Integrating Benzoxazine-PDMS 3D Networks with Carbon Nanotubes for flexible Pressure Sensors.

Shapeable and flexible pressure sensors with superior mechanical and electrical properties are of major interest as they can be employed in a wide range of applications. In this regard, elastomer-based composites incorporating carbon nanomaterials in the insulating matrix embody an appealing solution for designing flexible pressure sensors with specific properties. In this study, PDMS chains of different molecular weight were successfully functionalized with benzoxazine moieties in order to thermally cure them without adding a second component, nor a catalyst or an initiator. These precursors were then blended with 1 weight percent of multi-walled carbon nanotubes (CNTs) using an ultrasound probe, which induced a transition from a liquid-like to a gel-like behavior as CNTs generate an interconnected network within the matrix. After curing, the resulting nanocomposites exhibit mechanical and electrical properties making them highly promising materials for pressure-sensing applications.

Combined Effect of Basic Antiherpetic Drugs with a New Inhibitor of the Terminase Complex of Herpes Simplex Virus Type 1 in Vero Cell Cultures.

Carriers of herpes simplex virus type 1 (HSV-1) account for more than 90% of the global population. Infection manifests itself in the formation of blisters and ulcers on the face or genitals and can cause blindness, encephalitis, and generalized infection. All first- and second-line modern antiherpetic drugs selectively inhibit viral DNA polymerase. The purine-benzoxazine conjugate LAS-131 ((S)-4-[6-(purin-6-yl)aminohexanoyl]-7,8-difluoro-3,4-dihydro-3-methyl-2H-[1,4]benzoxazine), which we have described earlier, uses the large subunit of the HSV-1 terminase complex as a biotarget and selectively inhibits HSV-1 reproduction in vitro. Basically new results were for the first time obtained to characterize the combined effect on human herpesvirus infection for LAS-131 used in combination with practically significant antiviral compounds, including the nucleoside analogs acyclovir (ACV), penciclovir (PCV), ganciclovir (GCV), brivudine (BVdU), iododeoxyuridine (IdU), and adenine arabinoside (Ara-A); the nucleoside phosphonate analog cidofovir (CDV); and the pyrophosphate analog foscarnet (FOS). A cytopathic effect (CPE) inhibition assay showed that the drug concentration that inhibited the virus-induced CPE by 50% decreased by a factor of 2 (an additive effect, FOS) or more (a synergistic effect; ACV, PCV, GCV, IdU, BVdU, Ara-A, and CDV) when the drugs were used in combination with LAS-131. Nonpermissive conditions for HSV-1 reproduction were thus created at lower drug concentrations, opening up new real possibilities to control human herpesvirus infection.

Construction of Benzoxazine-linked One-Dimensional Covalent Organic Frameworks Using the Mannich Reaction.

Covalent polymerization of organic molecules into crystalline one-dimensional (1D) polymers is effective for achieving desired thermal, optical, and electrical properties, yet it remains a persistent synthetic challenge for their inherent tendency to adopt amorphous or semicrystalline phases. Here we report a strategy to synthesize crystalline 1D covalent organic frameworks (COFs) composing quasi-conjugated chains with benzoxazine linkages via the one-pot Mannich reaction. Through [4+2] and [2+2] type Mannich condensation reactions, we fabricated stoichiometric and sub-stoichiometric 1D covalent polymeric chains, respectively, using doubly and singly linked benzoxazine rings. The validity of their crystal structures has been directly visualized through state-of-the-art cryogenic low-dose electron microscopy techniques. Post-synthetic functionalizations of them with a chiral MacMillan catalyst produce crystalline organic photocatalysts that demonstrated excellent catalytic and recyclable performance in light-driven asymmetric alkylation of aldehydes, affording up to 94 % enantiomeric excess.

Synergistic Promotion of the Photocatalytic Preparation of Hydrogen Peroxide (H2 O2 ) from Oxygen by Benzoxazine and Si─O─Ti Bond.

Hydrogen peroxide (H2 O2 ) is considered one of the most important chemical products and has a promising future in photocatalytic preparation, which is green, pollution-free, and hardly consumes any non-renewable energy. This study involves the preparation of benzoxazine with Si─O bonds via the Mannich reaction, followed by co-hydrolysis to produce photocatalysts containing benzoxazine with Si─O─Ti bonds. In this study, a benzoxazine photocatalyst with Si─O─Ti bonds is synthesized and characterized using fourier transform infrared spectroscopy, nuclear magnetic resonance, and X-ray photoelectron spectroscopy. The size and elemental distribution of the nanoparticles are confirmed by transmission electron microscopy and scanning electron microscopy. The photocatalytic synthesis of H2 O2 is tested using the titanium salt detection method, and the rate is found to be 7.28 µmol h-1 . Additionally, the catalyst exhibits good hydrolysis resistance and could be reused multiple times. The use of benzoxazine with Si─O─Ti bonds presents a promising experimental and theoretical foundation for the industrial production of H2 O2 through photocatalytic synthesis.

Ring-Opening Oligomerization Mechanism of a Vanillin-Furfurylamine-Based Benzoxazine and a Mono-Azomethine Derivative.

Exploring the ring-opening polymerization (ROP) mechanism of benzoxazines is a fundamental issue in benzoxazine chemistry. Though some research papers on the topic have been reported, the ROP mechanism of mono-benzoxazines is still elusive. The key point for mechanistic studies is to determine and characterize the structure and formation pathways of the products generated in ROP. In this paper, the ROP of a vanillin-furfurylamine-based benzoxazine and a mono-azomethine derivative is studied with differential scanning calorimetry, fourier transform infrared spectroscopy, nuclear magnetic resonance, and electrospray ionization mass spectrometry, respectively. The results show that the products consist of a range of cationic species, zwitterions, fragments, and series of cyclic and linear oligomers of varying molecular sizes. It is proposed that both mono-benzoxazines undergo thermally activated cationic ring-opening oligomerization via zwitterion intermediates. Upon thermal induction, multi-bond-cleavage takes place to form various zwitterionic intermediates, which react with a monomer, a fragment, or a second zwitterion by several pathways to generate cyclic and linear oligomers.

Novel (E)-3-(3-Oxo-4-substituted-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-N-hydroxypropenamides as Histone Deacetylase Inhibitors: Design, Synthesis and Bioevaluation.

Herein, we report the design, synthesis and evaluation of novel (E)-3-(3-oxo-4-substituted-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-N-hydroxypropenamides (4 a-i, 7 a-g) targeting histone deacetylases. Three human cancer cell lines were used to test the cytotoxicity of the synthesized compounds (SW620, colon; PC-3, prostate; NCI-H23, lung cancer); inhibitory activity towards HDAC; anticancer activity; as well as their impact on the cell cycle and apoptosis. As a result, compounds 4 a-i bearing the alkyl substituents seemed to be less potent than the benzyl-containing compounds 7 a-g in all biological assays. Compounds 7 e-f were found to be the most active HDAC inhibitors with IC50 of 1.498±0.020 µM and 1.794±0.159 µM, respectively. In terms of cytotoxicity and anticancer assay, 7 e and 7 f also showed good activity with IC50 values in the micromolar range. In addition, the cell cycle and apoptosis of SW620 were affected by compound 7 f in almost a similar manner to that of reference compound SAHA. Docking assays were carried out for analysis the binding mode and selectivity of this compound toward 8 HDAC isoforms. Overall, our data confirmed that the inhibition of HDAC plays a pivotal role in their anticancer activity.

Low-Temperature Terpolymerizable Benzoxazine Monomer Bearing Norbornene and Furan Groups: Synthesis, Characterization, Polymerization, and Properties of Its Polymer.

There is an urgency to produce novel high-performance resins to support the rapid development of the aerospace field and the electronic industry. In the present work, we designed and consequently synthesized a benzoxazine monomer (oHPNI-fa) bearing both norbornene and furan groups through the flexible benzoxazine structural design capability. The molecular structure of oHPNI-fa was verified by the combination characterization of nuclear magnetic resonance spectrum, FT-IR technology, and high-resolution mass spectrum. The thermally activated terpolymerization was monitored by in situ FT-IR as well as differential scanning calorimetry (DSC). Moreover, the low-temperature-curing characteristics of oHPNI-fa have also been revealed and discussed in the current study. Furthermore, the curing kinetics of the oHPNI-fa were investigated by the Kissinger and Ozawa methods. The resulting highly cross-linked thermoset based on oHPNI-fa showed excellent thermal stability as well as flame retardancy (Td10 of 425 °C, THR of 4.9 KJg-1). The strategy for molecular design utilized in the current work gives a guide to the development of high-performance resins which can potentially be applied in the aerospace and electronics industries.

Main-Chain Benzoxazines Containing an Erythritol Acetal Structure: Thermal and Degradation Properties.

In this paper, the bio-based raw material erythritol was used to introduce an acetal structure into the benzoxazine resins. The benzoxazine-based resins containing an erythritol acetal structure could be degraded in an acidic solution and were environmentally friendly thermosetting resins. Compounds and resins were characterized by 1H nuclear magnetic resonance (1H NMR) and Fourier-transform infrared (FT-IR) analyses, and melting points were studied by a differential scanning calorimeter (DSC); the molecular weight was analyzed by gel permeation chromatography (GPC). The dynamic mechanical properties and thermal stability of polybenzoxazine resins were studied by dynamic mechanical thermal analysis (DMTA) and a thermogravimetric analyzer (TGA), respectively. The thermal aging, wet-heat resistance, and degradation properties of polybenzoxazine resins were tested. The results showed that the polybenzoxazine resins synthesized in this paper had good thermal-oxidative aging, and wet-heat resistance and could be completely degraded in an acidic solution (55 °C DMF: water: 1 mol/L hydrochloric acid solution = 5:2:4 (v/v/v)).

Synthesis of Daidzein and Thiophene Containing Benzoxazine Resin and Its Thermoset and Carbon Material.

In this work, a novel bio-based high-performance bisbenzoxazine resin was synthesized from daidzein, 2-thiophenemethylamine and paraformaldehyde. The chemical structure was confirmed using nuclear magnetic resonance spectroscopy (NMR) and Fourier-transform infrared spectroscopy (FT-IR). The polymerization process was systematically studied using differential scanning calorimetry (DSC) and in situ FT-IR spectra. It can be polymerized through multiple polymerization behaviors under the synergistic reaction of thiophene rings with benzopyrone rather than a single polymerization mechanism of traditional benzoxazines, as reported. In addition, thermogravimetric analysis (TGA) and a microscale combustion calorimeter (MCC) were used to study the thermal stability and flame retardancy of the resulting polybenzoxazine. The thermosetting material showed a high carbon residue rate of 62.8% and a low heat release capacity (HRC) value of 33 J/gK without adding any flame retardants. Based on its outstanding capability of carbon formation, this newly obtained benzoxazine resin was carbonized and activated to obtain a porous carbon material doped with both sulfur and nitrogen. The CO2 absorption of the carbon material at 0 °C and 25 °C at 1 bar was 3.64 mmol/g and 3.26 mmol/g, respectively. The above excellent comprehensive properties prove its potential applications in many advanced fields.

Catalyzing Benzoxazine Polymerization with Titanium-Containing POSS to Reduce the Curing Temperature and Improve Thermal Stability.

Trisilanolphenyl-polyhedral oligomeric silsesquioxane titanium (Ti-Ph-POSS) was synthesized through the corner-capping reaction, and Ti-Ph-POSS was dispersed in benzoxazine (BZ) to prepare Ti-Ph-POSS/PBZ composite materials. Ti-Ph-POSS could catalyze the ring-opening polymerization (ROP) of BZ and reduce the curing temperature of benzoxazine. In addition, Ti immobilized on the Ti-Ph-POSS cage could form covalent bonds with the N or O atoms on polybenzoxazine, improving the thermal stability of PBZ. The catalytic activity of the Ti-Ph-POSS/BZ mixtures was assessed and identified through 1H nuclear magnetic resonance (1H-NMR) and Fourier-transform infrared (FTIR) analyses, while thermogravimetric analysis (TGA) and dynamic mechanical analysis (DMA) were used to determine the thermal properties of the composite. It was found that PBZ exhibited a higher glass transition temperature (Tg) and better thermal stability when Ti-Ph-POSS was added. The curing behavior of the Ti-Ph-POSS/BZ mixtures showed that the initial (Ti) and peak (Tp) curing temperatures sharply decreased as the content of Ti-Ph-POSS and the heating rate increased. The curing kinetics of these Ti-Ph-POSS/BZ systems were analyzed using the Kissinger method, and the morphology of Ti-Ph-POSS/PBZ was determined via scanning electron microscopy (SEM). It was found that the Ti-Ph-POSS particles were well distributed in the composites. When the content exceeded 2 wt%, several Ti-Ph-POSS particles could not react with benzoxazine and were only dispersed within the PBZ matrix, resulting in aggregation of the Ti-Ph-POSS molecules.

Synthesis and Cytotoxic Activity of the Derivatives of N-(Purin-6-yl)aminopolymethylene Carboxylic Acids and Related Compounds.

Testing a number of N-[omega-(purin-6-yl)aminoalkanoyl] derivatives of 7,8-difluoro-3,4-dihydro-3-methyl-2H-[1,4]benzoxazine in a panel of nine tumor cell lines has shown that the studied compounds exhibit high cytotoxic activity, especially against 4T1 murine mammary carcinoma, COLO201 human colorectal adenocarcinoma, SNU-1 human gastric carcinoma, and HepG2 human hepatocellular carcinoma cells. Synthesis and study of structural analogs of these compounds made it possible to find that the presence of both a difluorobenzoxazine fragment and a purine residue bound via a linker of a certain length is crucial for the manifestation of the cytotoxic activity of this group of compounds. The study of the effect of the most promising compound on the cell cycle of the human tumor cell lines, the most sensitive and least sensitive to cytotoxic action (MDA-MB-231 breast adenocarcinoma and COLO201 colorectal adenocarcinoma, respectively), allows us to conclude that this compound is an inhibitor of DNA biosynthesis. The found group of purine conjugates may be of interest in the design of new antitumor agents.

Ambient Preparation of Benzoxazine-based Phenolic Resins Enables Long-term Sustainable Photosynthesis of Hydrogen Peroxide.

Rational design of polymer structures at the molecular level promotes the iteration of high-performance photocatalyst for sustainable photocatalytic hydrogen peroxide (H2 O2 ) production from oxygen and water, which also lays the basis for revealing the reaction mechanism. Here we report a benzoxazine-based m-aminophenol-formaldehyde resin (APFac) polymerized at ambient conditions, exhibiting superior H2 O2 yield and long-term stability to most polymeric photocatalysts. Benzoxazine structure was identified as the crucial photocatalytic active segment in APFac. Favorable adsorption of oxygen/intermediates on benzoxazine structure and commendable product selectivity accelerated the reaction kinetically in stepwise single-electron oxygen reduction reaction. The proposed benzoxazine-based phenolic resin provides the possibility of production in batches and industrial application, and sheds light on the de novo design and analysis of metal-free polymeric photocatalysts.

Glycerol Valorization towards a Benzoxazine Derivative through a Milling and Microwave Sequential Strategy.

Glycerol and aminophenol intermolecular condensation has been investigated through a milling and microwave-assisted sequential strategy, towards the synthesis of a benzoxaxine derivative. Mechanochemical activation prior to the microwave-assisted process could improve the probability of contact between the reagents, and greatly favors the higher conversion of aminophenol. At the same time, following a mechanochemical-microwave sequential approach could tune the selectivity towards the formation of a benzoxazine derivative, which could find application in a wide range of biomedical areas.

6,6'-((Methylazanedyl)bis(methylene))bis(2,4-dimethylphenol) Induces Autophagic Associated Cell Death through mTOR-Mediated Autophagy in Lung Cancer.

Autophagy is the multistep mechanism for the elimination of damaged organelles and misfolded proteins. This mechanism is preceded and may induce other program cell deaths such as apoptosis. This study unraveled the potential pharmacological effect of 24MD in inducing the autophagy of lung cancer cells. Results showed that 24MD was concomitant with autophagy induction, indicating by autophagosome staining and the induction of ATG5, ATG7 and ubiquitinated protein, p62 expression after 12-h treatment. LC3-I was strongly conversed to LC3-II, and p62 was downregulated after 24-h treatment. The apoptosis-inducing activity was found after 48-h treatment as indicated by annexin V-FITC/propidium iodide staining and the activation of caspase-3. From a mechanistic perspective, 24-h treatment of 24MD at 60 µM substantially downregulated p-mTOR. Meanwhile, p-PI3K and p-Akt were also suppressed by 24MD at concentrations of 80 and 100 µM, respectively. We further confirmed m-TOR-mediated autophagic activity by comparing the effect of 24MD with rapamycin, a potent standard mTOR1 inhibitor through Western blot and immunofluorescence assays. Although 24MD could not suppress p-mTOR as much as rapamycin, the combination of rapamycin and 24MD could increase the mTOR suppressive activity and LC3 activation. Changing the substituent groups (R groups) from dimethylphenol to ethylphenol in EMD or changing methylazanedyl to cyclohexylazanedyl in 24CD could only induce apoptosis activity but not autophagic inducing activity. We identified 24MD as a novel compound targeting autophagic cell death by affecting mTOR-mediated autophagy.

Aerial Oxygen-Driven Selenocyclization of O-Vinylanilides Mediated by Coupled Fe3+/Fe2+ and I2/I- Redox Cycles.

In the past decade, selenocyclization has been extensively exploited for the preparation of a wide range of selenylated heterocycles with versatile activities. Previously, selenium electrophile-based and FeCl3-promoted methods were employed for the synthesis of selenylated benzoxazines. However, these methods are limited by starting material availability and low atomic economy, respectively. Inspired by the recent catalytic selenocyclization approaches based on distinctive pathways, we rationally constructed an efficient and greener double-redox catalytic system for the access to diverse selenylated benzoxazines. The coupling of I2/I- and Fe3+/Fe2+ catalytic redox cycles enables aerial O2 to act as the driving force to promote the selenocyclization. Control and test redox experiments confirmed the roles of each component in the catalytic system, and a PhSeI-based pathway is proposed for the selenocyclization process.

Synthesis of Pyrimidine Conjugates with 4-(6-Amino-hexanoyl)-7,8-difluoro-3,4-dihydro-3-methyl-2H-[1,4]benzoxazine and Evaluation of Their Antiviral Activity.

A series of pyrimidine conjugates containing a fragment of racemic 7,8-difluoro-3,4-dihydro-3-methyl-2H-[1,4]benzoxazine and its (S)-enantiomer attached via a 6-aminohexanoyl fragment were synthesized by the reaction of nucleophilic substitution of chlorine in various chloropyrimidines. The structures of the synthesized compounds were confirmed by 1H, 19F, and 13C NMR spectral data. Enantiomeric purity of optically active derivatives was confirmed by chiral HPLC. Antiviral evaluation of the synthesized compounds has shown that the replacement of purine with a pyrimidine fragment leads to a decrease in the anti-herpesvirus activity compared to the lead compound, purine conjugate. The studied compounds did not exhibit significant activity against influenza A (H1N1) virus.

Multigram-scale HPLC enantioseparation as a rescue pathway for circumventing racemization problem during enantioselective synthesis of ethyl 3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate.

Racemic ethyl 3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate is a key synthon for the design of promising therapeutic drugs. It is mainly synthesized from racemic ethyl 2,3-dibromopropionate and 2-aminophenol in presence of K2 CO3 in refluxed acetone. Unfortunately, synthesis of (R)- and (S)-enantiomers using the enantioselective version of this reaction, which should normally be performed with a double SN 2 mechanism, is unsuitable due to a racemization process involving the dehydrobromination of enantiopure ethyl 2,3-dibromopropionate into ethyl 2-bromoacrylate. For the first time, the enantioselective version is studied (ee ≈ 55-66%), and the percentage of racemization process has estimated to around 34-46% after determination of the optimal experimental conditions for analytical HPLC enantioseparation of racemate. The influence of the experimental and purification conditions on the racemization rate is also studied. The results indicate that racemization occurs faster at the beginning of the reaction but the initiation of the double SN 2 process takes place more faster to limit the racemization rate. The study of the influence of experimental conditions (reaction times, temperature, solvent or type of base, etc.) on the degree of racemization of the (R)- enantiomer is performed and shows that despite changes in the experimental conditions, the synthesis of the (R)- enantiomer is always accompanied by a racemization rate which is difficult in reducing. In parallel, (R)- and (S)-enantiomers are obtained in high enantiopurity (ee > 99.5%) by preparative HPLC enantioseparation of racemate on multigram scale and characterized by optical rotation measurements, ECD and UV spectra.

Crystallographic and Spectroscopic Investigations on Oxidative Coordination in the Heteroleptic Mononuclear Complex of Cerium and Benzoxazine Dimer.

Among lanthanide-based compounds, cerium compounds exhibit a significant role in a variety of research fields due to their distinct tetravalency, high economic feasibility, and high stability of Ce(IV) complexes. Herein, a systematic investigation of crystallographic information, chemical properties, and mechanistic formation of the novel Ce(IV) complex synthesized from cerium(III) nitrate hexahydrate and 2,2'-(methylazanediyl)bis(methylene)bis(4-methylphenol) (MMD) ligand has been explored. According to the analysis of the crystallographic information, the obtained complex crystal consists of the Ce(IV) center coordinated with two nitrate ligands and two bidentate coordinated (N-protonated and O,O-deprotonated) MMD ligands. The fingerprint plots and the Hirshfeld surface analyses suggest that the C-H⋯O and C-H⋯π interactions significantly contribute to the crystal packing. The C-H⋯O and C-H⋯π contacts link the molecules into infinite molecular chains propagating along the [100] and [010] directions. Synchrotron powder X-ray diffraction (XRD) and X-ray absorption spectroscopy (XAS) techniques have been employed to gain an understanding of the oxidative complexation of Ce(IV)-MMD complex in detail. This finding would provide the possibility to systematically control the synthetic parameters and wisely design the precursor components in order to achieve the desired properties of novel materials for specific applications.

Structure and Performance of Benzoxazine Composites for Space Radiation Shielding.

Innovative multifunctional materials that combine structural functionality with other spacecraft subsystem functions have been identified as a key enabling technology for future deep space missions. In this work, we report the structure and performance of multifunctional polymer matrix composites developed for aerospace applications that require both structural functionality and space radiation shielding. Composites comprised of ultra-high molecular weight polyethylene (UHMWPE) fiber reinforcement and a hydrogen-rich polybenzoxazine matrix are prepared using a low-pressure vacuum bagging process. The polybenzoxazine matrix is derived from a novel benzoxazine resin that possesses a unique combination of attributes: high hydrogen concentration for shielding against galactic cosmic rays (GCR), low polymerization temperature to prevent damage to UHMWPE fibers during composite fabrication, long shelf-life, and low viscosity to improve flow during molding. Dynamic mechanical analysis (DMA) is used to study rheological and thermomechanical properties. Composite mechanical properties, obtained using several standardized tests, are reported. Improvement in composite stiffness, through the addition of carbon fiber skin layers, is investigated. Radiation shielding performance is evaluated using computer-based simulations. The composites demonstrate clear advantages over benchmark materials in terms of combined structural and radiation shielding performance.

Benzoxazine derivatives of phytophenols show anti-plasmodial activity via sodium homeostasis disruption.

Development of new class of anti-malarial drugs is an essential requirement for the elimination of malaria. Bioactive components present in medicinal plants and their chemically modified derivatives could be a way forward towards the discovery of effective anti-malarial drugs. Herein, we describe a new class of compounds, 1,3-benzoxazine derivatives of pharmacologically active phytophenols eugenol (compound 3) and isoeugenol (compound 4) synthesised on the principles of green chemistry, as anti-malarials. Compound 4, showed highest anti-malarial activity with no cytotoxicity towards mammalian cells. Compound 4 induced alterations in the intracellular Na+ levels and mitochondrial depolarisation in intraerythrocytic Plasmodium falciparum leading to cell death. Knowing P-type cation ATPase PfATP4 is a regulator for sodium homeostasis, binding of compound 3, compound 4 and eugenol to PfATP4 was analysed by molecular docking studies. Compounds showed binding to the catalytic pocket of PfATP4, however compound 4 showed stronger binding due to the presence of propylene functionality, which corroborates its higher anti-malarial activity. Furthermore, anti-malarial half maximal effective concentration of compound 4 was reduced to 490 nM from 17.54 µM with nanomaterial graphene oxide. Altogether, this study presents anti-plasmodial potential of benzoxazine derivatives of phytophenols and establishes disruption of parasite sodium homeostasis as their mechanism of action.