Discovery of 3,4-Dihydrobenzo[f][1,4]oxazepin-5(2H)-one Derivatives as a New Class of Selective TNIK Inhibitors and Evaluation of Their Anti-Colorectal Cancer Effects.

The Traf2- and Nck-interacting protein kinase (TNIK) is a downstream signal protein of the Wnt/ß-catenin pathway and has been thought of as a potential target for the treatment of colorectal cancer (CRC) that is often associated with dysregulation of Wnt/ß-catenin signaling pathway. Herein, we report the discovery of a series of 3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one derivatives as a new class of TNIK inhibitors. Structure-activity relationship (SAR) analyses led to the identification of a number of potent TNIK inhibitors with compound 21k being the most active one (IC50: 0.026 ± 0.008 µM). This compound also displayed excellent selectivity for TNIK against 406 other kinases. Compound 21k could efficiently suppress CRC cell proliferation and migration in in vitro assays and exhibited considerable antitumor activity in the HCT116 xenograft mouse model. It also showed favorable pharmacokinetic properties. Overall, 21k could be a promising lead compound for drug discovery targeting TNIK and deserves further studies.

1,5-Benzoxazepines as a unique and potent scaffold for activity drugs: A review.

Benzoxazepines constitute a huge number of organic compounds widely described in the literature. Many of them are distinguished by their biological properties. Among them, our attention was drawn to 1,5-benzoxazepine derivatives due to their interesting pharmacological properties. As is reported in the literature, these compounds are not only good building blocks in organic synthesis but also have interesting biological and pharmacological properties. This article is the first review publication to describe the synthesis methods and unique properties of 1,5-benzoxazepines. Literature reports widely describe the biological properties of 1,5-benzoxazepine, like anticancer, antibacterial, or antifungal activities. 1,5-Benzoxazepine derivatives can also interact with G-protein-coupled receptors and could be incorporated into new potential drugs, among others, in treating neuronal disorders like Alzheimer's and Parkinson's disease.

Discovery of 3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one derivatives as a new class of ROCK inhibitors for the treatment of glaucoma.

The Rho-associated protein kinases (ROCKs) are associated with the pathology of glaucoma and discovery of ROCK inhibitors has attracted much attention in recent years. Herein, we report a series of 3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one derivatives as a new class of ROCK inhibitors. Structure-activity relationship studies led to the discovery of compound 12b, which showed potent activities against ROCK I and ROCK Ⅱ with IC50 values of 93 nM and 3 nM, respectively. 12b also displayed considerable selectivity for ROCKs. The mean IOP-lowering effect of 12b in an ocular normotensive model was 34.3%, and no obvious hyperemia was observed. Overall, this study provides a good starting point for ROCK-targeting drug discovery against glaucoma.

Structure-based bioisosterism design of thio-benzoxazepinones as novel necroptosis inhibitors.

Necroptosis is reported to play a critical role in contributing to a variety of human pathologies. The benzoxazepinone GSK'772 is a potent necroptosis inhibitor optimized using a hit from a DNA-encoded library, which is currently in phase II clinical trials for psoriasis, rheumatoid arthritis, and ulcerative colitis. In the present study, the bioisosterism strategy was applied to replace the amide and benzene ring of GSK'772 based on the co-crystal structure of GSK'772 with its binding target RIPK1. As a result, the novel thio-benzoxazepinones exhibited higher anti-necroptosis activity in a human HT-29 cell necroptosis model. The effect on anti-necroptosis activity by the chirality was significantly reduced in the thio-benzoxazepinones, which was explained by the ligand conformation calculation. Among these analogues, compound 11 (S) and 12 (R) specifically inhibited necroptosis rather than apoptosis with EC50 values of 2.8 and 22.6 nM. They blocked necrosome formation by inhibiting the phosphorylation of RIPK1, RIPK3 and MLKL in necroptotic cells. Collectively, the highly potent thio-benzoxazepinones represent promising lead structures for further development of necroptosis-related diseases.

Discovery of benzo[f]pyrido[4,3-b][1,4]oxazepin-10-one derivatives as orally available bromodomain and extra-terminal domain (BET) inhibitors with efficacy in an in vivo psoriatic animal model.

Bromodomain and extra-terminal domain (BET) protein plays an important role in epigenetic regulation, and the regulation of disruption contributes to the pathogenesis of cancer and inflammatory disease. With the goal of discovering novel BET inhibitors, especially BRD4 inhibitors, we designed and synthesized several compounds starting from our previously reported pyrido-benzodiazepinone derivative 4 to enhance BRD4 inhibitory activity while avoiding hERG inhibition. Molecular docking studies and structure-activity relationship studies led to the identification of 9-fluorobenzo[f]pyrido[4,3-b][1,4]oxazepin-10-one derivative 43, which exhibited potent BRD4 inhibitory activity with excellent potency in imiquimod-induced psoriasis model mice.

Design, synthesis and antifungal activity of (E)-3-acyl-5-(methoxyimino)-1,5-dihydrobenzo[e][1,2]oxazepin-4(3H)-one analogues.

Nitrogen- or oxygen-containing organic compounds which have significant antifungal activity, twenty one novel nitrogen or oxygen-containing (E)-3-acyl-5-(methoxyimino)-1,5-dihydrobenzo[e][1,2]oxazepin-4(3H)-one analogues were designed and synthesized, and their structures were confirmed by 1H NMR, 13C NMR and HRMS. Preliminary bioassay showed that most of them exhibited certain-to-good antifungal activity. Compounds 5k-2, 5n, 5p and 5r exhibited over 80% inhibitory rate against Sclerotinia sclerotiorum at 50 µg/mL, and 5r exhibited good antifungal activity against S. sclerotiorum with EC50 of 7.21 µg/mL. Compounds 5a and 5r also showed over 90% inhibition against Botrytis cinerea. In particular, 5r showed significant higher activity with the lowest EC50 of 7.92 µg/mL than the positive control trifloxystrobin (21.96 µg/mL) and azoxystrobin (9.43 µg/mL). Providing a practical method for the synthesis of new scaffolds 1,2-Benzoxazepinone and systematically investigate their antifungal activity.

Pyrido[2,3-b][1,5]benzoxazepin-5(6H)-one derivatives as CDK8 inhibitors.

CDK8 is a cyclin-dependent kinase that forms part of the mediator complex, and modulates the transcriptional output from distinct transcription factors involved in oncogenic control. Overexpression of CDK8 has been observed in various cancers, representing a potential target for developing novel CDK8 inhibitors in cancer therapeutics. In the course of our investigations to discover new CDK8 inhibitors, we designed and synthesized tricyclic pyrido[2,3-b][1,5]benzoxazepin-5(6H)-one derivatives, by introduction of chemical complexity in the multi-kinase inhibitor Sorafenib taking into account the flexibility of the P-loop motif of CDK8 protein observed after analysis of structural information of co-crystallized CDK8 inhibitors. In vitro evaluation of the inhibitory activity of the prepared compounds against CDK8 led us to identify compound 2 as the most potent inhibitor of the series (IC50 = 8.25 nM). Co-crystal studies and the remarkable selectivity profile of compound 2 are presented. Compound 2 showed moderate reduction of phosphorylation of CDK8 substrate STAT1 in cells, in line with other reported Type II CDK8 inhibitors. We propose herein an alternative to find a potential therapeutic use for this chemical series.

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.

Scaffolding-Induced Property Modulation of Chemical Space.

Physicochemical property switching of chemical space is of great importance for optimization of compounds, for example, for biological activity. Cyclization is a key method to control 3D and other properties. A two-step approach, which involves a multicomponent reaction followed by cyclization, is reported to achieve the transition from basic moieties to charge neutral cyclic derivatives. A series of multisubstituted oxazolidinones, oxazinanones, and oxazepanones as well as their thio and sulfur derivatives are synthesized from readily available building blocks with mild conditions and high yields. Like a few other methods, MCR and cyclization allow for the collective transformation of a large chemical space into a related one with different properties.

Synthesis and Characterization of Tetrachloro-1,3-Oxazepine Derivatives and Evaluation of their Biological Activities.

6,7,8,9-Tetrachloro[1,3]oxazepine-1,5-dione derivatives 1b-10b have been synthesized by reacting Schiff bases 1a-10a with tetrachlorophthalic anhydride (TCPA) under (2 + 5 ∆ 7) cycloaddition reaction conditons. All reactions had been monitored using TLC. FT IR and melting points have been used to characterize the Schiff bases; oxazepine compounds 1b-10b were characterized using FT IR, 1H NMR and their melting points. Biological activity for oxazepine compounds has been evaluated against bacterial types (Staphylococcus aureus, Escherichia coli, Klebsiella spp.) and against a fungus (Geotrichum spp.). Variable activities have been observed against used strains of bacteria and fungi.

Unprotected primary sulfonamide group facilitates ring-forming cascade en route to polycyclic [1,4]oxazepine-based carbonic anhydrase inhibitors.

4-Chloro-3-nitrobenzenesulfonamide reacted cleanly at room-temperature with a range of bis-electrophilic phenols bearing an NH-acidic functionality (secondary carboxamide or pyrazole) in the ortho-position. This produced a novel class of [1,4]oxazepine-based primary sulfonamides which exhibited strong inhibition of therapeutically relevant human carbonic anhydrases. 2-Chloronitrobenzene did not enter a similar cyclocondensation process, even under prolonged heating. Thus, the primary sulfonamide functionality plays a dual role by enabling the [1,4]oxazepine ring construction and acting as a enzyme prosthetic zinc-binding group when the resulting [1,4]oxazepine sulfonamides are employed as carbonic anhydrase inhibitors.

Homology Modeling Inspired Synthesis of 5-HT2A Receptor Inhibitors: A Diazepine Analogue of the Atypical Antipsychotic JL13.

BACKGROUND: The benzoxazepine JL13 is an analogue of the clozapine family of antipsychotic agents which target the 5-HT2A receptor, and has showed promise as an atypical antipsychotic agent. Based on the dearth of clinically effective anti-psychotic agents available, we sought to design and chemically synthesize additional analogues. METHODS: Structure function analysis was conducted using state of art computational methods, which were designed to highlight new candidates for chemical synthesis. Efficient syntheses were then conducted and the products screened for affinity to the receptor. RESULTS: Among many new analogues prepared, an aza analogue demonstrated seventeen times greater affinity for the receptor than JL13. CONCLUSION: An efficient synthetic route to an aza-analogue of JL13 was developed and will allow rapid modifications of the core and synthesis of related libraries.

Efficient Synthesis of Fused Oxazepino-isoquinoline Scaffolds via an Ugi, Followed by an Intramolecular Cyclization.

A mild and efficient protocol was developed for the synthesis of oxazepino-isoquinolines via a one-pot Ugi four-component reaction, followed by the intramolecular addition of the resulting alcohol to an alkyne moiety under microwave irradiation conditions. Notably, this process only required one purification step, providing facile access to two series of complex and potentially interesting biologically active scaffolds.

Two new similar alkaloids from Portulaca oleracea L.

Two novel alkaloids named oleraciamide A (1) and oleraciamide B (2) were isolated from Portulaca oleracea L., and spectroscopic methods including 1D and 2D nuclear magnetic resonance and high-resolution electrospray ionisation quadrupole-time of flight mass spectrometer spectrometry techniques are employed to determine their structures. Oleraciamide A (1) was evaluated no cytotoxicity at concentrations up to 80 µM over 72 h against human adipose-derived stem cells (hADSCs) by CCK-8 method.

Structure-Based Design of Tricyclic NF-κB Inducing Kinase (NIK) Inhibitors That Have High Selectivity over Phosphoinositide-3-kinase (PI3K).

We report here structure-guided optimization of a novel series of NF-κB inducing kinase (NIK) inhibitors. Starting from a modestly potent, low molecular weight lead, activity was improved by designing a type 11/2 binding mode that accessed a back pocket past the methionine-471 gatekeeper. Divergent binding modes in NIK and PI3K were exploited to dampen PI3K inhibition while maintaining NIK inhibition within these series. Potent compounds were discovered that selectively inhibit the nuclear translocation of NF-κB2 (p52/REL-B) but not canonical NF-κB1 (REL-A/p50).

Synthesis of Pyrido-annelated Diazepines, Oxazepines and Thiazepines.

The immense amount of research on benzodiazepines resulted in the synthesis of heterocycle-fused diazepine derivatives with potential pharmacological activity. Pyridoazepines are recognized to be active in the central nervous system and have a comparable activity to the well-known benzodiazepines. This makes the synthesis and the study of pyridodiazepines an important research topic. This review comprises of the synthesis and activity of pyridodiazepines, pyridooxazepines and pyridothiazepines. Although these structures have a great similarity with benzodiazepines, much less work has been published on their synthesis or derivatization. Therefore, there is a need to further develop these classes of underexplored scaffolds, in search for new chemistry, new methodology and hence new biological features.

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.

Discovery and development of benzo-[1,2,4]-triazolo-[1,4]-oxazepine GPR142 agonists for the treatment of diabetes.

A novel series of benzo-[1,2,4]-triazolo-[1,4]-oxazepine GPR142 agonists are described. The series was designed to address the suboptimal PK (pharmacokinetic) and off-target profile of a class of N-aryl-benzo-[1,4]-oxazepine-4-carboxamides, represented by 1, that were identified from a high-throughput screen of the Merck compound collection for GPR142 agonists. This work led to the discovery of 3-phenoxy-benzo-[1,2,4]-triazolo-[1,4]-oxazepine 47, a potent GPR142 agonist with an off-target and PK profile suitable for in vivo studies. This compound and a related analogue 40 were shown to be active in mouse oral glucose tolerance tests (OGTTs). Furthermore, a GPR142 knock-out mouse OGTT study with compound 40 provides evidence that its glucose-lowering effect is mediated by GPR142.

DNA-Encoded Library Screening Identifies Benzo[b][1,4]oxazepin-4-ones as Highly Potent and Monoselective Receptor Interacting Protein 1 Kinase Inhibitors.

The recent discovery of the role of receptor interacting protein 1 (RIP1) kinase in tumor necrosis factor (TNF)-mediated inflammation has led to its emergence as a highly promising target for the treatment of multiple inflammatory diseases. We screened RIP1 against GSK's DNA-encoded small-molecule libraries and identified a novel highly potent benzoxazepinone inhibitor series. We demonstrate that this template possesses complete monokinase selectivity for RIP1 plus unique species selectivity for primate versus nonprimate RIP1. We elucidate the conformation of RIP1 bound to this benzoxazepinone inhibitor driving its high kinase selectivity and design specific mutations in murine RIP1 to restore potency to levels similar to primate RIP1. This series differentiates itself from known RIP1 inhibitors in combining high potency and kinase selectivity with good pharmacokinetic profiles in rodents. The favorable developability profile of this benzoxazepinone template, as exemplified by compound 14 (GSK'481), makes it an excellent starting point for further optimization into a RIP1 clinical candidate.

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.