Diazepine Derivatives Research Articles

Synthetic strategies and anticancer evaluation for the novel 3-(6-heteroaryltriazolo[3,4-b][1,3,4]thiadiazol-3-yl)chromeno [2,3-b]pyridines

The novel chromonyltriazolo[3,4-b][1,3,4]thiadiazole derivative 5 was efficiently synthesized and utilized as key intermediate for construction of a diversity of heterocyclic rings; through reactions with binucleophilic reagents. Treating electron deficient substrate 5 with hydrazine hydrate, phenylhydrazine and hydroxylamine furnished pyrazolyl/isoxazolyltriazolo[3,4-b][1,3,4]thiadiazoles 6-8. Also, reacting substrate 5 with guanidine, cyanoguanidine and thiourea provided pyrimidinyltriazolo[3,4-b][1,3,4]thiadiazoles 9-11. Reaction of substrate 5 with ethylenediamine and o-phenylenediamine afforded diazepine derivatives 12 and 13. Reaction of substrate 5 with malononitrile, ethyl cyanoacetate and cyanoacetamide afforded pyrans 14, 15 and pyridine 16 linked triazolo[3,4-b][1,3,4]thiadiazolyl chromeno[2,3-b]pyridines. The anticancer efficiency of the current compounds presented diverse inhibitory action against certain cancer cell lines. On the basis of analytical and spectral findings, the structures of the synthesized products were confirmed.

Identification of 3H-benzo[b] [1,4] diazepine derivatives as PPARα agonists by in silico studies and biochemical evaluation

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world, whose pathologic features include dysregulated glucose homeostasis and lipid accumulation. Peroxisome proliferators-activated receptor α (PPARα) is a key regulator of fatty acid metabolism and ketogenesis due to its regulatory pathways involve activating fatty acid uptake, accelerating fatty acid oxidation, inhibiting gluconeogenesis, and suppressing inflammation and fibrosis. Therefore, PPARα is considered as a potential target for the treatment of NAFLD and some agonists have entered clinical trials, which drove us to discover more novel PPARα agonists. In current work, new 3H-benzo[b] [1,4] diazepine PPARα agonists were identified from the ChemDiv database by pharmacophore modeling, molecular docking, derivative structure search, and bioassays, where compound LY-2 and its derivatives (LY-10∼LY-19) were discovered to promote the expression of PPARα downstream gene, carnitine palmitoyl transterase-1 α (cpt1α). Among these active compounds, the EC50 value of LY-2 against increasing cpt1α was 2.169 μΜ. Furthermore, the effect of LY-2 on cpt1α was weakened when PPARα knock down, which confirmed that it is a PPARα agonist again. Finally, the results from molecular dynamics simulations and binding free energy calculations showed that π-π stacking and hydrogen bonding interactions played key roles in the binding of LY-2 and PPARα protein and their complex maintained a stable structure to facilitate LY-2 to have a better binding affinity with PPARα protein. Taken together, compound LY-2 might be a novel lead compound for the development of potent PPARα agonists. Communicated by Ramaswamy H. Sarma

Design, synthesis, biological evaluation, and bio-computational modeling of imidazo, thieno, pyrimidopyrimidine, pyrimidodiazepene, and motifs as antimicrobial agents

Abstract In the drug chemistry industry, synthesizing a talented exclusive series of aza-polyheterocyclic compounds was crucial. Aminopyrimidine nucleus reacted with two equivalents of benzaldehyde in the presence of KOH as a starting material to bring about imidazopyrimidine derivative, which experienced intermolecular cyclization using carbon disulfide, Br2/AcOH, and/or HNO2 to produce thiazole, thieno, and/or nitro pyrimidine derivative, respectively. Accordingly, the nucleus of Aminopyrimidine was prepared and used to develop the novel polyheterocyclic systems acylated with two moles of succinic anhydride to furnish the imidazolopyrimidine derivative. Benzylidene ethyl cyanoacetate and aminopyrimidine undergo (3 + 4) intermolecular cycloaddition 1,3 H shift followed by hydrolysis and after CO2 evolution provided diazepine derivative. The diazepine derivative was attained due to the cyclo-condensation of the starting material and acetylacetone. Moreover, the structure of the novel synthesized compound series was exploited and verified via spectroscopic approaches. The synthesized series were tested for antimicrobial activity against gram-positive and gram-negative bacterial strains and antifungal activity. The thienopyrimidine derivatives and diazepine exhibited unusual antimicrobial activity. Furthermore, the molecular docking studies confirmed the biological studies with Molecular Operating Environment and petro orisis molinspiration studies, which proved the activity of compounds 4, 5, 7, 10, 13, and 16.

Synthesis, anticancer for prostate cancer cells and antibacterial activity of new diazepine derivatives

In the current study, four new benzodiazepine derivatives were synthesized via a reaction of o-phenylenediamine with some chalcone derivatives. The synthesized compounds were characterized by 1H NMR and FT-IR spectroscopies. The antibacterial activity of the obtained diazepines was screened against E. coli, Bacillus subtilis, and Staphylococcus aureus. The results showed that compound 8 had the highest activity toward Bacillus subtilis and Staphylococcus aureus, while compounds 5 and 7 showed the highest activity toward E. coli. To support in vitro studies, docking studies have been performed to determine whether the title compounds (5–8) are inhibitors of the androgen receptor prostate cancer mutant H874Y ligand binding domain bound with testosterone and an AR 20–30 peptide (2Q7K), and the relationship between calculated energies and docking studies has been investigated. Among the synthesized diazepines, compound 5 was subjected to anticancer screening, where its activity against human prostate cancer (PC3) was tested. According to the obtained results, compound 5 has good anticancer activity against PC3.

Crystal structure, Hirshfeld surface analysis and computational studies of two benzo[b] [1,4]diazepine derivatives.

The DFT computational studies, crystal structures and Hirshfeld surface analysis of (E)-4-(2-chlorostyryl)-2,2-dimethyl-2,3-dihydro-1H-benzo[b][1,4]diazepine (1) and (E)-4-(2-(2,2-dimethyl-2,3-dihydro-1H-benzo[b][1,4]diazepin-4-yl)vinyl)phenol (2) have been presented. The compounds crystallized in the monoclinic space group P21/c with 4 molecules in their unit cells each. The experimental and computed bond lengths and bond angles deviated from each other to some extent but also showed good agreement with each other in some cases. Hirshfeld surface analysis of the compounds provided further information about the structural properties of the compounds.

Design, synthesis and molecular docking of new fused 1H-pyrroles, pyrrolo[3,2-d]pyrimidines and pyrrolo[3,2-e][1, 4]diazepine derivatives as potent EGFR/CDK2 inhibitors

A new series of 1H-pyrrole (6a–c, 8a–c), pyrrolo[3,2-d]pyrimidines (9a–c) and pyrrolo[3,2-e][1, 4]diazepines (11a–c) were designed and synthesised. These compounds were designed to have the essential pharmacophoric features of EGFR Inhibitors, they have shown anticancer activities against HCT116, MCF-7 and Hep3B cancer cells with IC50 values ranging from 0.009 to 2.195 µM. IC50 value of doxorubicin is 0.008 µM, compounds 9a and 9c showed IC50 values of 0.011 and 0.009 µM respectively against HCT-116 cells. Compound 8b exerted broad-spectrum activity against all tested cell lines with an IC50 value less than 0.05 µM. Compound 8b was evaluated against a panel of kinases. This compound potently inhibited CDK2/Cyclin A1, DYRK3 and GSK3 alpha kinases with 10–23% compared to imatinib (1–10%). It has also arrested the cell cycle of MCF-7 cells at the S phase. Its antiproliferative activity was further augmented by molecular docking into the active sites of EGFR and CDK2 cyclin A1.

Synthesis and Glycogen Phosphorylase Inhibitory Activity of the Conjugates of 5-Chloroindoledicarboxylic Acid and Diazepine Derivatives

Synthesis and Glycogen Phosphorylase Inhibitory Activity of the Conjugates of 5-Chloroindoledicarboxylic Acid and Diazepine Derivatives

Synthesis and antimicrobial evaluation of some novel 1,5 benzodiazepine derivatives derived from pyrrolyl chalcones

The α,β unsaturated ketone 3-(2,4-dimethyl-1H-pyrrol-3-yl)-1-phenylprop-2-en-1-onederivatives were treated with benzene-1,2-diamine to obtain 2-(2,4-dimethyl-1H-pyrrol-3-yl)-4-phenyl-2,3-dihydro-1H-benzo[b][1,4]diazepine derivatives. These synthesized compound were characterized by IR, 1H NMR, and mass spectroscopy. These synthesized molecules were evaluated for invitro antimicrobial activity. All The synthesized compounds, showed potent anti-microbial activity as compare to reference drug. In these study the synthesized were docked with Type IIA topoisomerases 2XCT using glide dock program and binding affinity were predicted for the synthesized compounds. The compound AP8 and AP9 have shown more active as per binding energy.

Survey reaction of 2-amino-N-(aryl) benzimidamides with ninhydrin in different conditions and investigation of reaction mechanism using density functional theory (DFT).

In this investigation, firstly, 1-(2-amino-phenyl)-N-(aryl) methane diamine derivatives were synthesized by reaction of 2-aminobenzo nitrile with aromatic amines in the presence of aluminum chloride as the catalyst. Then, the reaction of these intermediates with ninhydrin in different conditions was investigated. The reaction between ninhydrin and 2-amino-N'-(aryl) benzimidamide derivatives in water as solvent under reflux conditions resulted in the synthesis of diazepine derivatives. The same results were obtained when the reaction was done in EtOH and in the presence of a few drops of sulfuric acid at room temperature. Also, this reaction was carried out in ethanol as solvent without the presence of sulfuric acid at room temperature which resulted in the synthesis of spiro [indene-2,2'-quinazoline] derivatives. And finally, the reaction was carried out in ethanol as solvent without the presence of sulfuric acid at the reflux conditions which resulted in the synthesis of isoquinolino-quinazoline derivatives. These N-heterocycles compounds are important biologically. Mild reaction conditions, simple procedure and purification and also product diversity with changing conditions are important advantages of this method. Also, to better understanding reaction mechanism on the condensation reactions of 2-amino-N-(aryl) benzimidamides with ninhydrin in different conditions, density functional theory (DFT)-based quantum chemical methods have been applied. Calculated atomic charges suggest that the C-1 (+ 0.54 a.u.) center of ninhydrin is a better electrophile than C-2 (+ 0.42 a.u.) center.

Polymorphism in a benzo[b][1,4]diazepine derivative: Crystal structure, phase behavior and selective influence of solvents

Ethyl 4-[(Z)-3-ethoxy-2,3-dioxopropylidene]-4,5-dihydro-1H-benzo[b][1,4]diazepine-2-carboxylate forms two polymorphic modifications α and β, which differ in molecular conformations, as well as in the dimension of H-bonded supramolecular motifs in crystals that are a 1D chain or a 0D dimer, respectively. The formation of polymorphs can be controlled by choice of the solvent used. Crystallization from a solution in a polar protic solvent, ethanol, results in the thermodynamically favorable α-form, while using a low-polarity solvent, chloroform, and melt crystallization lead to the metastable β-form.

Graphite oxide catalyzed one-pot synthesis of highly functionalized spirodibenzo[1,4]diazepine derivatives in aqueous ethanol medium

We presented the synthesis of highly functionalized spirodibenzo[1,4]diazepine derivatives using graphite oxide (GO) as a metal-free carbocatalyst via a one-pot three-component strategy.

Synthesis, QSAR modeling, and molecular docking of novel fused 7-deazaxanthine derivatives as adenosine A2A receptor antagonists.

Predictive QSAR models for the search of new adenosine A2A receptor antagonists were developed by using OCHEM platform. The predictive ability of the regression models has coefficient of determination q2 =0.65-0.71 with cross-validation and independent test set. The inhibition activities of novel fused 7-deazaxanthine compounds were predicted by the developed QSAR models. A preparative method for the synthesis of pyrimido[5',4':4,5]pyrrolo[1,2-a][1,4]diazepine derivatives was developed, and 11 new adenosine A2A receptor antagonists were obtained. Preliminary investigations into the toxicology of fused 7-deazaxanthine compounds toward commonly used model organism to assess toxicity invertebrate cladoceran D.magna were also described.

New 2,3-Benzodiazepine Derivative: Synthesis, Activity on Central Nervous System, and Toxicity Study in Mice

We report the design and synthesis of a new diazepine derivative, 4-(4-methoxyphenyl)-2,3,4,5-tetrahydro-2,3-benzodiazepin-1-one (VBZ102), and the evaluation of its anxiolytic-like profile, memory impairment effect, and toxicity in Swiss mice. VBZ102 was evaluated for central nervous system effects in an open field, light–dark box, and novel object recognition tests under oral administration for acute and sub-acute treatment. We tested the VBZ102 toxicity in mice through a determination of LD50 values and examination of the biochemical and histopathological parameters. The VBZ102 induced an anxiolytic effect at different doses both in the light–dark box and open field tests. Unlike other benzodiazepines (e.g., bromazepam), a sedative effect was noted only after administration of the VBZ102 at 10.0 mg/kg.

O-Phenylenediamine as a Source of Fused Azole, Azine, and Diazepine Derivatives

o-Phenylenediamine as a Source of Fused Azole, Azine, and Diazepine Derivatives

Reagent-Based Diversity-Oriented Synthesis of Triazolo[1,5-a][1,4]diazepine Derivatives from Polymer-Supported Homoazidoalanine.

Herein, we report the synthesis of skeletally different triazolo[1,5-a][1,4]diazepines starting from immobilized homoazidoalanine. After sulfonylation with 2/4-nitrobenzenesulfonyl chlorides and Mitsunobu alkylation with various alkynols, the corresponding N-substituted nitrobenzenesulfonamides were obtained. Their catalyst-free Huisgen cycloaddition provided immobilized and functionalized triazolo[1,5-a][1,4]diazepines as the key intermediates for further modification. Using the concept of diversity-oriented, reagent-based synthesis, the key intermediates were subsequently converted to heterocycles bearing [5 + 7 + 5], [5 + 7 + 6], and [5 + 7 + 7] scaffolds. Furthermore, the synthesis of spirocyclic triazolodiazepines was developed.

A sustainable water-tolerant catalyst with enhanced Lewis acidity: Dual activation of Cp2TiCl2 via ligand and solvent

A new strategy was developed to enhance the activity of titanocene dichloride for the synthesis of 2,4-disubstituted-3H-benzo[b]-[1,4]diazepine derivatives by using Cp2TiCl2 as a pre-catalyst. The titanocene was activated in situ in the catalytic system via the coordination with m-phthalic acid and alcohol solvent accompanied with the secession of a cyclopentadienyl ring, leading to the formation of an activated species, [CpTi(OEt)2(η1-C8H5O4)]. In particular, the novel developed half-titanocene catalyst exhibited more superior stability than representative half-titanocene complex, indicated by not only water compatibility for the employment of 30 % aqueous ethanol solution but also the recyclability that the products could be generated without apparent yield decrease after 5 runs. In general, we present a paradigm for sustainable molecular catalysis of titanocene.

Efficacy of DRIVEN-FLOW® M7-II, a new on-site drug screening kit in postmortem urine compared with Triage DOA®

The efficacy of DRIVEN-FLOW® M7-II(DFM7II) for seven drug groups was compared with Triage DOA® (Triage) using 340 autopsy urine samples taken from bodies within 1month of death based on mass screening analysis of GC/MS and LC-MS/MS. The sensitivity to benzodiazepines was 0.56 in Triage and 0.53 in DFM7II with few false positives, and their accuracy was 0.88. Triage detected triazolo diazepine derivatives more easily than DFM7II. DFM7II detected diazepam and nitro benzodiazepines more easily than Triage. There were nine amphetamine false-positive cases of more than 10days after death in Triage, but these were absent in DFM7II during this period. The accuracy of amphetamines for Triage was 0.96 and for DFM7II was 1. Tricyclic antidepressant (TCA) was detected in five cases by mass analysis, while there were four false-positive cases using Triage and eight cases using DFM7II. In the TCA false-positive cases of both kits, tricyclic psychotics such as chlorpromazine, carbamazepine, and quetiapine were included as well as the drug poisoning cases. There were no samples containing cocaine or THC. The accuracy of DFM7II for opiate and barbiturates was 1, but those of Triage was less than 1. Based on the above, DFM7II is a more accurate kit with fewer false-positives for target drug groups, other than TCA, than Triage.

Synthesis of Some Coumarin and Diazepine Derivatives and Evaluation of Their Antibacterial Activities

Synthesis of Some Coumarin and Diazepine Derivatives and Evaluation of Their Antibacterial Activities

A Gold(I)‐Catalyzed Tandem Cyclization to Benzo[b]indeno[1,2‐e][1,4]diazepines from o‐Phenylenediamines and Ynones

AbstractA gold‐catalyzed tandem cyclization of o‐phenylenediamines with ynones to synthesize benzo[b]indeno[1,2‐e][1,4]diazepine has been developed. The mechanism was explored by control experiments. The method provides a way to access a range of benzo[b]indeno[1,2‐e][1,4]diazepine derivatives in diversity‐oriented synthesis aiming at discovering structurally diverse scaffolds.magnified image

Rhodium(III)-Catalyzed [4+3] Annulation of N-Aryl-pyrazolidinones and Propargylic Acetates: Access to Benzo[c][1,2]diazepines.

The generation of 2,3-dihydro-benzo[c][1,2]diazepine derivatives via rhodium(III)-catalyzed [4+3] annulation of pyrazolidinones and propargylic acetates is disclosed. The reaction proceeds smoothly under relatively mild conditions from propargylic acetates as novel C3 synthons. A range of dinitrogen-fused heterocyclic compounds are readily accessed by this approach.