting materials. Full article

4-(2-Nitrobenzoyl)isoxazoles are readily available from 3,5-disubstituted 4-iodoisoxazoles through iodine–lithium exchange and trapping with 2-nitrobenzaldeyde, followed by Jones oxidation of the obtained secondary alcohols. Reductive ring transformation by means of treatment with iron in acetic acid gives 2-substituted 3-acyl-4-quinolones. The mechanism of the cyclization reaction was elucidated by using appropriately substituted isoxazole building blocks and 2D NMR investigation of the products. In contrast, catalytic hydrogenation leaves the isoxazole ring untouched, whereas reduction with NaBH₄/NiCl₂ gives 2-substituted 3-acylquinolines in an unprecedented reductive ring transformation. Full article

Functionalized nitrile oxides have attracted increasing attention because the incorporated functional groups not only influence cycloaddition reactivity but also provide valuable handles for subsequent molecular diversification. Despite their considerable synthetic potential, however, the development of practical methods for generating functionalized nitrile oxides has remained challenging because suitable precursors are often difficult to access and many functional groups are incompatible with conventional generation conditions. Consequently, only a limited number of reliable precursor systems have been established. This review summarizes recent advances in the generation of nitrile oxides bearing synthetically valuable acyl, ester, amide, and cyano functionalities, together with the development of synthetic equivalents that circumvent the intrinsic instability of these reactive intermediates. Particular emphasis is placed on 2-methyl-4-nitroisoxazoline-5(2H)-one (MeIOx), which serves as a practical precursor to (N-methylcarbamoyl)nitrile oxide. Remarkably, this nitrile oxide is generated simply by treatment with water under neutral conditions and undergoes efficient 1,3-dipolar cycloaddition with alkenes, alkynes, nitriles, and 1,3-dicarbonyl compounds to afford structurally diverse isoxazol(in)e and 1,2,4-oxadiazole derivatives. Furthermore, post-cycloaddition transformation of the N-methylcarbamoyl group into carboxyl, ester, amide, acyl, and formyl functionalities enables MeIOx to function as a practical synthetic equivalent of a broad range of functionalized nitrile oxides. The review also highlights the unique chemistry of the pyridinium salt PyIOx, whose ring-opening reaction provides cyano-aci-nitroacetate as a synthetic equivalent of the highly unstable (cyano)nitrile oxide. These complementary strategies significantly expand the scope of nitrile oxide chemistry and establish practical platforms for the synthesis of highly functionalized heterocycles. Full article

Tyrosyl-DNA phosphodiesterase 1 (TDP1) represents a compelling pharmacological target for the development of agents designed to circumvent tumor resistance to topoisomerase 1 (TOP1) inhibitors, a major class of clinically relevant antineoplastic drugs. This paper describes the design and synthesis of novel hybrid TDP1 inhibitors combining coumarin and monoterpene moieties via rigid isoxazole and 1,2,3-triazole heterocyclic linkers. The synthesis was accomplished via [3 + 2] cycloaddition of nitrile oxides to alkynes and copper-catalyzed click chemistry. Biological tests have demonstrated the crucial role of linker nature in the activity of the compounds. Isoxazole-linked conjugates showed strong inhibitory effects on TDP1, with IC₅₀ values in the submicromolar to low micromolar range (0.8–3.2 μM). Overall, these values slightly surpassed those of the triazole-linked analogues, whose IC₅₀ values ranged from 1.1 to 23.3 μM. At noncytotoxic doses, compounds 26e and 16b enhanced the sensitivity of human cervical cancer (HeLa) cells to the antitumor agent topotecan, a TOP1 inhibitor, thereby supporting the promise of this structural class as components of combination chemotherapy. Full article

Self-injurious behavior (SIB) is a devastating and potentially life-threatening action with high prevalence in adolescents and patients with neuropsychiatric disorders. Accumulating evidence indicates that disruptions in multiple cellular and circuit mechanisms underlie vulnerability to SIB. We used an inducible SIB rat model to study synaptic modification during SIB. At 0.5 and 1 h after bilateral injection of muscimol (1.0 μg/side) into the rat endopeduncular nucleus (EP, a rodent homolog of the internal globus pallidus (GPi)), which induced SIB in rats, expression of the α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) subunit 1 (GluA1) and the phosphorylation of GluA1 at Ser831 and Ser845 were tested in the lateral habenula (LHb), ventral tegmental area (VTA), nucleus accumbens (NAc), amygdala, and medial prefrontal cortex (mPFC) of the rat brain. We also tested if modulation of NAc activity with a GABA_A receptor agonist or antagonist or dopamine receptor agonist or antagonist or inhibiting the mPFC–NAc pathway affected SIB in rats. At 1 h after EP inhibition, total GluA1 expression and phosphorylated GluA1 were decreased in the mPFC, VTA, and NAc, but were increased in the amygdala compared with control rats. When the EP was inhibited by 0.2 μg/side muscimol, hyperactivation of the NAc increased SIB in rats. However, if the EP was inhibited by 1.0 μg/side muscimol, hyperactivation of the NAc had no effects on SIB. Inhibiting the mPFC–NAc pathway increased wound areas in rats with SIB. At the onset of SIB, excitatory synaptic transmission is simultaneously dampened in the reward and control circuitry (VTA, NAc, mPFC) and potentiated in the aversion circuitry (amygdala), indicating that SIB is associated with molecular signatures suggestive of a shift from reward to threat processing. Hyperactivation of the NAc increased SIB incidence in rats, but administration of dopamine receptor agonists and antagonists into the NAc did not significantly affect the incidence of SIB in this study. These findings provide a novel mechanistic perspective on SIB, offering a basis for the treatment of SIB. Full article

A DMAP-catalyzed Michael addition/cyclization cascade reaction has been developed for the efficient construction of a bispirooxindole–cyclopentene–isoxazolone framework. Under the optimized conditions (10 mol% DMAP, CH₂Cl₂, room temperature), the desired product was obtained in 92% yield with >20:1 diastereoselectivity. The reaction exhibited broad substrate scope, tolerating various substituents on both the isoxazolone and oxindole rings, and affording the corresponding products in 72–96% yields. The relative configuration of a representative product was determined as rel-(2’S,3R,3’R) by X-ray single-crystal diffraction. The utility of this method was further demonstrated by a gram-scale experiment (82% yield). This cascade reaction provides a concise and efficient route to structurally novel spiroisoxazolone derivatives bearing a cyano group and multiple spiro chiral centers. Full article

A new series of isoxazole-fused thiazole–oxazole derivatives (11a–n) was rationally designed and synthesised with the aim of developing potent carbonic anhydrase (CA) I and II inhibitors. The synthesis was achieved in five steps starting from 4-bromoacetophenone, involving key intermediates such as hydroxylamine hydrochloride, hydrazine hydrate, thioisocyanate, and various phenacyl bromide derivatives, using ethanol, triethylamine, tetrahydrofuran (THF), and dimethylformamide (DMF) as solvents. The synthetic route included the formation of a β-ketoester, isoxazole ester, hydrazine adduct, thiourea derivative, and, ultimately, a thiazole ring. The structures of the final compounds were confirmed by ¹H-NMR, ¹³C-NMR, IR spectroscopy, and elemental analysis. All compounds were examined as inhibitors of human carbonic anhydrase (hCA) I and II, and all of them inhibited hCA I and hCA II. Kinetic investigation results revealed that these compounds inhibited hCA I and hCA II in a non-competitive manner. To further explore the molecular basis of their inhibitory activity, in silico studies, including molecular docking and 300 ns molecular dynamics (MD) simulations, were carried out against both CA I and CA II isoforms. These simulations provided detailed insights into the dynamic behaviour, stability, and key binding interactions of the compounds within the enzyme active sites, supporting their potential as promising carbonic anhydrase inhibitors. Full article

Alkyn-1,2-diones have gained great attention as useful building blocks in organic synthesis. Regioselective synthetic routes towards 3,5-disubstituted isoxazoles, containing the methylfuroyl or diterpenylfuroyl moiety at the C-3 or C-5 position from alkyne-1,2-diones 1, 2, 3, are reported. The reaction with hydroxylamine hydrochloride 6 in ethanol afforded the 1,2-addition products: 5-aryl-3-(methylfuran-2-carbonyl)isoxazoles (yield 61–94%) or 16-(5-arylisoxazole-3-carbonyl)labdatrienes (yield 48–97%). The reaction of alkynediones 1–3 with 6 in THF in the presence of triethylamine led to 5-hydroxy-4,5-dihydroisoxazoles and subsequent dehydration afforded regioisomeric 3-aryl-5-(methylfuran-2-carbonyl)isoxazoles or 16-(3-arylisoxazole-5-carbonyl)labda-trienes (yield 65–98%). New heterocyclic compounds exhibited significant analgesic action in acetic acid writhing and hot-plate tests, and the activity was comparable to reference drugs diclofenac sodium and celecoxib. Isoxazoles, which possessed the most analgesic activity, reduced the concanavalin A-induced inflammation by 34–51%; the effect was comparable to the drug indomethacin. The results of in vitro biological assays (MTT test) revealed that isoxazoles were non-toxic against the normal epithelial VERO cells, and 16-(3-aryl-5-hydroxyisoxazoline-5-carbonyl)labdatrienes 20–24 exhibited selective cytotoxicity against the breast adenocarcinoma MCF 7 (GI₅₀ = 4.7–8.3 μM) and cervical cancer cells C33 A (GI₅₀ = 3.4–4.7 μM). Molecular docking analysis to determine the binding potential of new molecules to the active site of human COX-1 and COX-2 enzymes was conducted. Full article

In this study, the synthesis of a series of alkaloid analogs—isoxazole and isothiazole esters of 2-substituted 3-oxoindoline-4-carboxylic acid was performed. The target derivatives were obtained by the carbodiimide method. It was established that the studied esters have low cytotoxicity and are able to enhance the effect of the anticancer drug carboplatin, taken in low doses (0.5–5 μM), by up to 30%. Quantum chemical modeling of the obtained compounds and their conjugates with carboplatin was carried out to analyze the relationship between various calculated parameters and the observed biological effects. Full article

In the present study, a series of isoxazole derivatives were severally evaluated for their antifungal activity against the yeast Candida albicans and molds such as Aspergillus niger, Aspergillus flavus, and Fusarium oxysporum. The results demonstrate that the isoxazole derivatives exhibit considerable antifungal potential, particularly isoxazole-sulfonate ester 4b (Ar= 4-(Cl)C₆H₄, Ar′= 4-(CH₃)C₆H₄), which was found to be active with significant inhibition zones; the diameters of the C. albicans and F. oxysporum samples were measured at 17.00 ± 0.00 mm and 14.00 ± 0.00 mm, respectively. Furthermore, compounds 4a (Ar= 4-(CH₃)C₆H₄, Ar′= 4-(CH₃)C₆H₄), 4c (Ar: 4-(Cl)C₆H₄, Ar′: 4-(NO₂)C₆H₄) and 4d (Ar: 4-(Cl)C₆H₄, Ar′: 3-(Cl)-2-(OCH₃)C₆H₃) demonstrated MIC and MFC values of 20 µg/mL against C. albicans. In addition, the anti-hemolytic activity of these derivatives was evaluated. Compounds 4a, 4e (Ar: 4-(Cl)C₆H₄, Ar′: 3,4-(OCH₃)₂C₆H₃) and aroylisoxazole 3a (Ar: 4-(CH₃)C₆H₄) demonstrated a high degree of anti-hemolytic activity (>99%) at all concentrations evaluated (10, 15, and 20 mg/mL). Molecular docking and molecular dynamics studies over 200 ns revealed protein–ligand complexes to have high affinity and stability, which agrees with the experimental results. The compounds 4d, 4e, and 3a have shown significant interaction with the target proteins of C. albicans, A. flavus, and F. oxysporum, respectively. The results have revealed that the major interaction sites are hydrogen bonding, hydrophobic interactions, and the presence of a water molecule, especially with key residues like TYR_84, ASP_120, SER_90, and THR_89. The crystal structure of compound 4a was also obtained. Full article

Mid-high-frequency ultrasound (375 kHz) and anodic oxidation at low current intensity (<50 mA, NaCl as the supporting electrolyte) were employed to treat sulfonamide antibiotics (sulfamethoxazole—SMX and sulfacetamide—SAM). The sonodegradation involved HO•, while electrogenerated HClO was mainly responsible for the antibiotics’ elimination in the electrochemical process. A comparison of the processes evidenced that the degradation of SMX by ultrasound was faster due to its higher hydrophobicity. In contrast, in the electrochemical system, the SAM degradation was more efficient, which was associated with a higher reactivity of its acetamide moiety toward HClO. Interestingly, SMX was selectively sonodegraded in synthetic hospital wastewater and seawater, whereas the matrix components strongly accelerated the electrochemical degradation but affected the process performance in the hospital wastewater. On the other hand, theoretical analyses of atomic charge indicated that the central S-N bond, the N and aromatic ring in the aniline moiety, the C=C bond, and methyl groups in the isoxazole groups on SMX are the most susceptible moieties to the attacks by HO• and HClO. Furthermore, for the typical byproducts, calculations of the probability of being active against bacteria were slightly lower than that of the parent pharmaceutical, even being much lower for the byproducts from the electrochemical treatment. Full article

Glioblastoma (GBM) is an aggressive human malignancy. Recent advances in GBM research have highlighted innovative therapeutic approaches, including the use of small molecules that eliminate GBM in mouse models. However, there are few reports on the restoration of lost neuronal functions in patients. Considering that GBM contains GBM-initiating cells (GICs) with characteristics of both cancer and neural stem cells, we investigated whether GICs could be redirected toward non-tumorigenic neurons to support the preservation of neural function in the brain with GBM. We demonstrated that the neuronal differentiation inducer Isoxazole 9 (ISX9) effectively induced GICs to differentiate into neurons, accompanied by significant changes in their gene expression profiles. The sequential application of ISX9 and the DHODH inhibitor brequinar (BRQ), which successfully eradicated undifferentiated GICs, not only promoted neuronal differentiation but also inhibited GIC tumorigenesis in the mouse brain, leading to prolonged survival and preservation of motor function in tumor-bearing mice. Furthermore, pathological analysis revealed that this combination not only reduced the size of GIC brain tumors but also facilitated the formation of synapse-like structural contacts between GIC-derived cells and host mouse neurons, suggesting remodeling of the tumor–neural interface within the tumor-developed area. Collectively, these findings suggest that the modulation of tumorigenic GIC differentiation may represent a strategy to preserve neural circuit integrity within the tumor-bearing brain. Full article

Despite notable progress in drug discovery, cancer treatment remains hindered by limited therapeutic efficacy, poor target specificity, adverse effects, and the development of drug resistance. Molecular hybridization, which integrates two or more bioactive entities into a single molecule, has shown considerable potential to overcome these limitations. Since both azoles and flavonoids have demonstrated anticancer potential, extensive studies have been undertaken to combine the two entities and enhance the bioactivity of the resulting hybrids. In this context, numerous azole–flavonoid hybrids have been synthesized and investigated for their anticancer potential. This review provides an overview of the azole–flavonoid hybrids that are promising candidates for novel anticancer drug development, highlighting their superior antitumor potency compared to reference drugs, multitarget activity, tumor-selective cytotoxicity, efficacy against drug-resistant tumor cells, and structure–activity relationships. The review covers 250 hybrids, primarily triazole–chalcone hybrids but also triazole–flavone, flavanone, flavonol, and isoflavone hybrids, as well as other azole–flavonoid hybrids (imidazole–, pyrazole–, isoxazole–, and thiazole–flavonoid hybrids). Full article

Azaoxyallyl cations, as novel and versatile three-atom components, have been widely utilized in cycloaddition reactions, with the competition between O- and N-cyclization pathways remaining a key research focus. This study investigates the mechanism and site selectivity of (3+2) cycloaddition between azaoxyallyl cations and 1,2-benzisoxazoles using density functional theory calculations. The results reveal a stepwise (3+2) addition to the C=N double bond, followed by base-assisted N-O bond cleavage and isoxazole ring-opening, leading to oxazoline (via O-cyclization) or imidazolone (via N-cyclization) derivatives. When unsubstituted 1,2-benzisoxazole is used as the substrate, O-cyclization dominates as a kinetically controlled process due to lower activation barriers, while N-cyclization, as a thermodynamically controlled process, is minor. The presence of a methyl group at the C(3) position in 1,2-benzisoxazoles completely blocks N-O bond cleavage, forcing exclusive (3+2) cycloaddition to yield less stable tricyclic products via N-cyclization rather than O-cyclization. These findings align with experimental observations and provide new mechanistic insights into the site selectivity of azaoxyallyl cation cycloadditions. Full article

Glutamate receptors represent a potential target for neuroprotection in neurodegenerative neurological conditions. Perampanel, a non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor (AMPAR) antagonist, is clinically approved for the management of epilepsy. Perampanel’s neuroprotective effects have been reported in global and focal cerebral ischemia models, but the cellular mechanisms remain incompletely understood. Therefore, we studied the potential neuroprotective effects of perampanel in rats using the pial vessel disruption (PVD) stroke model, an established focal cortical non-reperfusion ischemic stroke model. Perampanel was given once intraperitoneally (3 mg/kg body weight) 1 h after PVD surgery and repeated on days 2–3 post-surgery. On the fourth day post PVD, animal behavioral assays and imaging, biochemical, and electrophysiological analyses were performed. Compared to vehicle control, perampanel in PVD-treated rats significantly inhibited hippocampal neurodegeneration and long-term potentiation deficits. Perampanel also attenuated PVD-induced motor deficits, depressive/anxiety-like behaviors, and hippocampal-dependent cognitive impairment. In addition, perampanel prevented the PVD-induced downregulation of surface-expressed GluA1 and GluA2 AMPARs and increased phosphorylation of GluA1 at S831 and S845. Molecular docking analysis revealed perampanel binding to transmembrane regions M1, M3 and M4 of GluA1 and GluA2 subunits. Together, our results show that perampanel attenuated PVD-induced neurodegeneration and behavioral deficits by blocking AMPARs and decreasing GluA1 and GluA2 internalization. In addition, this study shows the neuroprotective potential of perampanel through the inhibition of neuroinflammation mediated by activated microglia and astrocytes following cerebral ischemia. This study is the first to evaluate perampanel in the pial vessel disruption model of ischemia without reperfusion, a clinically relevant stroke paradigm that differs fundamentally from middle cerebral carotid artery occlusion and photothrombosis stroke models. Full article