Hauser-Kraus Annulation Initiated Multi-Cascade Reactions for Facile Access to Functionalized and Fused Oxazepines, Carbazoles and Phenanthridinediones.

The Hauser-Kraus (H-K) annulation of N-unsubstituted 3-olefinic oxindoles with 3-nucleophilic phthalides triggers a cascade of ring expansion and ring contraction reactions through several regioselective steps in one pot. While oxazepines were isolated in the presence of stoichiometric amounts of base at room temperature, carbazoles and phenanthridinediones were the products in the presence of excess base and microwave irradiation. Mechanistic studies guided by stepwise reactions and control experiments revealed that the isolable oxazepine intermediate, formed via ring expansion of the H-K adduct, is the key precursor to carbazole and phenanthridinedione via decarboxylative regioselective cyclizations.

Unexpected regio- and stereoselective [4 + 3] cycloaddition reaction of azomethine ylides with benzylidene thiazolidinediones: synthesis of pharmacologically active spiroindoline oxazepine derivatives and theoretical study.

An unexpected regio- and stereoselective [4 + 3] cycloaddition reaction of azomethine ylides with 5-benzylidenethiazolidine-2,4-diones has been successfully developed for the synthesis of the novel pharmacologically active 4',5'-dihydro-3'H-spiro[indoline-3,2'-[1, 3] oxazepin]-2-one derivatives in basic condition. Easy purification, high yield, short experimental time and operational simplicity are specific advantages of this protocol. Furthermore, all the synthesized compounds have been evaluated for antioxidant and antibacterial activities. According to the results, most of the synthesized compounds exhibited DPPH radical scavenging activity and nine of them showed antibacterial properties. The reaction mechanism and 1H NMR spectrum have been evaluated by B3LYP/6311G method.

Comparative safety evaluation of riot control agents of synthetic and natural origin.

Riot control agents (RCA) are lachrymatory, irritating compounds which temporarily incapacitate the uncontainable crowd. Ortho-Chlorobenzylidene-malononitrile (CS), 2-chloroacetophenone (CN), dibenz[b,f]1:4-oxazepine (CR), and nonivamide (PAVA) are synthetic RCAs, while oleoresin extract of chili known as oleoresin capsicum (OC) a natural irritant has been in use by various law enforcement agencies. Though efficacy of these agents is beyond doubt, they suffer from certain drawbacks including toxicity, production cost, and ecological compatibility. Presently, we have evaluated the safety of CR, OC, and PAVA on inhalation variables along with oral lethality. Additionally, the liver function test (LFT) in serum and lungs function was evaluated in broncho-alveolar-lavage fluid (BALF), both collected on the 14th day after RCA exposure. Animals then sacrificed and histopathology of liver and lungs was carried out. Results showed OC and PAVA to be more toxic than CR with an oral LD50 of 150 and 200 mg/kg body weight, respectively, while CR was safe at >3 g/kg body weight. All three agents caused severe impairment of respiratory variables bringing down normal respiration by >80% with rise in sensory irritation. Recovery from the irritating effect of CR was more rapid than OC and PAVA. LFT and BALF variables were not significantly different from that of control. There were no remarkable histopathological changes in liver and lungs. Hence, as per results, CR is safest among all synthetic and natural origin RCAs and can be safely used for effective dispersion of disobedient mob.

Dibenzo[b,f][1,4]oxazepines and dibenzo[b,e]oxepines: Influence of the chlorine substitution pattern on the pharmacology at the H1R, H4R, 5-HT2AR and other selected GPCRs.

Inspired by VUF6884 (7-Chloro-11-(4-methylpiperazin-1-yl)dibenzo[b,f][1,4]oxazepine), reported as a dual H1/H4 receptor ligand (pKi: 8.11 (human H1R (hH1R)), 7.55 (human H4R (hH4R))), four known and 28 new oxazepine and related oxepine derivatives were synthesised and pharmacologically characterized at histamine receptors and selected aminergic GPCRs. In contrast to the oxazepine series, within the oxepine series, the new compounds showed high affinity to the hH1R (pKi: 6.8-8.7), but no or moderate affinity to the hH4R (pKi:≤5.3). For one oxepine derivative (1-(2-Chloro-6,11-dihydrodibenzo[b,e]oxepin-11-yl)-4-methylpiperazine), the enantiomers were separated and the R-enantiomer was identified as the eutomer at the hH1R (pKi: 8.83 (R), 7.63 (S)) and the guinea-pig H1R (gpH1R) (pKi: 8.82 (R), 7.41 (S)). Molecular dynamic studies suggest that the tricyclic core of the compounds is bound in a similar mode into the binding pocket, as described for doxepine in the hH1R crystal structure. Moreover, docking studies of all oxepine derivatives at the hH1R indicate that the oxygen and the position of the chlorine in the tricyclic core determines, if the R- or the S-enantiomer is the eutomer. For some of the oxazepines and oxepines the affinity to other aminergic GPCRs is in the same range as to hH1R or hH4R, thus, those compounds have to be classified as dirty drugs. However, one oxazepine derivative (3,7-Dichloro-11-(4-methylpiperazin-1-yl)dibenzo[b,f][1,4]oxazepine was identified as dual hH1/h5-HT2A receptor ligand (pKi: 9.23 (hH1R), 8.74 (h5-HT2AR), ≤7 at other analysed GPCRs), whereas one oxepine derivative (1-(3,8-Dichloro-6,11-dihydrodibenzo[b,e]oxepin-11-yl)-4-methylpiperazine) was identified as selective hH1R antagonist (pKi: 8.44 (hH1R), ≤6.7 at other analyzed GPCRs). Thus, the pharmacological results suggest that the oxazepine/oxepine moiety and additionally the chlorine substitution pattern toggles receptor selectivity and specificity.

Synthesis, Spectroscopic, X-ray Diffraction and DFT Studies of Novel Benzimidazole Fused-1,4-Oxazepines.

A series of benzimidazole-tethered oxazepine heterocyclic hybrids has been synthesized in good to excellent yields from an N-alkylated benzimidazole 2-carboxaldehyde, which in turn was accomplished from o-phenylenediamine in three good yielding steps. The calculated molecular structure of compounds 2-methyl-4-(2-((phenylimino)methyl)-1H-benzo-[d]imidazol-1-yl)-butan-2-ol 9 and 10 3,3-dimethyl-N-phenyl-1,2,3,5-tetrahydrobenzo-[4,5]imidazo[2,1-c][1,4]oxazepin-5-amine using the B3LYP/6-31 G(d, p) method were found to agree well with their X-ray structures. The charge distributions at the different atomic sites were computed using the natural bond orbital (NBO) method. The regions of electrophilic and nucleophilic reactivity were shown using a molecular electrostatic potential (MEP) map. In addition, the frontier molecular orbitals of these compounds were discussed at the same level of theory. Nonlinear optical (NLO) properties have also been investigated by computational hyperpolarizability studies, and it was found that Compound 9 is the best candidate for NLO applications.

Facile Synthesis for Benzo-1,4-Oxazepine Derivatives by Tandem Transformation of C-N Coupling/C-H Carbonylation.

A tandem transformation of C-N coupling/C-H carbonylation has been developed for the synthesis of benzo-1,4-oxazepine pharmaceutically derivatives. Notably, this reaction was accomplished by various phenylamine with ally halides under carbon dioxide atmosphere employing 2-(2-dimethylamino-vinyl)-1H-inden-1-olcatalyzed. Furthermore, under the optimized conditions, various benzo-1,4-oxazepine derivatives were obtained in good yields. Finally, a plausible CuI/CuIII mechanism of C-N coupling/C-H carbonylation transformation was proposed.

6,7-Dihydrobenzo[f]benzo[4,5]imidazo[1,2-d][1,4]oxazepine derivatives as selective inhibitors of PI3Kα.

Twenty eight 6,7-dihydrobenzo[f]benzo[4,5]imidazo[1,2-d][1,4]oxazepine derivatives were synthesized and evaluated their biological activities as PI3K inhibitors. Biological evaluation against four human tumor cell lines revealed that most target compounds showed impressively better antiproliferative activities than that of LY294002. Among these compounds, compound 25 exhibited the most potent and selective activity for PI3Kα, with the IC50 value of 0.016µM, an approximately 30-fold increase in comparison with LY294002, it also has an increased potency of approximately 11-fold for PI3Kß. It indicated the potential of developing 6,7-dihydrobenzo[f]benzo[4,5]imidazo[1,2-d][1,4]oxazepine derivatives as the new PI3Kα selective inhibitors for tumor treatment.

Design, Synthesis, and Molecular Docking of Novel Pyrrolooxazepinediol Derivatives with Anti-Influenza Neuraminidase Activity.

A series of novel pyrrolo[2,1-b][1,3]oxazepine-8,9-diol derivatives 12-15 were synthesized starting from l-tartaric acid, which was transformed into anhydride which then reacted with allylamine in xylene to afford the imide 2. The target molecules 12-15 were achieved via ring-closing metathesis with the Grubbs catalyst, followed by reduction of the carbonyl group and deprotection of hydroxyl groups. Finally, catalytic hydrogenation of the double bond afforded the title compounds 12-15. Molecular docking study of the title compounds 12-15 was carried out against neuraminidase as the target enzyme, in an attempt to understand the mechanism of action of the tested compounds as potential neuraminidase inhibitors. Molecular docking of the target compounds showed that all tested compounds bind to the active site of neuraminidase, with moderate to high binding energy. Compounds 12-15 were examined for their antiviral activity against H5N1 virus (A/chicken/Egypt/1/2008). Oseltamivir phosphate was used as a control for antiviral activity. The results show that compound 12 (EC50 = 0.016 µg/mL) exhibited potent anti-influenza (H5N1) activity, which approximately equals that of oseltamivir (EC50 = 0.012 µg/mL). Also, it had a therapeutic index similar to that of oseltamivir phosphate (∼20). The data also revealed that compounds 13, 14, and 15 had slightly lower antiviral activity and lower cytotoxicity than oseltamivir phosphate, with LD50 of 0.188, 0.162, and 0.176 µg/mL, respectively. However, 13, 14, and 15 had lower therapeutic indices than 12. In conclusion, we were able to synthesize cheap and potent anti-H5N1 compounds.

Crystal structures of methyl 3-phenyl-4,5-di-hydro-1H,3H-benzo[4,5]imidazo[2,1-c][1,4]oxazepine-4-carboxyl-ate and methyl 1-methyl-3-phenyl-4,5-di-hydro-1H,3H-benzo[4,5]imidazo[2,1-c][1,4]oxazepine-4-carboxyl-ate.

The title compounds, C19H18N2O3, (I), and C20H20N2O3, (II), differ only by a methyl substituent on the seven-membered oxazepine ring in (II). In both compounds, these rings have a twist-chair conformation. The phenyl ring makes a dihedral angle of 73.42 (10)° with the benzimidazole ring system mean plane (r.m.s. deviation = 0.015 Å) in (I) and 83.07 (7)° in (II) (r.m.s. deviation = 0.026 Å). The methyl carboxyl-ate groups are planar to within 0.031 (2) in (I) and 0.003 (2) Šin (II). They are inclined to the phenyl and benzimidazole ring system by 33.78 (16) and 87.56 (14)°, respectively, in (I) and by 53.04 (12) and 60.22 (11)°, respectively, in (II). In the crystal of (I), mol-ecules stack in a herringbone fashion and are linked by C-H⋯O hydrogen bonds, forming chains along [100]. In the crystal of (II), there are no significant inter-molecular inter-actions present.

Ferrocenyl conjugated oxazepines/quinolines: multiyne coupling and ring-expanding or rearrangement.

Ferrocenyl conjugated oxazepine/quinoline derivatives were presented through the reaction of hexadehydro-Diels-Alder (HDDA) generated arynes with ferrocenyl oxazolines under mild conditions via ring-expanding or rearrangement processes. Water molecule participated in this unexpected rearrangement process to produce quinoline skeletons, and DFT calculations supported a ring-expanding and intramolecular hydrogen migration process for the formation of oxazepine derivatives. Two variants of this chemistry, expanded the reactivity between ferrocenyl conjugated substances and arynes, further providing an innovative approach for the synthesis of ferrocene derivatives.

Chemical-proteomics Identify Peroxiredoxin-1 as an Actionable Target in Triple-negative Breast Cancer.

Triple-negative breast cancer (TNBC) is difficult to treat; therefore, the development of drugs directed against its oncogenic vulnerabilities is a desirable goal. Herein, we report the antitumor effects of CM728, a novel quinone-fused oxazepine, against this malignancy. CM728 potently inhibited TNBC cell viability and decreased the growth of MDA-MB-231-induced orthotopic tumors. Furthermore, CM728 exerted a strong synergistic antiproliferative effect with docetaxel in vitro and this combination was more effective than the individual treatments in vivo. Chemical proteomic approaches revealed that CM728 bound to peroxiredoxin-1 (Prdx1), thereby inducing its oxidation. Molecular docking corroborated these findings. CM728 induced oxidative stress and a multi-signal response, including JNK/p38 MAPK activation and STAT3 inhibition. Interestingly, Prdx1 downregulation mimicked these effects. Finally, CM728 led to DNA damage, cell cycle blockage at the S and G2/M phases, and the activation of caspase-dependent apoptosis. Taken together, our results identify a novel compound with antitumoral properties against TNBC. In addition, we describe the mechanism of action of this drug and provide a rationale for the use of Prdx1 inhibitors, such as CM728, alone or in combination with other drugs, for the treatment of TNBC.

Synthesis and Anticancer Properties of Oxazepines Related to Azaisoerianin and IsoCoQuines.

In this article, we report the synthesis and biological properties of a series of novel oxazepines related to isoCA-4 having significant antitumor properties. Among them, three oxazepin-9-ol derivatives display a nanomolar or a sub-nanomolar cytotoxicity level against five human cancer cell lines (HCT116, U87, A549, MCF7, and K562). It was demonstrated that the lead compound in this series inhibits tubulin assembly with an IC50 value of 1 µM and totally arrests the cellular cycle in the G2/M phase at the low concentration of 5 nM in HCT116 and K562 cells. Molecular modeling studies perfectly corroborates these promising results.

Effect of dibenz(b,f)-1,4-oxazepine aerosol on the breathing pattern and respiratory variables by continuous recording and analysis in unanaesthetised mice.

A riot control agent has to be a sensory irritant of a reversible type without pulmonary irritation as the later can cause lung injury. The aim of the present study is to continuously record and analyse breathing pattern and respiratory variables of dibenz (b,f)-1,4-oxazepine (CR) in unanaesthetised mice during and after exposure. The lowest concentration of 0.65 mg/m3 did not produce any effect on the breathing pattern. As high as 500 fold increase (315.9 mg/m3) in the concentration was used and no mortality was observed. CR produced a concentration dependent sensory irritation, without pulmonary irritation or airflow obstruction, showing that it may not cause any lung injury. The sensory irritation was initiated within 5 min of exposure due to the activation of TRPA1 receptors of the upper respiratory tract. Immediate recovery of normal breath without sensory irritation was observed in all the concentrations except the highest concentration of 315.9 mg/m3. Corresponding to the sensory irritation there was concentration dependent respiratory depression. The 50 percent respiratory depression (RD50) in this experiment was 152 mg/m3 and the estimated threshold limit value for occupational exposure was 4.56 mg/m3. The present study shows that CR causes sensory irritation only which is completely recoverable.

A One-Pot Synthesis of Oxazepine-Quinazolinone bis-Heterocyclic Scaffolds via Isocyanide-Based Three-Component Reactions.

A novel, efficient and environmentally friendly approach has been developed for the synthesis of biologically important bis-heterocyclic oxazepine-quinazolinone derivatives. The structurally interesting compounds of high purity were synthesized by a one-pot three-component reaction of 2-(2-formylphenoxy) acetic acid and 2-aminobenzamide as bifunctional reagents and an isocyanide without using any catalyst, with excellent overall yields.

Crystal structure of a mixed solvated form of amoxapine acetate.

The mixed solvated salt 4-(2-chloro-dibenzo[b,f][1,4]oxazepin-11-yl)piperazin-1-ium acetate-acetic acid-cyclo-hexane (2/2/1), C17H17ClN3O(+)·C2H3O2 (-)·C2H4O2·0.5C6H12, crystallizes with one mol-ecule of protonated amoxapine (AXPN), an acetate anion and a mol-ecule of acetic acid together with half a mol-ecule of cyclo-hexane. In the centrosymmetric crystal, both enanti-omers of the protonated AXPN mol-ecule stack alternatively along [001]. Acetate anions connect the AXPN cations through N-H⋯O hydrogen bonding in the [010] direction, creating a sheet lying parallel to (100). The acetic acid mol-ecules are linked to the acetate anions via O-H⋯O hydrogen bonds within the sheets. Within the sheets there are also a number of C-H⋯O hydrogen bonds present. The cyclo-hexane solvent mol-ecules occupy the space between the sheets.

Skeletally Diverse Synthesis of Innovative [2,1-c]-1,4-Oxazepine and [1,4]-Quinoxaline Systems.

An efficient, innovative synthesis of [2,1-c]-1, 4-oxazepine and [1,4]-quinoxaline heterocycles along with the embodied pyrimido-pyrrolo motifs was established. Initially, the pyrrole ring was installed using microwave irradiation through an intramolecular base-catalyzed cyclization between acetyl bromomethyl pyrimidine dione and o-amino phenyl methanol or o-phenylenediamine methyl benzoates. Furthermore, oxazepine, and quinoxaline scaffolds were constructed by an acid-catalyzed condensation with a variety of aldehydes by an unconventional Pictet-Spengler reaction strategy. An important aspect of this work is to build novel heterocyclic ring systems with potential medicinal interest.

Michael Reaction of 3-aAryl-2,4-Dicarboethoxy-5-Hydroxy-5-Methylcyclohexanones.

The reaction of 3-aryl-2,4-dicarboethoxy-5-hydroxy-5-methylcyclohexanones 1with benzalacetone, dibenzalacetone, benzalacetophenone, and 4-benzal-1-phenyl-3-methyl pyrazolone has been investigated to give Michael compounds 2-5. hydrolysis of the dioxo derivative 4 afforded1,5-dicarbonyl derivative 6which On condensation with hydrazine and/or substituted hydrazine and hydroxylamine produced1,2-diazepine and 1,2-oxazepine derivatives 7,8 respectively. Reaction of ß-Keto ester 1 with 1,3-diphenylacetone afforded 9. The structures of the hitherto unknown compounds have been confirmed by analytical and spectral data. The newly synthesized compounds have been screened to test their antimicrobial and antifungal activity.

New photostabilizers for polystyrene based on 2,3-dihydro-(5-mercapto-1,3,4-oxadiazol-2-yl)-phenyl-2-(substituted)-1,3,4-oxazepine- 4,7-dione compounds.

The photostabilization of polystyrene (PS) films by 2,3-dihydro-(5-mercapto-1,3,4-oxadiazol-2-yl)-phenyl-2-(substituted)-1,3,4-oxazepine-4,7-dione compounds was investigated. PS films containing concentration of complexes 0.5% by weight were produced by the casting method from chloroform as a solvent. The photostabilization activities of these compounds were determined by monitoring the carbonyl and hydroxyl indices with irradiation time. The changes in viscosity average molecular weight of PS with irradiation time were also tracked (using benzene as a solvent). The quantum yield of the chain scission (Φcs) of these complexes in PS films was evaluated and found to range between 3.31 × 10(-6) and 7.89 × 10(-6). Results obtained showed that the rate of photostabilization of PS in the presence of the additive follows the trend (I > II > III > IV). According to the experimental results obtained, several mechanisms were suggested depending on the structure of the additive like UV absorption, peroxide decomposer and radical scavenger.