Acridine-Isoxazole and Acridine-Azirine Hybrids: Synthesis, Photochemical Transformations in the UV/Visible Radiation Boundary Region, and Anticancer Activity.

Easy-to-handle N-hydroxyacridinecarbimidoyl chloride hydrochlorides were synthesized as convenient nitrile oxide precursors in the preparation of 3-(acridin-9/2-yl)isoxazole derivatives via 1,3-dipolar cycloaddition with terminal alkynes, 1,1-dichloroethene, and acrylonitrile. Azirines with an acridin-9/2-yl substituent attached directly or via the 1,2,3-triazole linker to the azirine C2 were also synthesized. The three-membered rings of the acridine-azirine hybrids were found to be resistant to irradiation in the UV/visible boundary region, despite their long-wave absorption at 320-420 nm, indicating that the acridine moiety cannot be used as an antenna to transfer light energy to generate nitrile ylides from azirines for photoclick cycloaddition. The acridine-isoxazole hybrids linked at the C9-C3 or C2-C3 atoms under blue light irradiation underwent the addition of such hydrogen donor solvents, such as, toluene, o-xylene, mesitylene, 4-chlorotoluene, THF, 1,4-dioxane, or methyl tert-butyl ether (MTBE), to the acridine system to give the corresponding 9-substituted acridanes in good yields. The synthesized acridine-azirine, acridine-isoxazole, and acridane-isoxazole hybrids exhibited cytotoxicity toward both all tested cancer cell lines (HCT 116, MCF7, and A704) and normal cells (WI-26 VA4).

Palladium-Catalyzed Cyclization/Alkenylation of Ynone Oximes with Vinylsilanes for the Assembly of Isoxazolyl Vinylsilanes.

A palladium-catalyzed cascade cyclization/alkenylation for the assembly of synthetically valuable isoxazolyl vinylsilane derivative has been accomplished. Easily accessible ynone oximes, and available vinylsilane agents were used as the reaction starting materials This protocol features broad substrate scope, good functional group tolerance, and good step- and atom-economy. Remarkably, this approach provides a new approach for the construction of structurally diverse isoxazolyl-containing vinylsilanes with high molecular complexity, showing a promising application in synthetic and pharmaceutical chemistry.

Design, synthesis, In-vitro, In-silico and DFT studies of novel functionalized isoxazoles as antibacterial and antioxidant agents.

A series of new isoxazolederivatives incorporating the sulfonate ester function has been synthesized from 2-benzylidenebenzofuran-3(2 H)-one, known as aurone. The synthesis of the target compounds was carried out following an efficient methodology that allows access to the desired products in a reproducible way and with good yield. The structures of the synthesized compounds were established using NMR (1H and 13C) spectroscopy and mass spectrometry. A theoretical study was performed to optimize the geometrical structures and to calculate the structural and electronic parameters of the synthesized compounds. The calculations were also carried out to understand the influence and the effect of substitutions on the chemical reactivity of the studied compounds. The synthesized isoxazoles were screened for their antioxidant and antibacterial activities. The findings demonstrate that the studied compounds exhibit good to moderate antibacterial activity against the tested bacteria (Staphylococcus aureus, Bacillus subtilis, and Escherichia coli). Moreover, a number of the tested isoxazole derivatives exhibit high effectiveness against DPPH free radicals. Besides that, molecular docking studies were carried out to predict binding affinity and identify the most likely binding interactions between the active molecules and the target microorganisms' proteins. A 100 ns molecular dynamics study was then conducted to examine the dynamic behavior and stability of the highly potent isoxazole 4e in complex with the target bacterial proteins. Finally, the ADMET analyses suggest that all the synthesized isoxazoles have good pharmacokinetic profiles and non-toxicity and non-carcinogenicity in biological systems.

Water-Soluble Arylazoisoxazole Photoswitches.

Azoheteroarenes are emerging as powerful alternatives to azobenzene molecular photoswitches. In this study, water-soluble arylazoisoxazole photoswitches are introduced. UV/vis and NMR spectroscopy revealed moderate to very good photostationary states and reversible photoisomerization between the E- and Z-isomers over multiple cycles with minimal photobleaching. Several arylazoisoxazoles form host-guest complexes with ß- and γ-cyclodextrin with significant differences in binding constants for each photoisomer as shown by isothermal titration calorimetry and NMR experiments, indicating their potential for photoresponsive host-guest chemistry in water. One carboxylic acid functionalized arylazoisoxazole can act as a hydrogelator, allowing gel properties to be manipulated reversibly with light. The hydrogel was characterized by rheological experiments, atom force microscopy and transmission electron microscopy. These results demonstrate that arylazoisoxazoles can find applications as molecular photoswitches in aqueous media.

Synthesis of gem-Difluorinated Isoxazoles via Palladium-Catalyzed Oxylallylation of Alkynone Oxime Ethers.

A novel and reliable palladium-catalyzed oxylallylation of alkynone oxime ethers with fluorine-containing alkenes was accomplished. Using the bulk industrial chemical 3-bromo-3,3-difluoroprop-1-ene as the coupling partner, this synthetic methodology offers the first example for the assembly of structurally diverse gem-difluorinated isoxazole derivatives in moderate to good yields with high atom- and step-economy and excellent functional group compatibility. More importantly, this strategy allows for the direct combination of the isoxazole motifs and gem-difluoroalkene unit, which is not easy to obtain through a general synthetic strategy.

Synthesis, antioxidant, antiproliferative activity, molecular docking and DFT studies of novel isoxazole derivatives of diosgenin, a steroidal sapogenin from Dioscorea deltoidea.

Diosgenin [25R-spirost-5-en-3ß-ol], isolated from Dioscorea deltoidea was used as a starting material for synthesizing its various isoxazole derivatives. A library of fifteen isoxazole analogues (DG1-DG15) were synthesised via modification at the C-3 hydroxyl group. The resulting analogues were fully characterized by spectral techniques and evaluated for their antioxidant and anticancer activity against four breast cancer cell lines; MDA-MB-231, MDA-MB-468, MCF-7, and 4 T1, using MTT assay. Molecular docking studies were carried out for all analogues with EGFR protein (PDB id: 6LUD) to check their activity by inhibiting EGFR protein, which is an effective strategy for cancer cell death. Furthermore, DFT studies were carried out for four analogues. Among all analogues, compound DG6 and DG9 showed the highest scavenging activity and compound DG9 exhibited a maximum cytotoxic effect on the MDA-MB-468 and MCF-7 cell lines with an IC50 value of 6.25 µg/mL and 6.81 µg/mL, while compound DG5 was the least potent (IC50 25.89 µg/mL). Molecular docking results revealed that DG8 and DG9 afforded the highest binding energy of -14.33 and - 14.71 kcal/mol, respectively for the target EGFR protein. These results demonstrate the potential of diosgenin analogues as drug candidates for breast cancer therapy. Furthermore, DFT studies revealed that the molecules are more polarizable and have smaller energy gap between their HOMO and LUMO orbitals, the smallest being of DG9 (3.221 eV) and hence are more reactive.

Design of novel water-soluble isoxazole-based antimicrobial agents and evaluation of their cytotoxicity and acute toxicity.

Based on the readily available 3-organyl-5-(chloromethyl)isoxazoles, a number of previously unknown water-soluble conjugates of isoxazoles with thiourea, amino acids, some secondary and tertiary amines, and thioglycolic acid were synthesized. The bacteriostatic activity of aforementioned compounds has been studied against Enterococcus durans B-603, Bacillus subtilis B-407, Rhodococcus qingshengii Ac-2784D, and Escherichia coli B-1238 microorganisms (provided by All-Russian Collection of Microorganisms, VKM). The influence of the nature of the substituents in positions 3 and 5 of the isoxazole ring on the antimicrobial activity of the obtained compounds has been determined. It is found that the highest bacteriostatic effect is observed for compounds containing 4-methoxyphenyl or 5-nitrofuran-2-yl substituents in position 3 of the isoxazole ring as well as methylene group in position 5 bearing residues of l-proline or N-Ac-l-cysteine (5a-d, MIC 0.06-2.5 µg/ml). The leading compounds showed low cytotoxicity on normal human skin fibroblast cells (NAF1nor) and low acute toxicity on mice in comparison with the well-known isoxazole-containing antibiotic oxacillin.

5-Membered Heterocyclic Compounds as Antiviral Agents.

Viral infections range from self-limiting to more serious and fatal infections; therefore, some viral infections are of great public health concern worldwide, e.g., Hepatitis B virus, Hepatitis C virus, and HIV. Recently, the world faced a new infection due to the coronavirus, COVID-19, which was announced as a pandemic in early 2020. This virus infected more than 500 million people, killing around 6 million people worldwide. On the other hand, the increase in drug-resistant strains is also creating serious health problems. Thus, developing new selective antiviral agents with a different mode of action to fight against mutated and novel viruses is a primary goal of many researchers. Taking into account the role of heterocyclic compounds in drug discovery as a key structural component of most of the bioactive molecules; herein, we report an extensive review of the antiviral activity of five-membered heterocyclic compounds reported from 2015 to date. In this review, the antiviral activities of the agents containing the specified ring systems thiadiazoles, triazoles, oxadiazoles, and thiazoles are discussed.

Identification of pyrrolo[3',4':3,4]cyclohepta[1,2-d][1,2]oxazoles as promising new candidates for the treatment of lymphomas.

Unsatisfactory outcomes for relapsed/refractory lymphoma patients prompt continuing efforts to develop new therapeutic strategies. Our previous studies on pyrrole-based anti-lymphoma agents led us to synthesize a new series of twenty-six pyrrolo[3',4':3,4]cyclohepta[1,2-d] [1,2]oxazole derivatives and study their antiproliferative effects against a panel of four non-Hodgkin lymphoma cell lines. Several candidates showed significant anti-proliferative effects, with IC50's reaching the sub-micromolar range in at least one cell line, with compound 3z demonstrating sub-micromolar growth inhibitory effects towards the entire panel. The VL51 cell line was the most sensitive, with an IC50 value of 0.10 µM for 3z. Our earlier studies had shown that tubulin was a prominent target of many of our oxazole derivatives. We therefore examined their effects on tubulin assembly and colchicine binding. While 3u and 3z did not appear to target tubulin, good activity was observed with 3d and 3p. Molecular docking and molecular dynamics simulations allowed us to rationalize the binding mode of the synthesized compounds toward tubulin. All ligands exhibited a better affinity for the colchicine site, confirming their specificity for this binding pocket. In particular, a better affinity and free energy of binding was observed for 3d and 3p. This result was confirmed by experimental data, indicating that, although both 3d and 3p significantly affected tubulin assembly, only 3d showed activity comparable to that of combretastatin A-4, while 3p was about 4-fold less active. Cell cycle analysis showed that compounds 3u and especially 3z induced a block in G2/M, a strong decrease in S phase even at low compound concentrations and apoptosis through the mitochondrial pathway. Thus, the mechanism of action of 3u and 3z remains to be elucidated. Very high selectivity toward cancer cells and low toxicity in human peripheral blood lymphocytes were observed, highlighting the good potential of these agents in cancer therapy and encouraging further exploration of this compound class to obtain new small molecules as effective lymphoma treatments.

Naphtho[1,8-de][1,2]Oxazin-4-ol: Precursor to 1,2,8-Trisubstituted Naphthalenes and 1-Unsubstituted Naphtho[1,2-d]isoxazole 2-Oxide: A Novel Isomerization of the N-Oxide to Nitrile Oxide en Route to Isoxazol(in)es.

Naphtho[1,8-de][1,2]oxazin-4-ol and its acyl or benzyl derivatives ring open to various 2,8-dihydroxy-1-naphthonitriles, which, through (de)protection protocols and reduction, afford the target (E)-2-hydroxy-8-methoxy-1-naphthaldehyde. This was converted to its corresponding oxime, which was oxidatively o-cyclized with phenyliodine(III) diacetate (PIDA) to 9-methoxynaphtho[1,2-d]isoxazole 2-oxide. The latter, in deuterated DMSO at room temperature, was rearranged to its isomer 2-hydroxy-8-methoxy(naphthalen-1-yl)nitrile oxide. The isomerization was detected by time-course plot 1H NMR spectroscopy and further identified from its 13C NMR and HRMS spectra. The nitrile oxide was stable in (non)deuterated DMSO for at least 18 h. A 3,4-bis(2-hydroxy-8-methoxynaphthalen-1-yl)-1,2,5-oxadiazole 2-oxide, as a dimerization product or an isocyanate as a rearrangement isomer, was ruled out, the former by its HRMS spectrum and the latter by its 1,3-dipolar cycloaddition reactions to substituted isoxazoles.

Acid-Switchable Synthesis of Trifluoromethylated Triazoles and Isoxazoles via Reaction of CF3-Ynones with NaN3: DFT Study of the Reaction Mechanism.

A detailed study of the reaction of CF3-ynones with NaN3 was performed. It was found that the reaction permits the selective synthesis of either 4-trifluoroacetyltriazoles or 5-CF3-isoxazoles. The chemoselectivity of the reaction was switchable via acid catalysis. The reaction of CF3-ynones with NaN3 in EtOH produced high yields of 4-trifluoroacetyltriazoles. In contrast, the formation of 5-CF3-isoxazoles was observed under catalysis by acids. This acid-switchable procedure can be performed at sub-gram scale. The possible reaction mechanism was supported by DFT calculations. The synthetic utility of the prepared 4-trifluoroacetyltriazoles was demonstrated.

Synthesis and Biological Evaluation of New Isoxazolyl Steroids as Anti-Prostate Cancer Agents.

Steroids with a nitrogen-containing heterocycle in the side chain are known as effective inhibitors of androgen signaling and/or testosterone biosynthesis, thus showing beneficial effects for the treatment of prostate cancer. In this work, a series of 3ß-hydroxy-5-ene steroids, containing an isoxazole fragment in their side chain, was synthesized. The key steps included the preparation of Weinreb amide, its conversion to acetylenic ketones, and the 1,2- or 1,4-addition of hydroxylamine, depending on the solvent used. The biological activity of the obtained compounds was studied in a number of tests, including their effects on 17α-hydroxylase and 17,20-lyase activity of human CYP17A1 and the ability of selected compounds to affect the downstream androgen receptor signaling. Three derivatives diminished the transcriptional activity of androgen receptor and displayed reasonable antiproliferative activity. The candidate compound, 24j (17R)-17-((3-(2-hydroxypropan-2-yl)isoxazol-5-yl)methyl)-androst-5-en-3ß-ol, suppressed the androgen receptor signaling and decreased its protein level in two prostate cancer cell lines, LNCaP and LAPC-4. Interaction of compounds with CYP17A1 and the androgen receptor was confirmed and described by molecular docking.

Isoxazole Nucleosides as Building Blocks for a Plausible Proto-RNA.

The question of how RNA, as the principal carrier of genetic information evolved is fundamentally important for our understanding of the origin of life. The RNA molecule is far too complex to have formed in one evolutionary step, suggesting that ancestral proto-RNAs (first ancestor of RNA) may have existed, which evolved over time into the RNA of today. Here we show that isoxazole nucleosides, which are quickly formed from hydroxylamine, cyanoacetylene, urea and ribose, are plausible precursors for RNA. The isoxazole nucleoside can rearrange within an RNA-strand to give cytidine, which leads to an increase of pairing stability. If the proto-RNA contains a canonical seed-nucleoside with defined stereochemistry, the seed-nucleoside can control the configuration of the anomeric center that forms during the in-RNA transformation. The results demonstrate that RNA could have emerged from evolutionarily primitive precursor isoxazole ribosides after strand formation.

Effects of feed intake and water hardness on fluralaner pharmacokinetics in layer chickens.

BACKGROUND: Fluralaner is a novel drug belonging to the isoxazoline class that acts on external parasites of domestic animals. It is used systemically via drinking water, especially against red poultry mite in layer chickens. Fluralaner is frequently used in layers infected with D. gallinae. However, no study to date has investigated the effects of feed intake and water hardness. OBJECTIVES: This study aimed to investigate the effects of variable water hardness and feed intake on the pharmacokinetic profile of fluralaner. METHODS: Layer chickens were divided into four groups (n = 8): fed + purified water (Group 1), feed restricted + purified water (Group 2), feed restricted + hard water (Group 3), and feed restricted + soft water (Group 4). After administering a single dose of the drug with drinking water, the blood samples were collected for 21 days. Fluralaner concentrations in plasma samples were determined by liquid chromatography/tandem mass spectrometry. The maximum plasma concentration (Cmax), time to reach maximum plasma concentration (tmax), area under the concentration-time curve values (AUC0-21d), half-life (t1/2), and other pharmacokinetic parameters were calculated. RESULTS: Although the highest maximum plasma concentration (Cmax) was determined in Group 1 (fed + purified water), no statistically significant difference was found in the Cmax, tmax, t1/2, MRT0-inf_obs, Vz/Fobs, and Cl/F_obs parameters between the experimental groups. CONCLUSIONS: It was concluded that the feed intake or water hardness did not change the pharmacokinetic profile of fluralaner in layer chickens. Therefore, fluralaner could be used before or after feeding with the varying water hardness in poultry industry.

Synthesis of 3,4,5-trisubstituted isoxazoles in water via a [3 + 2]-cycloaddition of nitrile oxides and 1,3-diketones, ß-ketoesters, or ß-ketoamides.

Herein we report a method for the synthesis of 3,4,5-trisubstituted isoxazoles in water under mild basic conditions at room temperature via a [3 + 2]-cycloaddition of nitrile oxides and 1,3-diketones, ß-ketoesters, or ß-ketoamides. We optimized the reaction conditions to control the selectivity of the production of isoxazoles and circumvent other competing reactions, such as O-imidoylation or hetero [3 + 2]-cycloaddition. The reaction happens fast in water and completes within 1-2 hours, which provides an environmentally friendly access to 3,4,5-trisubstituted isoxazoles, an important class of structures found in numerous bioactive natural products and pharmaceuticals. Additionally, we optimized the reaction conditions to produce trifluoromethyl-substituted isoxazoles, a prevalent scaffold in biomedical research and drug discovery programs. We also proposed a plausible mechanism for the selectivity of the [3 + 2]-cycloaddition reaction to produce 3,4,5-trisubstituted isoxazoles. Not to be overlooked are our optimized reaction conditions for the dimerization of hydroximoyl chlorides to form furoxans also known as 1,2,5-oxadiazole 2-oxides, a class of structures with important biological activities due to their unique electronic nature and coordination ability.

Synthesis and Characterization of the Potential Energetic Propellant Plasticizer 3-Nitratoethyl-N-nitramino-5-nitratomethyl Isoxazole.

The synthesis of 3-(nitratoethyl-N-nitramino)-5-(nitratomethyl) isoxazole (C6 H7 N5 O9 , 1) is presented, and its energetic properties were ascertained and analyzed for energetic applications potential. 1 was found to be a solid without melting behavior, begins to decompose at 140 °C, and has a thermal onset decomposition temperature of 171.5 °C. 1 was synthesized in 5 steps from glyoxylic acid, and was found to exhibit acceptable sensitivities to impact, friction, and electrostatic discharge. The presence of the nitratoethyl nitramino (NENA) moiety, coupled with the high density (1.71 g cm-3 ) and superior calculated specific impulse (247.6 s) over the commonly employed gun propellant n-butyl NENA (density=1.22 g cm-3 , specific impulse=221 s), makes 1 a potential energetic plasticizer for next generation gun and rocket propellants. In addition, a modified procedure for the synthesis of dibromoformaldoxime (DBFO) was developed to provide this material in respectable yields on one mole scale. The safety considerations of DBFO are also highlighted, in which this compound sublimes, and must be handled with care, as it will cause burns upon contact with the skin.

A Study on Synthesis of Chalcone Derived -5- Membered Isoxazoline and Isoxazole Scaffolds.

Chalcone-derived isoxazole scaffolds remain the central focus due to their greater biological, clinical, and pharmacological properties. The present study reviews the synthesis of various chalcone derived - 5- membered isoxazoline and isoxazole scaffolds with the available literature until 2021.

5-Chloroisoxazoles: A Versatile Starting Material for the Preparation of Amides, Anhydrides, Esters, and Thioesters of 2H-Azirine-2-carboxylic Acids.

Amides, anhydrides, esters, and thioesters of 2H-azirine-2-carboxylic acids were prepared by a rapid procedure at room temperature involving FeCl2-catalyzed isomerization of 5-chloroisoxazoles to 2H-azirine-2-carbonyl chlorides, followed by reaction with N-, O-, or S-nucleophiles mediated by an ortho-substituted pyridine. With readily available chloroisoxazoles and a nucleophile, 2-picoline can be used as an inexpensive base. When a high yield of the acylation product is important, the reagent 2-(trimethylsilyl)pyridine/ethyl chloroformate is more suitable for the acylation with 2H-azirine-2-carbonyl chlorides.

Trifluoromethylated Flavonoid-Based Isoxazoles as Antidiabetic and Anti-Obesity Agents: Synthesis, In Vitro α-Amylase Inhibitory Activity, Molecular Docking and Structure-Activity Relationship Analysis.

Diabetes mellitus is a major health problem globally. The management of carbohydrate digestion provides an alternative treatment. Flavonoids constitute the largest group of polyphenolic compounds, produced by plants widely consumed as food and/or used for therapeutic purposes. As such, isoxazoles have attracted the attention of medicinal chemists by dint of their considerable bioactivity. Thus, the main goal of this work was to discover new hybrid molecules with properties of both flavonoids and isoxazoles in order to control carbohydrate digestion. Moreover, the trifluoromethyl group is a key entity in drug development, due to its strong lipophilicity and metabolic stability. Therefore, the present work describes the condensation of a previously synthesized trifluoromethylated flavonol with different aryl nitrile oxides, affording 13 hybrid molecules indicated as trifluoromethylated flavonoid-based isoxazoles. The structures of the obtained compounds were deduced from by 1H NMR, 13C NMR, and HRMS analysis. The 15 newly synthesized compounds inhibited the activity of α-amylase with an efficacy ranging from 64.5 ± 0.7% to 94.7 ± 1.2% at a concentration of 50 µM, and with IC50 values of 12.6 ± 0.2 µM-27.6 ± 1.1 µM. The most effective compounds in terms of efficacy and potency were 3b, 3h, 3j, and 3m. Among the new trifluoromethylated flavonoid-based isoxazoles, the compound 3b was the most effective inhibitor of α-amylase activity (PI = 94.7 ± 1.2% at 50 µM), with a potency (IC50 = 12.6 ± 0.2 µM) similar to that of the positive control acarbose (IC50 = 12.4 ± 0.1 µM). The study of the structure-activity relationship based on the molecular docking analysis showed a low binding energy, a correct mode of interaction in the active pocket of the target enzyme, and an ability to interact with the key residues of glycosidic cleavage (GLU-230 and ASP-206), explaining the inhibitory effects of α-amylase established by several derivatives.

Synthesis and Antiprotozoal Profile of 3,4,5-Trisubstituted Isoxazoles.

A series of 60 4-aminomethyl 5-aryl-3-substituted isoxazoles were synthesized by an efficient method and evaluated in vitro against Leishmania amazonensis and Trypanosoma cruzi, protozoa that cause the neglected tropical diseases leishmaniasis and Chagas disease, respectively. Thirteen compounds exhibited a selective index greater than 10. The series of 3-N-acylhydrazone isoxazole derivatives bearing the bithiophene core exhibited the best antiparasitic effects.