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The authors previously developed a divide-and-conquer (DC)-based non-local excited-state calculation method for large systems using dynamical polarizability [Nakai and Yoshikawa, J. Chem. Phys. 146, 124123 (2017)]. This method evaluates the excitation energies and oscillator strengths using information on the dynamical polarizability poles. This article proposes a novel analysis of the previously developed method to obtain further configuration information on excited states, including excitation and de-excitation coefficients of each excitation configuration. Numerical applications to simple molecules, such as ethylene, hydrogen molecule, ammonia, and pyridazine, confirmed that the proposed analysis could accurately reproduce the excitation and de-excitation coefficients. The combination with the DC scheme enables both the local and non-local excited states of large systems with an excited nature to be treated. [ABSTRACT FROM AUTHOR]

The gas-phase rotational spectrum from 8 to 750 GHz and the high-resolution infrared (IR) spectrum of pyridazine (o-C4H4N2) have been analyzed for the ground and four lowest-energy vibrationally excited states. A combined global fit of the rotational and IR data has been obtained using a sextic, centrifugally distorted-rotor Hamiltonian with Coriolis coupling between appropriate states. Coriolis coupling has been addressed in the two lowest-energy coupled dyads (ν16, ν13 and ν24, ν9). Utilizing the Coriolis coupling between the vibrational states of each dyad and the analysis of the IR spectrum for ν16 and ν9, we have determined precise band origins for each of these fundamental states: ν16 (B1) = 361.213 292 7 (17) cm−1, ν13 (A2) = 361.284 082 4 (17) cm−1, ν24 (B2) = 618.969 096 (26) cm−1, and ν9 (A1) = 664.723 378 4 (27) cm−1. Notably, the energy separation in the ν16-ν13 Coriolis-coupled dyad is one of the smallest spectroscopically measured energy separations between vibrational states: 2122.222 (72) MHz or 0.070 789 7 (24) cm−1. Despite ν13 being IR inactive and ν24 having an impractically low-intensity IR intensity, the band origins of all four vibrational states were measured, showcasing the power of combining the data provided by millimeter-wave and high-resolution IR spectra. Additionally, the spectra of pyridazine-dx isotopologues generated for a previous semi-experimental equilibrium structure (reSE) determination allowed us to analyze the two lowest-energy vibrational states of pyridazine for all nine pyridazine-dx isotopologues. Coriolis-coupling terms have been measured for analogous vibrational states across seven isotopologues, both enabling their comparison and providing a new benchmark for computational chemistry. [ABSTRACT FROM AUTHOR]

Ponatinib, the only approved all known-BCR::ABL1 inhibitor, is a third-generation tyrosine-kinase inhibitor (TKI) designed to inhibit BCR::ABL1 with or without any single resistance mutation, including T315I, and induced robust and durable responses at 45 mg/day in patients with CP-CML resistant to second-generation TKIs in the PACE trial. However, cardiovascular toxicities, including arterial occlusive events (AOEs), have emerged as treatment-related AEs within this class of TKIs. The OPTIC trial evaluated the efficacy and safety of ponatinib using a novel, response-based, dose-reduction strategy in patients with CP-CML whose disease is resistant to ≥2 TKIs or who harbor T315I. To assess the dose-response relationship and the effect on the safety of ponatinib, we examined the outcomes of patients with CP-CML enrolled in PACE and OPTIC who received 45 mg/day of ponatinib. A propensity score analysis was used to evaluate AOEs across both trials. Survival rates and median time to achieve ≤1% BCR::ABL1IS in OPTIC were similar or better than in PACE. The outcomes of patients with T315I mutations were robust in both trials. Patients in OPTIC had a lower exposure-adjusted incidence of AOEs compared with those in PACE. This analysis demonstrates that response-based dosing for ponatinib improves treatment tolerance and mitigates cardiovascular risk.

Two novel copper-catalyzed cyclization reactions involving a remote propargylic substitution/cyclization/isomerization cascade are disclosed. Derivatives of the seldomly studied heterocycles thieno[2,3- c ]pyrrole and thieno[2,3- d ]pyridazine are conveniently synthesized in moderate to good yields from primary amines or arylhydrazines through [4+1] and [4+2] reactions, respectively. Preliminary mechanistic experiments corroborated the occurrence of the designed cascade reactions. [ABSTRACT FROM AUTHOR]

The manuscript describes the synthesis of eight Novel 1,2,4-triazine and 1,2-diazino derivatives having the 5-nitro isatin moiety. Antiradical and anticancer activities were evaluated using the DPPH method and the MTT assay against breast cancer (MCF-7) cell lines. The compound with the strongest antioxidant and anticancer properties after 24 h was compound 9 (1,2,4-triazine-3-thione) but after 48 h, compound 7 (1,2,4- triazine-3-ol) with good anticancer activity while compound 11 (1,2-diazino) after 72 h. [ABSTRACT FROM AUTHOR]

Conjugated tetrazine‐containing polymers that undergo inverse electron demand Diels‐Alder (IEDDA) reactions with trans‐cyclooctenes are interesting not only for their intrinsic optoelectronic properties, but also their interactions with π‐conjugated surfaces. Here, we prepared a series of poly(fluorene‐co‐tetrazine) polymers and carried out IEDDA reactions to decorate them with hydroxyl, hexadecyl, or triethylene glycol side chains. The polymers were investigated pre‐ and post‐IEDDA coupling in terms of their ability to disperse single‐walled carbon nanotubes (SWNTs) in organic solvent. It was found that polymer molecular weight, side chain structure, and degree of conjugation all impacted the quality of SWNT dispersions. While the starting poly(fluorene‐co‐tetrazine) polymer produced concentrated dispersions, the post‐IEDDA polymer containing dihydropyridazine groups did not produce dispersions of equal concentration. However, upon oxidation to the fully aromatic pyridazines, the polymers regained their ability to form concentrated dispersions. Furthermore, the post‐IEDDA polymers exhibited increased selectivity toward metallic SWNTs relative to the starting polymer. Due to the efficiency of the IEDDA reaction, it was also possible to use this chemistry to derivatize the nanotube complex with poly(fluorene‐co‐tetrazine) post‐dispersion. Overall, this work demonstrates the first use of reactive polytetrazines to disperse SWNTs, allowing rapid modification of polymer‐nanotube complexes. [ABSTRACT FROM AUTHOR]

The transition metal‐catalyzed direct coupling reactions involving electron‐rich Fischer carbene species are largely underdeveloped and remain a big challenge. Here, a direct coupling reaction of azoles and azine N‐oxides is reported with Fischer copper carbene species bearing an α‐siloxy group i, which can be in situ generated from acylsilanes catalytically under photoirradiation and redox‐neutral conditions. This coupling reaction between electron‐rich α‐siloxy Fischer Cu‐carbene species with hard carbanion nucleophiles may undergo a bimetallic relay process, which is confirmed by the kinetic analysis and in situ NMR analysis. This reaction features mild conditions and remarkable heterocycle compatibility. Notably, this protocol tolerates a series of azole or azine N‐oxide derivatives, including benzoxazole, benzothiazole, benzoimidazole, benzoisoxazole, oxazole, oxadiazole, triazolo[4,3‐a]pyridine, purine, caffeine, pyridine N‐oxide, quinoline N‐oxide, pyrazine N‐oxide, pyridazine N‐oxide, etc. The synthetic value of this approach is demonstrated by the efficient synthesis of a histamine h4 receptor ligand and a marketed drug carbinoxamine. [ABSTRACT FROM AUTHOR]

Pyridazine derivatives hold significant interest due to their broad applications in pharmaceuticals and materials science, where they serve as valuable scaffolds for bioactive compounds and functional materials. Here, we report a formal [4 + 2] reaction for the synthesis of 5'-sulfonyl-4'-aryl-3-cyano substituted pyridazine compounds from the reaction between vinylogous enaminonitriles and sulfonyl hydrazides. The key features of our pyridazine synthesis include the transamidation of vinylogous enaminonitriles with sulfonyl hydrazide, radical sulfonylation of the resulting intermediate, and subsequent 6-endo-trig radical cyclization. This reaction proceeds smoothly to deliver a series of pyridazine derivatives in good to high yields. We also found that the sulfonyl group of the synthesized pyridazines can be transformed into C-, O-, or N-containing functional groups. A gram-scale experiment and a diverse transformation of synthesized pyridazines were also performed to validate the practicality of our developed process. In the synthesis of sulfonyl-substituted pyridazines, a 6-endo-trig cyclization via a radical pathway is both kinetically and thermodynamically favored over the cyclization via an ionic pathway, as supported by DFT calculations. Pyridazine is an aromatic heterocyclic compound that is utilized as a bioisostere for benzene or pyridine, and is found in the core scaffold of various drug molecules, making synthetic methods to access pyridazine scaffolds of high interest. Here, the authors report the synthesis of 5'-sulfonyl-4'-aryl-3-cyano substituted pyridazine compounds from a formal [4 + 2] reaction between vinylogous enaminonitriles and sulfonyl hydrazides. [ABSTRACT FROM AUTHOR]

The synthesis of 3-chloro-6-(4-chloro-3,5-dimethyl-1H-pyrazol-1-yl)pyridazine and its deuterated analogue was performed using a novel two-step sequence. On the first step, a double chlorination of 3-(3,5-dimethyl-1H-pyrazol-1-yl)-6-hydrazinyl-1,2,4,5-tetrazine with trichloroisocyanuric acid was performed to synthesize 3-chloro-6-(4-chloro-3,5-dimethyl-1H-pyrazol-1-yl)-1,2,4,5-tetrazine for the first time. The latter reacted with calcium carbide-derived acetylene and D2-acetylene at heating in a two-chamber reactor (COware) producing 3-chloro-6-(4-chloro-3,5-dimethyl-1H-pyrazol-1-yl)pyridazine or 3-chloro-6-(4-chloro-3,5-dimethyl-1H-pyrazol-1-yl)-4,5-dideuteropyridazine respectively in quantitative yields. [ABSTRACT FROM AUTHOR]

AbstractPyridazinone derivatives, 6-aryl-pyridazinone (2a–f) and 2-(N-substituted)-6-aryl-pyridazinone (3a–h) derivatives were synthesized and assessed for cytotoxicity action using brine shrimp assessment method and in silico molecular studies. In silico molecular study of pyridazine derivatives used as NNRTIs and Doravirine is used as reference drug. The compounds were investigated for docking modes onto probable binding sites with HIV reverse transcriptase. The majority of these demonstrated favorable binding interactive connections with the active receptor domain. The majority of the compounds exhibited a remarkable docked binding affinity score when compared with the reference drugs. Among the synthesized pyridazine derivatives, compounds 3a and 3c–h exhibited a good docking score. For the designed compounds, in silico ADME assessment indicated the favorable physicochemical properties to be a suitable drug candidate. The synthesized compounds could serve as a novel alternative in designing safe and effective anti-HIV options with reverse transcriptase inhibitor potential. In the cytotoxicity study, all the compounds were evaluated at dose levels 10, and 20 (μg/mL), and potassium dichromate was used as a reference. Compounds 2c and 2e have shown potent lethality through LC50 2.23 and 3.20 μg respectively. Various compounds, including 2a, 2b, 2d, and 2f have demonstrated significant cytotoxicity. Their LC50 values are 7.58, 6.76, 8.91, and 4.46 μg, respectively. Additionally, compounds 3b and 3d exhibited potent lethality with LC50 values of 4.023 and 4.20 μg. Other compounds, namely 3g, 3f, 3c, 3h, 3a, and 3e, displayed noteworthy cytotoxicity ability13.91, 12.58, 11.91, 11.76, 10.58, 9.76, and 7.46 μg, respectively having LC50 values. This study supports the use of in silico molecular design and the brine shrimp bioassay as a suitable, reliable, and simple method for assessing the bioactivity of compounds. It provides further evidence for their use in medicine. [ABSTRACT FROM AUTHOR]

Pyridazine is a significant skeleton that widely exists in drugs and bioactive molecules. We herein describe expeditious approaches to access polysubstituted pyridazines from readily accessible unactivated ketones and acylhydrazones via Cu-promoted C(sp3)–C(sp3) coupling/cyclization sequences in a single-step fashion. Notably, the disparate 3,4,6-trisubstituted pyridazines and 3,5-disubstituted pyridazines could be obtained by tailoring the ketone's structure and reaction conditions. These transformations feature good functional group compatibility, excellent step-economy, and chemoselectivity. The potential synthetic utility of these conversions is illustrated by scale-up reactions and late-stage derivatizations of the as-prepared pyridazine products. [ABSTRACT FROM AUTHOR]

The review covers the results of studies published in the literature on the use of hydrazonoyl halides in the synthesis of five‐ (pyrazoles, thiazoles, triazoles, oxa‐ and thiadiazoles), six‐ (oxa‐ and thiadiazines, indazoles, pyridazines, pyrazines, tetrazines) or seven‐membered (benzotriazepine) heterocycles. In the formation of these heterocycles, the main intermediate stage of the reaction is the in situ generation of nitrilimine, which enters into a cycloaddition reaction with substituted acetylenes (including in situ generated benzynes, naphthynes), allenes, activated olefins, anthranilic acid derivatives, organosulfur compounds (mercaptoaldehydes, mercaptocarboxylic acids) or with fused heterocycles. Examples are given of the formation of heterocycles by replacing the halogen atom from a hydrazonoyl halide molecule with a nucleophilic group, followed by exhaustive intramolecular cyclization into the target compound. There are discussions of reactions in which the cycloaddition of the nitrilimine to the in situ synthesized Knoevenagel condensation product (from CH‐acid compounds, such as di‐ and monocarbonyl compounds, dinitrile malonic acid) occurs, leading to spiro‐linked or conventional pyrazoles. Some syntheses of biologically active representatives are shown. [ABSTRACT FROM AUTHOR]

Aqueous zinc‐based energy storage devices have competitive advantages such as high power density, good safety, and wide source. However, because of the direct touch among zinc anode and aqueous electrolyte, dendrite growth and electrode side reactions are easy to occur in the plating and striping process, which seriously hinders the further development of aqueous zinc‐based energy storage devices. Therefore, it is urgent to solve the above problems to expand the existing energy storage devices. In this work, by adding an imidazo[1,2‐b]pyridazine (IP) electrolyte additive, the dendrites' growth and corrosion on the zinc anode surface could be effectively inhibited by the shielding‐anchoring double effects, which are verified by the comprehensive in situ and ex situ characterization techniques as well as the theoretical calculation support. Accordingly, the IP‐based electrolyte encourages extremely high stable zinc anode (cycling 2200 h at 1 mA cm−2) with high average Coulombic efficiency (98.72%). Moreover, the IP‐based Zn‐V2O5 full battery also exhibits excellent reversible capacity, reaching 160.8 mAh g−1 after 400 cycles at 2 A g−1. Through a straightforward alteration to the Zn anode surface, this study considerably enhances the use of highly stable and secure aqueous zinc‐ion batteries. [ABSTRACT FROM AUTHOR]

An array of cyanopyridazine derivatives have been developed through a sequence of (3+3) cycloaddition/oxidative aromatization/derivatization steps. Investigation of the physicochemical properties of these compounds shows that four have interesting fluorescence properties and have the potential to be developed into bimodal photoredox catalysts. One has been confirmed to be an photoredox catalyst in the reactions of N‐aryl‐ tetrahydroisoquinolines with phosphite, nitromethane, malonitrile and sodium thiocyanate, led to 22%–95% yields. The catalyst capabilities remain with recyclable using under the reaction conditions. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is one of the fastest-growing metabolic disorders. Worldwide, one out of 10 people suffer from diabetes mellitus. In this manuscript, we establish the antidiabetic potential of previously synthesized pyridazine derivatives using in silico and in vitro experiments. Molecular docking studies of pyridazine derivatives with pullulanase Amy12, isomaltase, and alpha-amylase receptors revealed that Molecules 45, 46, and 29 showed good docking interaction scores. ADMET analysis of the top three docked pyridazine derivatives (45, 46, and 29) showed lesser solubility and poor distribution behavior. Molecules 45, 46, and 29 maintained drug-like properties with good oral bioavailability. Molecules 45 and 29 showed reproductive toxicity without any sign of mutagenicity, tumorigenicity, or other irritancy. Molecule 46 emerged as a nontoxic molecule in all aspects. In vitro alpha-amylase inhibition data of molecules 45, 46, 29, and acarbose showed IC50 values of 8.67, 8.46, 8.83, and 66.65 µg/mL, respectively. The antidiabetic activity of pyridazine derivatives is increased with the presence of phenothiazine coupled with a biphenyl group, indole with a biphenyl group, and phenothiazine with an ethylphenyl group. Establishing these pyridazine derivatives using in vivo experiments could be beneficial in managing diabetes. [ABSTRACT FROM AUTHOR]

Effecient green tools of β-(3,4-dichlorophenyl-acrylic acid, thioglycolic acid and β-(2-oxopyrrolidin-1-yl) ethanol under ultrasonic and microwave-assisted irradiation (MW-US) as found to be a simple approach for preparing interesting Spiro derivatives. A novel class Spiro-pyrrolidine-2,3'-thieno[2,3-d]pyridazine derivatives (2–6) were efficiently synthesized via one-pot multicomponent reactions. Ethoxy acetyl Spiro pyrrolidine-2,3'-thieno[2,3-d]pyridazin-hydrazide (5) assessed as ecofriendly microbicidal and insecticidal activities to establish a structure-activity relationship. Elemental analysis and spectroscopic data were used to describe the structures of all synthesized products. The Spiro-heterocyclic compounds are exclusive non-planar structures and branded for binding to biomolecules. The microbicidal and insecticidal activities of the compounds were investigated on ATCC coded test microorganisms upon the applied dose and time was studied through two kinetic study. The interaction with these antibacterial and insect's third instar larvae was medicinal and economically valuable. The preliminary testing demonstrated flourishing microbicidal capability to prevent the growth of threatening pathogenic bacteria as well as blossoming insecticidal efficacy. Moreover, Molecular docking and density functional theory simulations can be used to validate the experimental results. Also, we utilized the docking approach with secondary bacterial infection indicated that Ethoxy acetyl Spiro hydrazide (5) and Spiro arylidene hybrid (6) have exerted the strongest docking binding value against the active sites of 6LU7. [ABSTRACT FROM AUTHOR]

A series of fifteen novel amide derivatives based on imidazo[1,2‐b]pyridazine scaffold were synthesized by taking imidazo[1,2‐b]pyridazine‐3‐carboxylic acid intermediates with respective substituted amines to yield good to excellent. The molecular structures of the newly synthesized compounds were elucidated using spectroscopic techniques (1H NMR, 13C NMR, and LCMS) and supported by single‐crystal X‐ray diffraction (SXRD) for the two compounds, 9 and 18. These compounds were evaluated in vitro for antimicrobial activity against two Gram‐positive bacteria (S. aureus and B. subtilis) and two Gram‐negative bacteria (E. coli and P. aeruginosa). Interestingly, compounds 10 and 16, displayed comparable antibacterial activity to the positive control (Tetracycline: 6.25 μg/mL) against Gram‐negative bacteria, particularly Pseudomonas aeruginosa, with a minimum inhibitory concentration (MIC) of 6.25 μg/mL. Compound 17 exhibited moderate antibacterial activity with an MIC of 10 μg/mL against the Gram‐positive bacterium Bacillus subtilis, whereas the positive control demonstrated an MIC of 6.25 μg/mL. These antibacterial activities were found to have a good correlation with Insilco computational molecular docking experiments using the receptor UDP‐N‐acetylglucosamine‐enolpyruvate reductase, Mtb MurB. [ABSTRACT FROM AUTHOR]

For the first time, eco-friendly ultrasound-assisted synthesis of a series of S-substituted 6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridazine-3(2H)-thione derivatives based on 3-chloro-6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridazine was performed. The reaction times, temperatures, and yields of reaction products were compared with MW-assisted and conventional methods. An in silico study to predict the biological activity of the studied compounds was carried out. Physicochemical and pharmacokinetic properties, ADMET properties and bioavailability index were calculated. [ABSTRACT FROM AUTHOR]

This article provides an overview of heteroatom-embedded polycyclic aromatic compounds (hetero-PACs) and their importance in various scientific and technological fields. Hetero-PACs are structurally diverse compounds that contain multiple fused aromatic rings and embedded heteroatoms such as boron, nitrogen, oxygen, phosphorus, and sulfur atoms. They exhibit diverse optoelectronic properties and have applications in organic electronics and chemical biology. The article discusses the stepwise synthesis of hetero-PACs and the challenges associated with it. It then introduces the concept of heteroatom-embedding annulative π-extension (hetero-APEX) reactions as a more efficient synthetic strategy for hetero-PACs. Hetero-APEX reactions allow for the direct construction of fused heteroaromatic structures, offering advantages in terms of step-economy and late-stage tunability. The article concludes by highlighting the potential of hetero-APEX reactions in expanding the structural diversity of hetero-PACs and promoting the discovery of novel heteroaromatics with unique structures, properties, and functions. [Extracted from the article]

The results of modeling the structure of compounds 2,4,7,9-tetranitrobenzo[c]cinnoline (1) and 1,2,3,4-tetrazino[5,6-f]pyridazino-1,2,3,4-tetrazine 1,3,7,9-tetra-N-oxides (2) containing a pyridazine core are presented. The structure in the gas phase was estimated by quantum chemistry methods (DFT, B3LYP), on the basis of which the Atom-Atom Potentials method was used to model crystal packings in 35 most common space symmetry groups, which made it possible to identify the optimal packings and structural classes corresponding to them. Some physicochemical properties of the compounds have been calculated. It has been determined that the compounds under consideration have a molecular-crystal density of 2 g/cm3 and a high enthalpy of formation, which indicates the prospects for their use as high-energy-density materials.

The nature of π-hole spodium bonds in the HgLCl2⋯ZH3/CH2Y complexes (L = pyrrole 1, pyrazole 2, imidazole 3, pyridine 4, pyridazine 5, and pyrimidine 6; Z = N, P, As, and Sb; Y = O, S, Se, and Te) has been studied using theoretical calculations. The electrophilicity of the π-hole in the tri-coordinated HgII complexes varies with the type of N-heterocyclic ligand. The strength and nature of the π-hole spodium bond is closely related to the properties of the Lewis bases. In the case of HgLCl2⋯ZH3, the strength of the π-hole spodium bond weakens as the nucleophilicity of the base decreases, following the sequence HgLCl2⋯NH3 > HgLCl2⋯PH3 > HgLCl2⋯AsH3 > HgLCl2⋯SbH3. The Hg⋯Z spodium bonds change from a partially covalent interaction to a close-shelled noncovalent interaction. The nucleophilic ability of CH2Y decreases in the order CH2O > CH2S > CH2Se > CH2Te, while the strength of the π-hole spodium bond follows the order HgLCl2⋯OCH2 < HgLCl2⋯SCH2 < HgLCl2⋯SeCH2 < HgLCl2⋯TeCH2. The Hg⋯Y spodium bond undergoes a transition from a close-shelled noncovalent to a partially covalent interaction, resulting in an incremental increase in the degree of covalence. The Hg⋯Te spodium bond exhibits certain characteristics resembling those of a coordinate covalent bond. The inter-orbital interactions observed in the formation of the HgLCl2⋯YCH2 complexes appear to be significantly stronger compared to those observed in the HgLCl2⋯ZH3 complexation. [ABSTRACT FROM AUTHOR]

New pyridazine and pyridazinone derivatives 3a–g, 4a–f, 6a, and 6b were designed and synthesized. Cell viability of all compounds was established based on the viability of lipopolysaccharide‐induced RAW264.7 macrophage cells determined via the MTT assay. In vitro inhibition assays on human COX‐1 and COX‐2 enzymes were conducted to probe the newly synthesized compounds' anti‐inflammatory activity. The half maximal inhibitory concentration values for the most active compounds, 3d, 3e, and 4e towards COX‐2 were 0.425, 0.519, and 0.356 µM, respectively, in comparison with celecoxib. The newly synthesized compounds' ability to inhibit the production of certain proinflammatory cytokines, such as inducible nitric oxide synthase, tumor necrosis factor‐α, interleukin‐6, and prostaglandin‐E2, was also estimated in lipopolysaccharide‐induced macrophages (RAW264.7 cells). Compounds 3d and 3e were identified as the most potent cytokine production inhibitors. The results of molecular modeling studies suggested that these compounds were characterized by a reasonable binding affinity toward the active site of COX‐2, when compared to a reference ligand. These results might be taken into consideration in further investigations into new anti‐inflammatory agents. [ABSTRACT FROM AUTHOR]

In this study, we investigate the inhibitory potential of a series of hydrazide derivatives bearing different substituents with the pyridazine structure (5 a–i and 6 a–f) against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using a modified Ellman's method. The inhibitory profiles of the synthesized compounds were assessed by comparing their IC50 and Ki values. Our results demonstrate that all the compounds exhibit significant inhibitory activity against both AChE and BChE when compared to the reference compound, tacrine. Particularly, compound 6 a exhibited the highest activity against Electrophorus electricus AChE (EeAChE) with a Ki value of 3.26 nM, while compound 5 a displayed the most potent inhibition against equine BChE (eqBChE) with a Ki value of 0.94 nM. The compounds did not possess significant cytotoxicity action using the MTT assay on the cancer cell lines. The DPPH assays revealed that all the compounds have moderate antioxidant activities. Furthermore, molecular docking studies provided valuable insights into the interaction mechanisms of these compounds within the active sites of AChE and BChE crystal structures (PDB ID: 4EY7 and 4BDS, respectively). The above results indicated that the pyridazine‐based compounds were a promising functional agent for the treatment of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

In the present study, a novel coordination polymer (CP) based on Ni(II), namely, [Ni(L)(D-CAM)(H2O)]n (1) (H2D-CAM = (1R,3S)-1,2,2-trimethylcyclopentane-1,3-dicarboxylic acid and L = 3,6-bis(benzimidazol-1-yl)pyridazine), has been produced successfully through applying a mixed ligand synthesis method via reacting Ni(NO3)2·6H2O with 3,6-bis(benzimidazol-1-yl)pyridazine ligand in the presence of a carboxylic acid co-ligand. Hyaluronic acid (HA) and carboxymethyl chitosan (CMCS) are representatives of natural polysaccharides and have good biocompatibility. Based on the chemical synthesis method, HA/CMCS hydrogel was successfully prepared. SEM showed that the lyophilized gel presented a typical macroporous structure with three-dimensional connected pores, which had unique advantages as a drug carrier. Using paclitaxel as a drug model, we further synthesized a novel paclitaxel-loaded metal gel and evaluated its therapeutic effect on cervical cancer. Finally, novel drugs from the reinforcement learning simulation are suggested to have better biological activity against ovarian cancer due to low affinity energy and stronger interaction strength towards the protein receptor. [ABSTRACT FROM AUTHOR]

Organometallic η6-arene ruthenium(II) complexes with 3-chloro-6-(1H-pyrazol-1-yl)pyridazine (Ru1, Ru2, and Ru5) and 3-chloro-6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridazine (Ru3-4) N,N' heterocyclic and η6-arene (cymene (Ru1-4) or toluene (Ru 5)) have been synthesized. The ruthenium(II) complexes have common "three-legged piano-stool" pseudo-octahedral structures known for half-sandwich complexes. Evolution of their UV–Visible absorption spectra in PBS buffer or DMSO over 24 h confirmed their good solvolysis stability. Titrations of the complexes with the calf thymus DNA (CT-DNA) were monitored using UV–Visible absorption and fluorescence spectroscopies. The complexes interact moderately with CT-DNA and their binding constants are in the order of 104 M−1. Competitive binding of the complexes to a DNA-Hoechst 33,258 depicted competitive displacement of Hoechst from DNA's minor grooves. These complexes bind to glutathione forming GSH-adducts through S coordination by replacement of a halide, with the iodo-analogues having higher binding constants than the chloro-complexes. Cyclic voltammograms of the complexes exhibited one electron-transfer quasi-reversible process. Trends in the molecular docking data of Ru1-5/DNA were similar to those for DNA binding constants. Of the five, only Ru1, Ru3 and Ru5 showed some activity (moderate) against the MCF-7 breast cancer cells with IC50 values in the range of 59.2–39.9 for which Ru5 was the most active. However, the more difficult-to-treat cell line, MDA-MB 231 cell was recalcitrant to the treatment by these complexes. Molecular docking simulations visualized the interactions of arene Ru(II) complexes with CT-DNA via minor grooving. The trends were corroborated by electrochemical and cytotoxicity data. [ABSTRACT FROM AUTHOR]

Constructing heat-resistant fused heterocyclic compounds is increasingly fascinating in the field of energetic materials due to their excellent energy, high thermal stability, and low sensitivity, as well as high density in general. This study synthesized a novel heat-resistant explosive based on the imidazo [1,2-b]pyridazine fused ring，3,7-dinitroimidazo [1,2-b]pyridazine-6,8-diamine (5)，using a three-step facile method. This compound exhibited a high density (1.856 g cm− 3 ) and low mechanical sensitivities (IS = 40 J, FS = 350 N). Meanwhile, it displayed a higher thermal decomposition temperature of 324 ◦C compared to conventional heat-resistant explosive HNS (Td = 318 ◦C). In addition, it demonstrated significantly higher detonation performance (D = 8336 m s −1, p = 27.25 GPa) than both TNT (D = 6881 m s −1, p = 19.5 GPa) and HNS (D = 7612 m s−1, p = 24.3 GPa). Theoretical analysis shows that the intramolecular hydrogen bonding interactions of NH2–NO2–NH2 might be the main reason for the heat resistance of energetic materials based on the imidazo [1,2-b]pyridazine fused ring. The results of this study suggest that compound 5 is a promising building block and a candidate for heatresistant energetic materials. [ABSTRACT FROM AUTHOR]

Five new mononuclear ruthenium(II) tris-ligated complexes have been synthesised, varying through the choice of azine in the family of 3-azinyl-4-(4-methylphenyl)-5-phenyl-4H-1,2,4-triazole ligands (Lazine): [Ru(Lpyridine)](PF6)2 (1), [Ru(Lpyridazine)](PF6)2 (2), [Ru(L4-pyrimidine)](PF6)2 (3), [Ru(Lpyrazine)](PF6)2 (4), [Ru(L2-pyrimidine)](PF6)2 (5). Three of them, 1·2MeCN·Et2O, 3·2MeCN·Et2O and 4·2MeCN, have been structurally characterised, confirming the presence of the meridional isomer, as was previously reported for the FeII analogues. Cyclic voltammetry studies, in dry CH3CN vs. Ag/0.01 M AgNO3, show that all five RuII complexes undergo a reversible RuIII/RuII process, with the midpoint potential (Em) increasing from 0.87 to 1.18 V as the azine is changed: pyridine < pyridazine < 2-pyrimidine < 4-pyrimidine < pyrazine. A strong inverse linear correlation (R2 = 0.98) is found between the RuIII/RuII redox potential and the calculated HOMO orbital energies, which is consistent with the expectation that it is easier to oxidise (lower Em) a metal ion with a higher HOMO orbital energy. The same trend was reported earlier for the family of analogous FeII complexes, albeit at lower values of Em in all cases. In addition, the ionisation potentials of the RuII complexes, as well as those of the other group 8 analogues (FeII and OsII), showed a linear relationship with Epa. As the MIII/II redox potentials of a family of complexes has been previously reported to correlate with ligand pKa values, a computational protocol to calculate, in silico, the pKa of the Lazine family of ligands was developed. A strong linear relationship was found between the readily calculated pKa of the Lazine ligand and the Epa of the MII complex, for all three families of complexes (R2 = 0.98). [ABSTRACT FROM AUTHOR]

Platinum-based drugs are widely recognized efficient anti-tumor agents, but faced with multiple undesirable effects. Here, four dinuclear platinum(II) complexes, [{Pt(1,2-pn)Cl}2(μ-pydz)]Cl2 (C1), [{Pt(ibn)Cl}2(μ-pydz)]Cl2 (C2), [{Pt(1,3-pn)Cl}2(μ-pydz)]Cl2 (C3) and [{Pt(1,3-pnd)Cl}2(μ-pydz)]Cl2 (C4), were designed (pydz is pyridazine, 1,2-pn is (±)-1,2-propylenediamine, ibn is 1,2-diamino-2-methylpropane, 1,3-pn is 1,3-propylenediamine, and 1,3-pnd is 1,3-pentanediamine). Interactions and binding ability of C1–C4 complexes with calf thymus DNA (CT-DNA) has been monitored by viscosity measurements, UV–Vis, fluorescence emission spectroscopy and molecular docking. Binding affinities of C1–C4 complexes to the bovine serum albumin (BSA) has been monitored by fluorescence emission spectroscopy. The tested complexes exhibit variable cytotoxicity toward different mouse and human tumor cell lines. C2 shows the most potent cytotoxicity, especially against mouse (4T1) and human (MDA-MD468) breast cancer cells in the dose- and time-dependent manner. C2 induces 4T1 and MDA-MD468 cells apoptosis, further documented by the accumulation of cells at sub-G1 phase of cell cycle and increase of executive caspase 3 and caspase 9 levels in 4T1 cells. C2 exhibits anti-proliferative effect through the reduction of cyclin D3 and cyclin E expression and elevation of inhibitor p27 level. Also, C2 downregulates c-Myc and phosphorylated AKT, oncogenes involved in the control of tumor cell proliferation and death. In order to measure the amount of platinum(II) complexes taken up by the cells, the cellular platinum content were quantified. However, C2 failed to inhibit mouse breast cancer growth in vivo. Chemical modifications of tested platinum(II) complexes might be a valuable approach for the improvement of their anti-tumor activity, especially effects in vivo. Dinuclear platinum(II) complex [{Pt(ibn)Cl}2(μ-pydz)]Cl2 shows anti-tumor activity, triggers the apoptosis and reduces the proliferation of mouse breast cancer cells in vitro. However, its inhibitory effect on tumor growth in vivo is absent. [ABSTRACT FROM AUTHOR]

N-phenyl benzohydrazonoyl halide derivatives are important building blocks in the synthesis of a large number of heterocyclic compounds that include pyrazoles, pyridazine, etc. The main factor in the importance of hydrazonyl halide is the easy release of the nitrile imine when treated in an alkaline medium through the preparation process. Owing to the wide range of applications of these precursors, we will introduce a general overview for the synthesis and reactions of these types of compounds. [ABSTRACT FROM AUTHOR]

BackgroundComputerized methodologies standardize the myocardial perfusion imaging (MPI) interpretation process.MethodsTo develop an automated relative perfusion quantitation approach for 18F-flurpiridaz, PET MPI studies from all phase III trial participants of 18F-flurpiridaz were divided into 3 groups. Count distributions were obtained in N = 40 normal patients undergoing pharmacological or exercise stress. Then, N = 90 additional studies were selected in a derivation group. Following receiver operating characteristic curve analysis, various standard deviations below the mean normal were used as cutoffs for significant CAD, and interobserver variability determined. Finally, diagnostic performance was compared between blinded visual readers and blinded derivations of automated relative quantitation in the remaining N = 548 validation patients.ResultsBoth approaches yielded comparable accuracies for the detection of global CAD, reaching 71% and 72% by visual reads, and 72% and 68% by automated relative quantitation, when using CAD ≥ 70% or ≥ 50% stenosis for significance, respectively. Similar results were observed when analyzing individual coronary territories. In both pharmacological and exercise stress, automated relative quantitation demonstrated significantly more interobserver agreement than visual reads.ConclusionsOur automated method of 18F-flurpiridaz relative perfusion analysis provides a quantitative, objective, and highly reproducible assessment of PET MPI in normal and CAD subjects undergoing either pharmacological or exercise stress.

C39H29F6IrN8P, orthorhombic, Pbca (no. 61), a = 19.6205(7) Å, b = 16.2026(6) Å, c = 23.0700(8) Å, V = 7334.0(5) Å3, Z = 8, R gt (F) = 0.0258, wR ref (F2) = 0.0611, T = 293 K. [ABSTRACT FROM AUTHOR]

Despite progress in prostate cancer (PC) therapeutics, distant metastasis remains a major cause of morbidity and mortality from PC. Thus, there is growing recognition that preventing or delaying PC metastasis holds great potential for substantially improving patient outcomes. Here we show receptor-interacting protein kinase 2 (RIPK2) is a clinically actionable target for inhibiting PC metastasis. RIPK2 is amplified/gained in ~65% of lethal metastatic castration-resistant PC. Its overexpression is associated with disease progression and poor prognosis, and its genetic knockout substantially reduces PC metastasis. Multi-level proteomics analyses reveal that RIPK2 strongly regulates the stability and activity of c-Myc (a driver of metastasis), largely via binding to and activating mitogen-activated protein kinase kinase 7 (MKK7), which we identify as a direct c-Myc-S62 kinase. RIPK2 inhibition by preclinical and clinical drugs inactivates the noncanonical RIPK2/MKK7/c-Myc pathway and effectively impairs PC metastatic outgrowth. These results support targeting RIPK2 signaling to extend metastasis-free and overall survival.

Following our recent work on the benzene molecule [P.-F. Loos, Y. Damour, and A. Scemama, J. Chem. Phys. 153, 176101 (2020)], motivated by the blind challenge of Eriksen et al. [J. Phys. Chem. Lett. 11, 8922 (2020)] on the same system, we report accurate full configuration interaction (FCI) frozen-core correlation energy estimates for 12 five- and six-membered ring molecules (cyclopentadiene, furan, imidazole, pyrrole, thiophene, benzene, pyrazine, pyridazine, pyridine, pyrimidine, s-tetrazine, and s-triazine) in the standard correlation-consistent double-ζ Dunning basis set (cc-pVDZ). Our FCI correlation energy estimates, with an estimated error smaller than 1 millihartree, are based on energetically optimized-orbital selected configuration interaction calculations performed with the configuration interaction using a perturbative selection made iteratively algorithm. Having at our disposal these accurate reference energies, the respective performance and convergence properties of several popular and widely used families of single-reference quantum chemistry methods are investigated. In particular, we study the convergence properties of (i) the Møller–Plesset perturbation series up to fifth-order (MP2, MP3, MP4, and MP5), (ii) the iterative approximate coupled-cluster series CC2, CC3, and CC4, and (iii) the coupled-cluster series CCSD, CCSDT, and CCSDTQ. The performance of the ground-state gold standard CCSD(T) as well as the completely renormalized CC model, CR-CC(2,3), is also investigated. We show that MP4 provides an interesting accuracy/cost ratio, while MP5 systematically worsens the correlation energy estimates. In addition, CC3 outperforms CCSD(T) and CR-CC(2,3), as well as its more expensive parent CCSDT. A similar trend is observed for the methods including quadruple excitations, where the CC4 model is shown to be slightly more accurate than CCSDTQ, both methods providing correlation energies within 2 millihartree of the FCI limit. [ABSTRACT FROM AUTHOR]

Treatment of 3-bromo-6-chloroimidazo[1,2-b]pyridazine with a variety of 1° or 2° alkylamines (2.0 equiv) with CsF (1.0 equiv), and BnNEt3Cl (10 mol %) in DMSO at 100 °C (24 hours) gave the corresponding C-6 aminated products in excellent isolated yields (79–98%; ave. yield = 92%). These conditions worked well for simple unfunctionalized 1° alkylamines, 1° amines with methylene- or ethylene-linked aromatic or heteroaromatic functionality (e.g. benzene, thiophene, furan, indole, and pyridine), and 2° alkylamines such as pyrrolidine, morpholine, and piperidine were also well tolerated. The method is cost-effect, providing C-6 aminated products in consistently high yields, while at the same time utilizing far less toxic fluoride (10 fold less), than previous fluoride-promoted aminations. [ABSTRACT FROM AUTHOR]

A series of bridged triazolo[4,5‐d]pyridazine based energetic materials were optimized at B3LYP/6‐311G(d, p) level of density functional theory (DFT), and their detonation properties and sensitivities were calculated. The results show that the NN bridge/N3 group were beneficial to improve values of heats of formation while NN bridge/C(NO2)3 group can improve detonation properties remarkably. In view of the sensitivities, compound F2 possesses the minimum values of impact sensitivity which reveals that NHNH bridge/C(NO2)3 group will decrease the stability of the designed compounds. Take both of detonation properties and sensitivities into consideration, compounds C8, E7, E8, F8 were screened as candidates of potential energetic materials since these compounds possess similar detonation properties and sensitivities values to those of RDX. All the calculated results were except to shine lights on the design and synthesis of novel high energy density materials. [ABSTRACT FROM AUTHOR]

The eco-friendly techniques were utilized for the straightforward synthesis of new heterocyclic compounds bearing the sulfadiazine moiety by employing ultrasound irradiation techniques. Initially, sulfadiazine (1) was subjected to diazotization, followed by a coupling reaction with an activated methylene group (ethyl acetoacetate) to yield a hydrazone compound (3). Subsequently, the coupling adducts (3) were reacted with ethyl benzoylacetate, benzyl hydrazine, thiosemicarbazide, and guanidine under ultrasound irradiation, leading to the formation of pyridazine (4), pyrazolines (5, 6), and pyrimidine (7), respectively. Furthermore, when pyrazoline compound (6) was treated with chloroacetone and bromoaceophenone under ultrasound conditions, thiazole compounds (6a) and (6b) were formed, respectively. Additionally, new derivatives (10) and (11) were synthesized through diazotizing compound (7), followed by coupling reactions with an activated methylene group (acetylacetone) and reactions with urea and thiourea, respectively, all under ultrasound conditions. All the synthesized compounds were characterized using spectroscopic techniques such as FT IR, ¹H-NMR, and 13C-NMR spectra. The synthesized chemicals exhibited promising antimicrobial activities against human pathogenic bacteria strains (Escherichia coli and Staphylococcus aureus) and Candida albicans fungi, as assessed through the broth microdilution technique. [ABSTRACT FROM AUTHOR]

The synthesis and analysis of new polymeric materials based on 1,2,4,5‐tetrazine are discussed in this study. Tetrazine was mixed with thermoplastic polyurethane in dimethylformamide (DMF) as solvent and dibutyl tin dilaurate as catalyst at 50°C for 24 h to create brush polyurethane‐urea, which was then reacted with an unsaturated center in dimethyl sulfoxide as solvent at 60°C for 48 h made of either polyenol or thermoplastic polyurethane through π–π interaction. Because 1,2,4,5‐tetrazine (red color) is known to act as an electron‐deficient dine in inverse electron demand Diels–Alder reactions and can be easily converted to pyridazine (peach color) via [4 + 2] cycloaddition with suitable followed by expulsion of molecular nitrogen (cycloreversion), we observed a highly colored red shift to peach and this monitor for this reaction. Additionally, polyamide was prepared via reaction of 3,6‐diamino‐1,2,4,5‐tetrazine with terephthaloyl chloride in DMF as a suitable solvent and triethylamine as basic catalyst at 0°C for 3 h and then 36 h at room temperature. The new polymers that were produced were elucidated by spectral data. [ABSTRACT FROM AUTHOR]

Various fluorogenic probes utilizing tetrazine (Tz) as a fluorescence quencher and bioorthogonal reaction partner have been extensively studied over the past few decades. Herein, we synthesized a series of boron‐dipyrromethene (BODIPY)‐Tz probes using monochromophoric design strategy for bioorthogonal cellular imaging. The BODIPY‐Tz probes exhibited excellent bicyclo[6.1.0]nonyne (BCN)‐selective fluorogenicity with three‐ to four‐digit‐fold enhancements in fluorescence over a wide range of emission wavelengths, including the far‐red region. Furthermore, we demonstrated the applicability of BODIPY‐Tz probes in bioorthogonal fluorescence imaging of cellular organelles without washing steps. We also elucidated the aromatized pyridazine moiety as the origin of BCN‐selective fluorogenic behavior. Additionally, we discovered that the fluorescence of the trans‐cyclooctene (TCO) adducts was quenched in aqueous media via photoinduced electron transfer (PeT) process. Interestingly, we observed a distinctive recovery of the initially quenched fluorescence of BODIPY‐Tz‐TCO upon exposure to hydrophobic media, accompanied by a significant bathochromic shift of its emission wavelength relative to that exhibited by the corresponding BODIPY‐Tz‐BCN. Leveraging this finding, for the first time, we achieved dual‐color bioorthogonal cellular imaging with a single BODIPY‐Tz probe. [ABSTRACT FROM AUTHOR]

The review focuses on recent advances in the methodologies for the formation or introduction of the CH2F moiety in N-heterocyclic substrates over the past 5 years. The monofluoromethyl group is one of the most versatile fluorinated groups used to modify the properties of molecules in synthetic medical chemistry. The review summarizes two strategies for the monofluoromethylation of N-containing heterocycles: direct monofluoromethylation with simple XCH2F sources (for example, ICH2F) and the assembly of N-heterocyclic structures from CH2F-containing substrates. The review describes the monofluoromethylation of pharmaceutically important three-, five- and six-membered N-heterocycles: pyrrolidines, pyrroles, indoles, imidazoles, triazoles, benzothiazoles, carbazoles, indazoles, pyrazoles, oxazoles, piperidines, morpholines, pyridines, quinolines and pyridazines. Assembling of 6-fluoromethylphenanthridine, 5-fluoromethyl-2-oxazolines, C5-monofluorinated isoxazoline N-oxides, and α-fluoromethyl-α-trifluoromethylaziridines is also shown. Fluoriodo-, fluorchloro- and fluorbromomethane, FCH2SO2Cl, monofluoromethyl(aryl)sulfoniummethylides, monofluoromethyl sulfides, (fluoromethyl)triphenylphosphonium iodide and 2-fluoroacetic acid are the main fluoromethylating reagents in recent works. The replacement of atoms and entire functional groups with a fluorine atom(s) leads to a change and often improvement in activity, chemical or biostability, and pharmacokinetic properties. The monofluoromethyl group is a bioisoster of -CH3, -CH2OH, -CH2NH2, -CH2CH3, -CH2NO2 and -CH2SH moieties. Bioisosteric replacement with the CH2F group is both an interesting task for organic synthesis and a pathway to modify drugs, agrochemicals and useful intermediates. [ABSTRACT FROM AUTHOR]

Multiple inhibitions of CA, COX-2 and 5-LOX enzymes has been recognised as a useful strategy for the development of anti-inflammatory drugs that can avoid the disadvantages of using NSAIDs alone. Here, we report new pyridazine-based sulphonamides (5a-c and 7a-f) as potential multi-target anti-inflammatory candidates. First, the furanone heterocycle in the dual CA/COX-2 inhibitor Polmacoxib was replaced with the pyridazinone one. Then, a hydrophobic tail was appended through benzylation of the 3-hydroxyl group of the pyridazinone scaffold to afford benzyloxy pyridazines 5a-c. Furthermore, the structures were adorned with the polar sulphonate functionality, in pyridazine sulphonates 7a-f, that are expected to be engaged in interactions with the hydrophilic half of the CA binding sites. All of the disclosed pyridazinones were tested for inhibitory activities against 4 hCA isoforms (I, II, IX, and XII), as well as against COX-1/2, and 5-LOX. Furthermore, in vivo anti-inflammatory and analgesic effects of pyridazinones 7a and 7b were examined. [ABSTRACT FROM AUTHOR]

A new class of pyridazine-based six Iron(II), Nickel(II) and Copper(II) metal complexes of (E)-2-(6-chloropyridazin-3-yl)-1-(1-(pyridin-2-yl)ethylidene)hydrazine ligand (L1)(1) derived from condensation of 2-(6-chloropyridazin-3-yl)hydrazine and pyridine-2-acetaldehyde were synthesized in 1:1 and 1:2 molar ratio with ligand and characterized by UV–visible, 1H- and 13C-NMR, FT-IR, mass and EPR spectroscopy, elemental analysis and molar conductance. The spectroscopic evidence specifies that the ligands behave as a tridentate ligand through the nitrogen atom of pyridine-2-acetaldehyde, nitrogen atoms of azomethine group and pyridazine ring. The mass spectra demonstrated that the complexes have prepared in 1:1 and 1:2 molar ratio with ligand and suitable metals salts. From the ESR spectroscopy, confirmed that the Cu(L1)(4) complex had the square planar geometry, whereas Cu(L1)2(7) complex had distorted octahedral geometry. The ligand and its six metal complexes were evaluated for their in vitro antibacterial activity against Staphylococcus aureus (MTCC 96), Streptococcus pyogenes (MTCC 442), Escherichia coli(MTCC 443), Pseudomonas aeruginosa (MTCC 1688) strains, and in vitro antifungal activity against Candida albicans (MTCC 227), Aspergillus niger (MTCC 282), and Aspergillus clavatus (MTCC 1323) strains by using micro-broth dilution method against standard antibiotics Gentamycin, Ampicillin, Chloramphenicol, Ciprofloxacin, Norfloxacin, and antifungal agents Nystatin and Griseofulvin. Cytotoxicity assays against human colon cancer MiaPaCa-2 and PanC-1 cell lines in vitro were completed for ligand (L1) by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium by (MTT) method. Finally, the optimized structures of the ligand and its complexes have been used to accomplish molecular docking studies with receptors of DNA Gyrase (PDB ID-1aj6) enzyme to determine the most preferred mode of interaction. [ABSTRACT FROM AUTHOR]

Selective cyclooxygenase (COX)‐2 inhibitors have several advantages over nonselective COX inhibitors (nonsteroidal anti‐inflammatory drugs [NSAIDs]), including the absence of adverse effects (renal and hepatic disorders) associated with the long‐term use of standard NSAIDs, as well as an improved gastrointestinal profile. The pyridazine nucleus is regarded as a promising scaffold for the development of powerful COX‐2 inhibitors, particularly when selectively functionalized. This article summarizes some methods for the synthesis of pyridazine derivatives. Furthermore, it covers all of the pyridazine derivatives that have appeared as selective COX‐2 inhibitors, making it useful as a reference for the rational design of novel selective COX‐2 inhibitors. [ABSTRACT FROM AUTHOR]

Inverse electron-demand Diels–Alder additions (iEDDA) between 1,2,4,5-tetrazines and suitable unsaturated dienophiles such as olefins, alkynes, or enol ethers provide facile access to pyridazines. Herein the use of cyclic enol ether derivatives for preparing pyridazines bearing 2-hydroxyethyl, 3-hyproxypropyl, and 3-oxopropyl substituents at the 4-position is disclosed and second order rate constants for the reactions with 2,3-dihydrofuran, 3,4-dihydro-2H-pyran, and 2-methoxy-3,4-dihydro-2H-pyran are presented. [ABSTRACT FROM AUTHOR]

N‐Substitution of a thermally unstable diboratriazole 1 with a trimethylsilyl group affords a remarkably stable diboratriazole derivative 2. Ring contraction of 2 with an N‐heterocyclic carbene accompanied by the release of N2 as well as 1,4‐hydrogen shift affords a carbene‐stabilized azadiboriridine 3. Abstraction of the H−B3mem hydride in 3 with methyl trifluoromethanesulfonate leads to the isolation of a hitherto unknown azadiboriridinylium 4, the first BN analogue of cyclopropenylium cation. X‐ray diffraction analysis and computational studies confirmed the delocalization of π electrons over the B2N three‐membered ring, indicating the 2π aromatic feature. Compound 4 undergoes ring expansion reactions with azobenzene and pyridazine to furnish triazadiborolidinylium species 5 and 6, the latter of which possesses a cationic B2N3 ring with a pronounced 6π aromatic property. Moreover, the reaction of 4 with a diazo compound produces a cationic B2N3C pentafulvene derivative 7. [ABSTRACT FROM AUTHOR]

We described a regioselective tri‐ and tetra‐functionalization of the pyridazine scaffold using two readily available building blocks: 3‐alkylthio‐6‐chloropyridazine and 3,4‐bis(methylthio)‐6‐chloropyridazine by performing selective metalations with TMPMgCl ⋅ LiCl and catalyst‐tuned cross‐coupling reactions with arylzinc halides. Several of the resulting pyridazines were converted into more elaborated N‐heterocycles such as thieno[2,3‐c]pyridazines and 1H‐pyrazolo[3,4‐c]pyridazines. [ABSTRACT FROM AUTHOR]

In contrast, under thermodynamically controlled reaction conditions (60 °C, 10 min) in a flow reactor with (Cy SB 2 sb N) SB 2 sb Zn-2LiCl, zincation proceeds preferentially at the C4-position (Scheme 9). In 2007, the Knochel group demonstrated metalation of a 2-chloro-3-nitropyridine ( B 40 b ) with (TMP) SB 2 sb Zn-2MgCl SB 2 sb -2LiCl B 2 b at -40 °C in 1.5 h followed by a subsequent copper-catalysed allylation with 3-bromocyclohexane (Scheme 10); the final product B 42 b was obtained in 80% yield. [19] Thus for most purposes, TMPZnCl-LiCl B 3 b remains the most convenient and widely applicable zinc base, and has come to be termed a "turbo-zinc" reagent. [59] Sales et al. tested both MgTMP and ZnTMP bases and found that the use of TMP SB 2 sb Zn-2MgCl SB 2 sb -2LiCl B 2 b not only results in higher yields than with TMPMgCl-LiCl (93% I vs. i 65%), but also the reaction proceeds at room temperature rather than at -30 °C. [Extracted from the article]

13C-Carbon is the most available source of carbon-13. It is a relatively inexpensive solid material, which can be easily converted to calcium carbide-13C2. In current work, Ca13C2 was used for in situ generation of 13C2-acetylene in 1,3-dipolar cycloaddition and [4+2] cycloaddition reaction. For the first time, 1H-1,2,3-triazoles-4,5-13C2 and isoxazoles-4,5-13C2 were synthesized using calcium carbide-13C2. A Diels-Alder type cycloaddition of 3,6-di(pyridin-2-yl)-1,2,4,5-tetrazine and Ca 13C2 was investigated, and the best way for the synthesis of 3,6-di(pyridin-2-yl)pyridazine-4,5-13C2 was proposed for the first time. Here we perform a detailled description of NMR spectra of 13C2-labeled triazoles, isoxazoles and 3,6-di(pyridin-2-yl)pyridazine. [ABSTRACT FROM AUTHOR]

A general and selective, microwave mediated synthesis of 5-methyl-pyridazin-3-amines (3a-e) and (E)-2-(3,6-dichloropyridazin-4-yl)vinyl-amines (8a-u and 9a-h) has been described starting from methyl-dichloropyridazines (2a and 2b). New synthetic possibility for bis(indolyl)methanes (11) also uncovered. [ABSTRACT FROM AUTHOR]