Multifunctional coating with hydrophobicity, antibacterial and flame-retardant properties on cotton fabrics by layer-by-layer self-assembly curing of phytic acid and a tyrosine-derived hyperbranched benzoxazine.

The inherent hydrophilicity and biocompatibility of cotton fabrics facilitated bacterial proliferation and safety concerns, limiting their applications. To address these issues, tyrosine-derived polyetherimide, bis(3-aminopropyl)-terminated poly(dimethylsiloxane), and paraformaldehyde were used to synthesize hyperbranched benzoxazine THB-BOZs-PDMS with potent antibacterial and antibiofilm activity. The protonated amino groups of benzoxazine facilitated electrostatic interactions with negatively charged bacteria, and hydrophobic interactions disrupted the cell membrane, leading to bacteria death. Notably, phytic acid interacts with benzoxazines through intermolecular forces, with its phosphoric acid groups facilitating the curing of benzoxazines, thereby imparting flame-retardant properties to the material. Consequently, a multifunctional coating was developed via LBL self-assembly and in-situ curing of benzoxazines and phytic acid on the fabric surfaces. The successful deposition of the coating was confirmed through compositional analysis and morphological characterization. After 4 cycles of LBL modification, the fabrics TBP + PA-CF-4 displayed outstanding antibacterial efficacy, bacterial anti-adhesion properties, and heat resistance. Furthermore, TBP + PA-CF-4 exhibited notable washing and mechanical durability, attributed to the stability conferred by in-situ cured of layers. Compared with other reported modified fabrics, TBP + PA-CF-4 displayed more comprehensive overall performances. These multifunctional fabrics provided a sustainable approach for advancing personal protective materials and public decoration, particularly suited for use in high-humidity environments or military settings.

Design and Synthesis of Novel Antioxidant 2-Substituted-5,7,8-Trimethyl-1,4-Benzoxazine Hybrids: Effects on Young and Senescent Fibroblasts.

The exponential growth of the aged population worldwide is followed by an increase in the prevalence of age-related disorders. Oxidative stress plays central role in damage accumulation during ageing and cell senescence. Thus, a major target of today's anti-ageing research has been focused on antioxidants counteracting senescence. In the current work, six novel 5,7,8-trimethyl-1,4-benzoxazine/catechol or resorcinol hybrids were synthesized connected through a methoxymethyl-1,2,3-triazolyl or a 1,2,3-triazoly linker. The compounds were evaluated for their antioxidant capacity in a cell-free system and for their ability to reduce intracellular ROS levels in human skin fibroblasts, both young (early-passage) and senescent. The most efficient compounds were further tested in these cells for their ability to induce the expression of the gene heme oxygenase-1 (ho-1), known to regulate redox homeostasis, and cellular glutathione (GSH) levels. Overall, the two catechol derivatives were found to be more potent than the resorcinol analogues. Furthermore, these two derivatives were shown to act coordinately as radical scavengers, ROS inhibitors, ho-1 gene expression inducers, and GSH enhancers. Interestingly, one of the two catechol derivatives was also found to enhance human skin fibroblast viability. The properties of the synthesized compounds support their potential use in cosmetic applications, especially in products targeting skin ageing.

New substituted benzoxazine derivatives as potent inducers of membrane permeability and cell death.

The search for new agents targeting different forms of cell death is an important research focus for developing new and potent antitumor therapies. As a contribution to this endeavor, we have designed and synthesized a series of new substituted 3,4-dihydro-2H-1,4-benzoxazine derivatives. These compounds have been evaluated for their efficacy against MCF-7 breast cancer and HCT-116 colon cancer cell lines. Overall, substituting this heterocycle led to improved antiproliferative activity compared to the unsubstituted derivative 1. The most active compounds, 2b and 4b, showed IC50 values of 2.27 and 3.26 µM against MCF-7 cells and 4.44 and 7.63 µM against HCT-116 cells, respectively. To investigate the mechanism of action of the target compounds, the inhibition profile of 8 kinases involved in cell signaling was studied highlighting residual activity on HER2 and JNK1 kinases. 2b and 4b showed a consistent binding mode to both receptor kinases, establishing significant interactions with known and catalytically important domains and residues. Compounds 2b and 4b exhibit potent cytotoxic activity by disrupting cell membrane permeability, likely triggering both inflammatory and non-inflammatory cell death mechanisms. This dual capability increases their versatility in the treatment of different stages or types of tumors, providing greater flexibility in clinical applications.

Protonation Effects on the Benzoxazine Formation Pathways and Products Distribution.

The effect of acidic media on the formation of the 3,4-dihydro-2H-3-phenyl-1,3-benzoxazine Bz is evaluated, focusing on the differentiation of intermediates and products formed by the distinct pathways observed in the presence and absence of acid. The use of real-time mass spectrometry (PSI-ESI-MS) coupled to tandem mass spectrometry and infrared multiple photon dissociation (IRMPD) allowed the differentiation of the species observed during the synthesis of benzoxazines in these different conditions. The results suggest that formic acid promotes the formation of aniline and phenol condensation products (IC and IIC) by protecting the aniline amino group and enhancing the formaldehyde electrophilicity. The results also suggest that although the presence of acid allow a more efficient potential energy landscape to be accessed, the last cyclization step for the formation of benzoxazines cannot be mediated by the protonation route intermediate (ROP Bz). Overall, the conclusions presented here provide important information about the synthesis of benzoxazines under acidic conditions, allowing the development of optimal reaction conditions.

Differential Effect of 4H-Benzo[d] [1, 3]oxazines on the Proliferation of Breast Cancer Cell Lines.

BACKGROUND: A family of 4H-benzo[d][1,3]oxazines were obtained from a group of N-(2-alkynyl)aryl benzamides precursors via gold(I) catalysed chemoselective 6-exo-dig C-O cyclization. METHOD: The precursors and oxazines obtained were studied in breast cancer cell lines MCF-7, CAMA-1, HCC1954 and SKBR-3 with differential biological activity showing various degrees of inhibition with a notable effect for those that had an aryl substituted at C-2 of the molecules. 4H-benzo[d][1,3]oxazines showed an IC50 rating from 0.30 to 157.4 µM in MCF-7, 0.16 to 139 in CAMA-1, 0.09 to 93.08 in SKBR-3, and 0.51 to 157.2 in HCC1954 cells. RESULTS: We observed that etoposide is similar to benzoxazines while taxol effect is more potent. Four cell lines responded to benzoxazines while SKBR-3 cell line responded to precursors and benzoxazines. Compounds 16, 24, 25 and 26 have the potent effect in cell proliferation inhibition in the 4 cell lines tested and correlated with oxidant activity suggesting a possible mechanism by ROS generation. CONCLUSION: These compounds represent possible drug candidates for the treatment of breast cancer. However, further trials are needed to elucidate its full effect on cellular and molecular features of cancer.

Microstructural Analysis of Benzoxazine Cationic Ring-Opening Polymerization Pathways.

Herein, an evaluation of the initial step of benzoxazine polymerization is presented by mass spectrometry, with a focus on differentiating the phenoxy and phenolic products formed by distinct pathways of the cationic ring opening polymerization (ROP) mechanism of polybenzoxazine formation. The use of infrared multiple photon dissociation (IRMPD) and ion mobility spectrometry (IMS) techniques allows for differentiation of the two pathways and provides valuable insights into the ROP mechanism. The results suggest that type I pathway is favored in the initial stages of the reaction yielding the phenoxy product, while type II product should be observed at later stages when the phenoxy product would interconvert to the most stable type II phenolic product. Overall, the findings presented here provide important information on the initial step of the benzoxazine polymerization, allowing the development of optimal polymerization conditions and represents a way to evaluate other multifunctional polymerization processes.

In vivo anticancer activity of benzoxazine and aminomethyl compounds derived from eugenol.

Background: Indonesia is the world's primary producer of clove. In order to find new utilization for clove and new biologically active compounds, eugenol, the main constituent of clove, has been converted to its derivatives. Objective: This study aims to examine in vivo anticancer activity of benzoxazine and aminomethyl compounds derived from eugenol. Methods: Fibrosarcoma was induced by injection of benzo(a)pyrene solution. The test compounds were given per oral at 20, 40, and 80 mg/Kg body weight, once a day for 30 days. Results: As a result, all the tested compounds showed activity in reducing the cancer incidence rate. All the tested compounds were also found to reduce tumor weight. Benzoxazine derivatives gave slightly better activity compared to aminomethyl derivatives. The strongest activity was exhibited by 6-allyl-3-(furan-2- ylmethyl)-8-methoxy-3,4-dihydro-2H-benzo(e)(1,3)oxazine. Conclusions: All four benzoxazine and aminomethyl compounds derived from eugenol that were tested exhibited anticancer activity in mice fibrosarcoma.

A Synthetic Overview of Benzoxazines and Benzoxazepines as Anticancer Agents.

Benzoxazines and benzoxazepines are nitrogen and oxygen-containing six and seven-membered benzo-fused heterocyclic scaffolds, respectively. Benzoxazepines and benzoxazines are well-known pharmacophores in pharmaceutical chemistry, which are of significant interest and have been extensively studied because of their promising activity against various diseases including their wide range of anticancer activity. Several reports are known for synthesizing benzoxazine and benzoxazepine-based compounds in the literature. Herein this review provides a critical analysis of synthetic strategies towards benzoxazines and benzoxazepines along with various ranges of anticancer activities based on these molecules that have been reported from 2010 onwards. This review also focuses on the structure-activity relationship of the benzoxazine and benzoxazepine scaffolds containing bioactive compounds and describes how the structural modification affects their anticancer activity.

Benzoxazine: A Privileged Scaffold in Medicinal Chemistry.

BACKGROUND: Benzoxazine is one of the most important privileged scaffolds in medicinal chemistry. Compounds bearing benzoxazine moiety usually have a variety of biological activities, such as anti-inflammatory, anti-microbial, anti-tuberculosis, anti- oxidant and anti-cancer activities. The fascinating bioactivity profile of benzoxazine scaffold in various fields has prompted medicinal chemists to design and discover novel benzoxazine derivatives as potential therapeutic candidates with the desired biological properties. OBJECTIVE: This review aimed to provide a comprehensive elucidation on the recent advances of benzoxazine derivatives in medicinal chemistry. METHODS: We have searched the recent literature about benzoxazine derivatives from the online resources and databases, such as PubMed, SciFinder and Google Scholar. RESULTS: Many benzoxazine derivatives with a wide range of bioactivities, such as anti- microbial, anti-cancer, anti-tuberculosis, anti-oxidant and anti-inflammatory, were summed up. Many compounds displayed good biological activities. CONCLUSION: Benzoxazine is a versatile structure and building block in medicinal chemistry. Benzoxazine derivatives have gained considerable attention from medicinal chemists due to their various pharmacological properties and multiple modification sites. This review might help medicinal chemists to seek new drug candidates with better bioactivities and pharmacokinetics properties.

Rational Design, Synthesis, and Anti-Proliferative Evaluation of Novel 4-Aryl-3,4-Dihydro-2H-1,4-Benzoxazines.

A synthetic pathway to a novel 4-aryl-3,4-dihydro-2H-1,4-benzoxazine scaffold was developed and a series of compounds based on the scaffold were synthesised as potential anticancer agents. The 4-aryl-substituted compounds were prepared via Buchwald-Hartwig cross-coupling between substituted bromobenzenes and various 1,4-benzoxazines, which in turn were generated from a cascade hydrogenation and reductive amination one-pot reaction. These analogues exhibited moderate to good potency against various cancer cell lines. Structure-activity relationship analysis indicated that the inclusion of hydroxyl groups on ring A and ring B was beneficial to biological activity, while having a para-amino group on ring C significantly enhanced potency. Molecule 14f displayed the most potent anticancer activity (IC50 = 7.84-16.2 µM against PC-3, NHDF, MDA-MB-231, MIA PaCa-2, and U-87 MG cancer cell lines), indicating its potential as a lead compound for further structural optimisation. All the synthesised compounds were fully characterised with NMR, HMRS, and IR. The novel benzoxazine scaffold described in this study holds promise and deserves further in-depth studies.

Mapping the Melatonin Receptor. 8. Selective MT2 Agonists Derived from 5,6-Dihydroindolo[2,1-a]isoquinolines and Related Systems.

A series of substituted indolo[2,1-a]isoquinolines and indolo[1,2-a]benzoxazines have been prepared, as melatonin analogues, to investigate the nature of the binding site of the melatonin receptor. Agonist and antagonist potency of all the analogues was measured using the [35S]GTPγS binding assay protocol. The binding affinity of the analogues were measured by competition binding studies against the human MT1 (hMT1) and MT2 (hMT2) receptors stably transfected in Chinese Hamster Ovarian (CHO) cells, using 2-[125 I]-iodomelatonin, as a ligand. N-Acetyl 2-(10-methoxy-5,6-dihydroindolo[2,1-a]isoquinolin-12-yl)propyl-1-amine (12 a) binds strongly to both the hMT1 and hMT2 receptors, and shows a preference for the hMT2, as does its propanamido counterpart 12 b. The introduction of two methyl groups into their side chain, analogues 15 a and 15 b, leads to antagonism, in the case of the former, and drastically diminishes its hMT1 binding; an analogous profile is seen for 15 b, which, however, is a partial agonist. Introduction of chlorine or methoxy groups into ring 4 gives compounds, that are weakly binding, with a preference for MT2. Substitution of oxygen for carbon at position 5 gives the indolo[1,2-c]benzoxazines 33, 36 a and b, that bind strongly to the human receptors, 33, 36 b being potent agonists at the melatonin receptors, but do not discriminate between hMT1 and hMT2.

Benzoxazines in the Root Exudates Responsible for Nonhost Disease Resistance of Maize to Phytophthora sojae.

It has been reported that the root exudates of nonhost maize inhibit Phytophthora sojae because of the presence of benzoxazines in maize roots. To understand the concentrations of benzoxazines (Bxs) in maize root exudates and the molecular mechanism of P. sojae being inhibited, the transcriptomes of P. sojae responding to three different Bxs, 2,4-dihydroxy-7-methoxy-2H-1,4-benzoxazin-3(4H)-one (DIMBOA), 6-methoxy-2-benzoxazolinone (MBOA), and benzoxazolinone (BOA), were analyzed by RNA sequencing method. We detected DIMBOA, MBOA, and BOA with a concentration range of 7 to 126 µg/ml in root exudates of three tested maize cultivars (A6565, Pengyu 1, and Xianyu 696). DIMBOA, MBOA, and BOA inhibited chemotaxis and invasiveness of P. sojae zoospores and mycelial growth. The inhibition was regulated mainly by endocytosis and the calcium signaling pathway, PI3K-Akt signaling pathway, and mTOR signaling pathway; meanwhile, the glutathione signaling pathway was activated to increase the antioxidant capacity and efflux of toxic substances. It was speculated that endocytosis plays an important role in the response of P. sojae to Bxs, and the specific functions of genes in this pathway must be further studied. This result provides new insights into the response mechanisms of P. sojae response to Bxs.

Screening of simple carbohydrates as a renewable organocatalyst for the efficient construction of 1,3-benzoxazine scaffold.

A convenient protocol for the two component preparation of 1,3-benzoxazines by using several protected and unprotected carbohydrate molecules as organocatalysts have been developed which is broadly applicable to condensation reaction between variety of Mannich bases and paraformaldehyde. This study revealed that fructose have much higher catalytic activity than the other carbohydrates and can be an alternative to metal-containing catalysts as a green renewable organocatalyst for efficient and rapid construction of 1,3-benzoxazine skeleton. In this context, 21 benzoxazine compounds were successfully synthesized and spectral characterizations of these compounds were carried out by spectroscopic methods and elemental analysis. Furthermore, density functional theory (DFT) calculations have been performed to study the detailed mechanism of organocatalyst assisted synthesis of the benzoxazine monomers. The results obtained from these calculations showed that the more realistic reaction pathway involves formation of a phenolate based intermediate which loses a water molecule to form benzenaminium ion. Subsequently, this ion provides the formation of the corresponding benzoxazines with good yields through the intramolecular ring closure step.

The Influence of Substituents in Phosphazene Catalyst-Flame Retardant on the Thermochemistry of Benzoxazine Curing.

This work is devoted to the influence of phosphazene modifiers with different substituents on the curing process, thermal properties and flammability of benzoxazine resin. Novel catalysts with m-toluidine substituents were introduced. The catalytic activity of studied phosphazene compounds decreased in the row: hexachlorocyclotriphosphazene (HCP) > tetra m-toluidine substituted phosphazene PN-mt (4) > hexa m-toluidine substituted phosphazene PN-mt (6) > hexaphenoxycyclotriphosphazene (HPP), where HPP is totally inactive. Two types of catalysis: basic and acid were proposed. A brief study of resulting properties of polybenzoxazines was presented. The addition of any studied modifier caused the decrease of glass transition temperature and thermal stability of polymers. The morphology of cured compositions was characterized by matrix-dispersion phase structure. All phosphazene containing polybenzoxazines demonstrated the improved flame resistance.

Practical One-Pot Multistep Synthesis of 2H-1,3-Benzoxazines Using Copper, Hydrogen Peroxide and Triethylamine.

In this article, we describe simple one-pot syntheses of 2H-1,3-benzoxazines from ketones utilizing an imino-pyridine directing group (R1R2-C=N-CH2-Pyr), which promotes a Cu-directed sp2 hydroxylation using H2O2 as oxidant and followed by an oxidative intramolecular C-O bond formation upon addition of NEt3. This synthetic protocol is utilized in the gram scale synthesis of the 2H-1,3-benzoxazine derived from benzophenone. Mechanistic studies reveal that the cyclization occurs via deprotonation of the benzylic position of the directing group to produce a 2-azallyl anion intermediate, which is oxidized to the corresponding 2-azaallyl radical before the C-O bond formation event. Understanding of the cyclization mechanism also allowed us to develop reaction conditions that utilize catalytic amounts of Cu.

Synthesis, ADMET predictions, molecular docking studies, and in-vitro anticancer activity of some benzoxazines against A549 human lung cancer cells.

OBJECTIVES: This study aims to synthesize a series of benzoxazines (1-5) to be examined as an epidermal growth factor receptor (EGFR) inhibitor by in-silico study. The overexpression of EGFR causes the growth of normal lung cells to become uncontrollable, which may lead to cancer formation. We also conducted the absorption, distribution, metabolism, excretions and toxicity (ADMET) properties evaluation and also examined in vitro anticancer assay on human lung cancer cells line, which is A549. METHODS: Benzoxazines (1-5) were synthesized by reacting anthranilic acid and benzoyl chlorides. The structures of the compounds were determined with 1H, 13C-NMR, HRMS, UV and FT-IR spectrometric methods. Prediction of ADMET was using online pkCSM, and the molecular docking studies were using MVD with EGFR-TKIs as the target (PDB ID: 1M17). In vitro assay of anticancer activity was performed by MTT assay. RESULTS: Compounds 1-5 were successfully synthesized in good yields (71-84%). The ADMET prediction showed that benzoxazines are able to be absorbed through GIT, metabolized by CYP 450, and not hepatotoxic. The title compounds have a greater Moldock Score than Erlotinib, and 3 has the highest activity against A549 compared with other benzoxazines, IC50=36.6 µg/mL. CONCLUSIONS: Compound (3) more active as anticancer against Human cancer cells line compared with other benzoxazines.

Transportability From Randomized Trials to Clinical Care: On Initial HIV Treatment With Efavirenz and Suicidal Thoughts or Behaviors.

In an analysis of randomized trials, use of efavirenz for treatment of human immunodeficiency virus (HIV) infection was associated with increased suicidal thoughts/behaviors. However, analyses of observational data have found no evidence of increased risk. To assess whether population differences might explain this divergence, we transported the effect of efavirenz use from these trials to a specific target population. Using inverse odds weights and multiple imputation, we transported the effect of efavirenz on suicidal thoughts/behaviors in these randomized trials (participants were enrolled in 2001-2007) to a trials-eligible cohort of US adults initiating antiretroviral therapy while receiving HIV clinical care at medical centers between 1999 and 2015. Overall, 8,291 cohort participants and 3,949 trial participants were eligible. Prescription of antidepressants (19% vs. 13%) and injection drug history (16% vs. 10%) were more frequent in the cohort than in the trial participants. Compared with the effect in trials, the estimated hazard ratio for efavirenz on suicidal thoughts/behaviors was attenuated in our target population (trials: hazard ratio (HR) = 2.3 (95% confidence interval (CI): 1.2, 4.4); transported: HR = 1.8 (95% CI: 0.9, 4.4)), whereas the incidence rate difference was similar (trials: HR = 5.1 (95% CI: 1.6, 8.7); transported: HR = 5.4 (95% CI: -0.4, 11.4)). In our target population, there was greater than 20% attenuation of the hazard ratio estimate as compared with the trials-only estimate. Transporting results from trials to a target population is informative for addressing external validity.

Synthesis of Novel Benzoxazines Containing Sulfur and Their Application in Rubber Compounds.

This work reports the synthesis and successful use of novel benzoxazines as reinforcing resins in polyisoprene rubber compounds. For this purpose, three new dibenzoxazines containing one (4DTP-fa) or two heteroatoms of sulfur (3DPDS-fa and 4DPDS-fa) were synthesized following a Mannich condensation reaction. The structural features of each benzoxazine precursor were characterized by 1H and 13C nuclear magnetic resonance (NMR), Fourier transform infrared (FTIR) and Raman. The new precursors showed well suited reactivity as characterized by differential scanning calorimetry (DSC) and rheology and were incorporated in rubber compounds. After the mixing, the curing profiles, morphologies and mechanical properties of the materials were tested. These results show that the structural feature of each isomer was significantly affecting its behavior during the curing of the rubber compounds. Among the tested benzoxazines, 3DPDS-fa exhibited the best ability to reinforce the rubber compound even compared to common phenolic resin. These results prove the feasibility to reinforce rubber compounds with benzoxazine resins as a possible alternative to replace conventional phenolic resins. This paper provides the first guide to use benzoxazines as reinforcing resins for rubber applications, based on their curing kinetics.

Benzoxazine Monomers and Polymers Based on 3,3'-Dichloro-4,4'-Diaminodiphenylmethane: Synthesis and Characterization.

To reveal the effect of chlorine substituents in the ring of aromatic amine on the synthesis process of benzoxazine monomer and on its polymerization ability, as well as to develop a fire-resistant material, a previously unreported benzoxazine monomer based on 3,3'-dichloro-4,4'-diaminodiphenylmethane was obtained in toluene and mixture toluene/isopropanol. The resulting benzoxazine monomers were thermally cured for 2 h at 180 °C, 4 h at 200 °C, 2 h at 220 °C. A comparison between the rheological, thermal and fire-resistant properties of the benzoxazines based on 3,3'-dichloro-4,4'-diaminodiphenylmethane and, for reference, 4,4'-diaminodimethylmethane was made. The effect of the reaction medium on the structure of the oligomeric fraction and the overall yield of the main product were studied and the toluene/ethanol mixture was found to provide the best conditions; however, in contrast to most known diamine-based benzoxazines, synthesis in the pure toluene is also possible. The synthesized monomers can be used as thermo- and fire-resistant binders for polymer composite materials, as well as hardeners for epoxy resins. Chlorine-containing polybenzoxazines require more severe conditions for polymerization but have better fire resistance.

Synthesis and Application of Arylaminophosphazene as a Flame Retardant and Catalyst for the Polymerization of Benzoxazines.

A novel type of phosphazene containing an additive that acts both as a catalyst and as a flame retardant for benzoxazine binders is presented in this study. The synthesis of a derivative of hexachlorocyclotriphosphazene (HCP) and meta-toluidine was carried out in the medium of the latter, which made it possible to achieve the complete substitution of chlorine atoms in the initial HCP. Thermal and flammability characteristics of modified compositions were investigated. The modifier catalyzes the process of curing and shifts the beginning of reaction from 222.0 °C for pure benzoxazine to 205.9 °C for composition with 10 phr of modifier. The additive decreases the glass transition temperature of compositions. Achievement of the highest category of flame resistance (V-0 in accordance with UL-94) is ensured both by increasing the content of phenyl residues in the composition and by the synergistic effect of phosphorus and nitrogen. A brief study of the curing kinetics disclosed the complex nature of the reaction. An accurate two-step model is obtained using the extended Prout-Tompkins equation for both steps.