Pyrazole Unit Research Articles

3 + 2] Cycloaddition Synthesis of New (Chromene‐1,3,4‐Oxadiazole) Hybrids Linked to Pyrazole Units as Potential Acetylcholinesterase Inhibitors

AbstractA lot of interest has been gained recently in developing novel acetylcholinesterase (AChE) inhibitors that can alleviate Alzheimer's symptoms. In the current study, we aimed to explore AChE inhibitory activity of new chromenes attached to 1,3,4‐oxadiazole and/or pyrazole units. The new hybrids were obtained via [3 + 2] cycloaddition reaction between the appropriate chromene‐based enaminones and hydrazonyl chlorides. The inhibition percentages of the new products against AChE were recorded at tested concentrations of 15 and 25 µM compared to donepezil. 3‐(3‐Acetyl‐1‐(4‐methoxyphenyl)‐1H‐pyrazole‐4‐carbonyl)‐6‐(((5‐phenyl‐1,3,4‐oxadiazol‐2‐yl)thio)methyl)‐2H‐chromen‐2‐one displayed promising activity with inhibition percentages of 73.2 and 87.3, respectively, at the aforementioned concentrations. Moreover, the previous hybrid gave promising 2,2‐diphenylpicrylhydrazyl (DPPH) inhibitory activity using the reference ascorbic acid. It had an inhibition percentage of 86.6 at a tested concentration of 25 µM.

Three multifunctional difluoroboron fluorescent dyes with five member N-heterocyclic ring for mechanofluorochromic behaviors, the ink-free writing and latent fingerprints imaging

To further advance the development of multifunctional fluorescent dyes, three difluoroboron compounds (F-1, F-2, and F-3) containing five-membered N-heterocyclic ring moieties that act as the electron-withdrawing units were synthesized. It was observed that compound F-1, which incorporated a 1,2,4-triazole segment, and compound F-3 with 1,2,3-triazole portion exhibited aggregation-induced emission activities suitable for latent fingerprints imaging. In contrast, compound F-2 featuring a pyrazole unit demonstrated an aggregation-caused quenching phenomenon. Additionally, all three compounds displayed mechanofluorochromic behaviors. Specifically, the emission spectra of compound F-1 in the solid state experienced only a slight shift of approximately 5 nm upon grinding, however, compound F-2 underwent a red shift from 475 to 501 nm while compound F-3 shifted from 482 to 507 nm. Furthermore, both compounds F-2 and F-3 could be utilized in ink-free writing applications. Notably, the safety paper prepared using compound F-2 was designed for single-use due to its irreversible mechanofluorochromic behavior, conversely, the safety paper derived from compound F-3 was rewritable owing to its reversible mechanofluorochromic behavior. It provided a foundation for exploration the application of multifunctional difluoroboron compounds with 1,2,3-triazole moiety.

The Study of Reaction of Hexafluoro‐1,4‐Napthoquinone With Substituted 5‐Aminopyrazoles

ABSTRACTFor the first time, the interaction of perfluoro‐1,4‐naphthoquinone with various 5‐aminopyrazoles was investigated. It was shown that three types of products can be obtained depending on the structure of starting aminopyrazole. For all examples, the substitution of one fluorine atom in quinone moiety was observed. Wherein, in most cases, the starting aminopyrazoles act as a C‐nucleophile leading to 2‐(5‐aminopyrazol‐4‐yl)‐3,5,6,7,8‐pentafluoronaphthalene‐1,4‐diones. At the same time substrates unsubstituted at ring nitrogen atom regiospecifically react at aminogroup resulting in the formation of 2,5,6,7,8‐pentafluoro‐3‐((pyrazol‐5‐yl)amino)naphthalene‐1,4‐diones. Besides that, the absence of steric hindrance in the pyrazole unit allowed us to direct the process at nitrogen atom in Position 2 and synthesize zwitter‐ionic 3‐(5‐aminopyrazol‐2‐ium‐2‐yl)‐5,6,7,8‐tetrafluoro‐1,4‐dioxo‐1,4‐dihydronaphthalen‐2‐olates. The structures of two types of obtained products were confirmed by x‐ray analysis.

Chemo- and regioselective controlled synthesis and thermal analysis characterization of trifluoromethyl polypyrazoles

This study details the chemo- and regioselective synthesis and spectroscopic and thermal analysis characterization of trifluoromethyl bipyrazoles and polypyrazoles by stepwise N-alkylation of pyrazoles using (E)-4-(amino)-5-bromo-1,1,1-trifluoro-but-3-en-2-ones (5-bromo enaminones), followed by cyclocondensation of the enaminone moiety with hydrazines. A mechanism for the cyclocondensation reaction was proposed. Sixteen new methylene-bridged bipyrazoles and polypyrazole chains with up to five pyrazole units were achieved at very good yields. All the compounds were characterized by 1H and 13C NMR, and the 1,3-regiochemistry was evidenced by single-crystal X-ray diffraction. The polypyrazoles’ thermal behavior was elucidated by thermogravimetric analysis and differential scanning calorimetry. It is suggested that at approximately 300°C the polypyrazoles thermally decompose independent of the number of repeating units. The second and third heating/cooling cycles of the differential scanning calorimetry indicate that the majority of the polypyrazoles are amorphous materials, with glass transition values that can be tuned by the number of repeating units in the polymeric chain and the type of linkage between the pyrazole rings.

Pyrazole appended Schiff base based sensor for Al3+ detection: Spectroscopic investigation, real sample analysis and cell imaging studies

Herein, we are reporting a new pyrazole derived chemosensor named H2QPC [(E)-N’-((2-hydroxyquinolin-3-yl)methylene)-3-methyl-1H-pyrazole-5-carbohydrazide] exhibiting selective “off–on” fluorimetric response towards Al3+ ion in different solvents. The probe exhibited a submicromolar detection level (LOD = 0.37 μM) for the Al3+. The density functional theory (DFT) and time dependent DFT (TD-DFT) of the probe and corresponding Al3+-complex revealed that a change of structural conformation of probe H2QPC upon complexation. The pyrazole unit creates a specific cavity to tether Al3+, and consequently H2QPC shows as a promising molecule for Al3+ detection. Further, the probe has been used successfully for qualitative determination of Al3+ using filter paper strips. The in situ Al3+ ion cell imaging in HCT116 cells discloses the cellular penetrability of the sensor, and holds pronounced promise for application in biological and environment sciences.

A Novel Fluorescence Sensor for Iodide Detection Based on the 1,3-Diaryl Pyrazole Unit with AIE and Mechanochromic Fluorescence Behavior.

A D-A type of luminophore, TPA-CDP, was designed and synthesized by using triphenylamine (TPA) as D (electron donor), 1,3-diaryl pyrazole with cyano groups (CDP) as A (electron acceptor) and employing a cyanovinyl segment as a recognition group. Firstly, TPA-CDP demonstrates effective fluorescence quenching as a sensor for I- by the nucleophilic addition reaction of the cyanovinyl segment with a high level of sensitivity, selectivity and a low determination limit of 4.43 μM. Interestingly, TPA-CDP exhibited an AIE phenomenon with the fw value reaching 50%. In addition, TPA-CDP displayed distinct mechanochromic fluorescence behavior with 70 nm red shift, which was observed over four repeated cycles. Furthermore, the mechanochromic fluorescence behavior of TPA-CDP, as observed in powder XRD experiments, was found to be associated with the morphological transition from a crystalline state to an amorphous state. These results confirm the significant potential of CDP as a powerful electron-deficient component in the creation of D-A-type mechanochromic fluorescence materials and biosensors for detecting I-.

Rh-Catalyzed C–H Functionalization of the (Pyrazol-5-yl)pyridine Core of GBT-440

AbstractThe Rh-catalyzed cross dehydrogenative coupling (CDC)/alkylation of the pyrazolylpyridine unit of GBT-440 proceeded smoothly under ambient conditions and selectively on the pyrazole unit while directed by the pyridine. The scope of these reactions was established by employing simple as well as conjugated olefins for CDC and various diazo esters and the TIPS-EBX reagent for alkylation. At the outset, a focused small molecule library around the bis-heterocyclic core of GBT-440 was developed via C–H functionalization.

3+2] Cycloaddition Synthesis of New Piperazine‐Linked Bis(chromene) Hybrids Possessing Pyrazole Units as Potential Acetylcholinesterase Inhibitors

Two series of piperazine-linked bis(chromene) hybrids that are attached to pyrazole units were synthesized in the current study. Both series are attached to an acyl unit at pyrazole-C3, with one series attached to an acetyl unit and the other to an ethoxycarbonyl unit. A [3+2] cycloaddition protocol was conducted to produce the target hybrids with good yields by reacting the appropriate hydrazonoyl chlorides with chromene-based bis(enaminone) in dioxane containing triethylamine at reflux for 4 h. New hybrids were tested for acetylcholinesterase inhibitory activity at concentrations of 15 and 25 μM, as well as their ability to quench 2,2-diphenylpicrylhydrazyl (DPPH) free radicals at a concentration of 25 μg/mL. In general, the inhibitory activity is related to the electronic properties of the para-substituent that is attached to the arene unit at pyrazole-N1. Furthermore, the acyl unit attached to pyrazole-C3 has a significant effect on the new hybrids' inhibitory activity. At the previous concentrations, the (3-acetylpyrazole)-linked hybrid attached to p-NO2 units demonstrated the best acetylcholinesterase inhibitory activity, with inhibition percentages of 79.7 and 90.2. Furthermore, the previous hybrid demonstrated the most effective DPPH inhibitory activity, with an inhibition percentage of 87.5.

Base metal complexes featuring a new pyrazole-derived PCP pincer ligand.

A new pyrazole-derived PCP pincer ligand featuring a 1-methylpyrazole backbone tethered to two di(isopropyl)phosphine moieties via phenylene spacers (P(CH)P-iPr) was prepared. When reacting the ligand with group six carbonyl complexes [M(CO)6] (M = Cr, Mo, W) at 130 °C, complexes of the type [M(κ2PN-PCP-iPr)(CO)4] were obtained featuring a κ2P,N-bound ligand with a pendant phosphine arm. Upon an increase of the reaction temperature to 150 °C, in the case of molybdenum, the formation of the complex [Mo(κ3PCP-PCP-iPr)(CO)3] was observed featuring a weak Mo-C bond. DFT calculations reveal that there is no agostic η2-C-H interaction. Treatment of [Mn2(CO)10], [Fe2(CO)9], [Co2(CO)8] and [Ni(COD)2] afforded complexes [Mn(κ3PCP-PCP-iPr)(CO)3], [Fe(κ3PCP-PCP-iPr)(H)(CO)2], [Co(κ3PCP-PCP-iPr)(CO)2] and [Ni(κ3PCP-PCP-iPr)(H)], respectively, where the PCP ligand is coordinated in the typical meridional κ3-fashion. Postfunctionalization of the anionic PCP pincer ligand was possible via N-methylation of the second nitrogen atom of the pyrazole unit with the oxonium salt [Me3O]BF4. Treatment of [Mn(κ3PCP-PCP-iPr)(CO)3] and [Fe(κ3PCP-PCP-iPr)(H)(CO)2] with [Me3O]BF4 resulted in the formation of the cationic complexes [Mn(κ3PCP-PCPMe-iPr)(CO)3]+ and [Fe(κ3PCP-PCPMe-iPr)(Cl)(CO)2]+. In the case of the latter, the chloride ligand seems to originate from the solvent CH2Cl2 undergoing a hydride chloride exchange. All complexes were characterized by means of 1H, 13C{1H}, and 31P{1H} NMR spectroscopy, IR spectroscopy and HR-MS. In addition, the structures of representative complexes were determined by X-ray crystallography.

Postmodification of voxelotor (GBT 440) via [Rh]-catalyzed cross dehydrogenative coupling with olefins

The directed Rh(III)-catalyzed cross dehydrogenative coupling of the pyrazole unit of the GBT-440 scaffold has been explored with simple as well as conjugated olefins to synthesize post-functionalized GBT-440 analogues. The screening of these synthesized compounds for improving the oxygen binding efficiency of the hemoglobin isolated from the sickled red blood cells revealed that some of these compounds are as good as GBT-440.

3 + 2] Cycloaddition synthesis of new (nicotinonitrile-chromene) hybrids linked to pyrazole units as potential acetylcholinesterase inhibitors

Two series of nicotinonitrile-linked chromenes attached to pyrazole units were synthesized in the current study. A [3 + 2] cycloaddition protocol was used to produce the target hybrids in high yields by reacting the respective nitrilimines, which were generated in situ by the action of triethylamine on hydrazonoyl chlorides, with chromene-based enaminone. Generally, the acetylcholinesterase and DPPH free radical inhibitory activity are related to the electronic properties of the para-substituent that is attached to the arene unit at pyrazole-C1. Furthermore, 3-acylpyrazole unit has a significant effect on the new hybrids' efficacy. At 25 and 50 µM concentrations, the 3-acetylpyrazole attached to p-OMe unit demonstrated the best acetylcholinesterase inhibitory activity, with inhibition percentages of 75.8 and 88.3, respectively. Furthermore, the previous hybrid demonstrated the most effective antioxidant activity, with an inhibition percentage of 82.6 at a tested concentration of 25 µg/mL. According to SwissADME, the majority of the pyrazoles tested are drug-like.

Aggregation-induced emission enhancement (AIEE)-active donor-acceptor type fluorophores based on the 1,3-diaryl pyrazole unit: Conspicuous mechanochromic fluorescence and biosensing of iodide ions

Two type luminophore 1 and 2, with the same triphenylamine (TPA) and malonitrile-functionalized 1,3-diaryl pyrazole (MDP) units but with different π-conjugated spacer, were designed and synthesized. The crystals solid-state emission behavior and mechanical stimuli-responsive fluorescence characteristics of 1 and 2 were investigated. Interestingly, the fluorophores 1 and 2 exhibited yellow-green and yellow crystals solid-state fluorescent, respectively. Furthermore, 1 and 2 also exhibited obvious mechanochromic fluorescence behavior with repeated four cycles. Compared to 1 with an 80 nm red-shift, 2 is more sensitive to mechanical stimuli and exhibits a large red-shift emission of 85 nm. The powder XRD experiments demonstrated that the mechanochromic fluorescence behavior of 1 and 2 were related to the morphology transformation from crystalline state to amorphous state. In addition, based on the MDP moiety as I− receptor, 1 and 2 were qualified for sensing of I− with low limit of detection (89.0 nM, 149.9 nM). The biosensing of I− based on the better detection performance of the probe 1 was achieved in A549 cells and zebrafish. These results certify the great potential of MDP as a strong electron-deficient unit for designing D-A type mechanochromic fluorescence materials and biosensors for the detection of I− in organism.

Dissociation of a tripodal pyridyl-pyrazole ligand and assortment of metal complex: Synthesis, structure, DFT, thermal stability, cytotoxicity, DNA cleavage, and molecular docking studies

A tripodal pyridyl-pyrazole based N,N,O donor ligand (L) has been designed, and it's copper(II) complex, [Cu(L1)Cl2]2.(dmpzH)2 (1) where dmpzH refers protonated dimethylpyrazole, and manganese(II) complex, [Mn(L)(Cl)2] (2)] have been synthesized and characterized by a combination of various spectroscopy, X-ray crystallography, electrochemical, thermogravimetric and density functional theory. The X-ray structure of 1 showed the copper(II) coordinated by the two sets of NO donors which had been assorted from the ligand (L) along with two bridging and one terminal chloride atoms. The distorted square-planar centrosymmetric structure of 1 is further stabilized by the hydrogen bonding with exogenous protonated pyrazole units that had been extracted from L. The title ligand retained its original structure when bound with Mn(II) giving a pseudo-octahedral geometry. The central Mn(II) was coordinated by two pyrazolyl nitrogen (N1, N7), one tertiary amine nitrogen (N3), one carbohydrazide oxygen atom O1, and two exogenous chloride ions in a cis disposition. Cytotoxicity experiments carried out in a series of human cell lines (IMR-32, HepG2 and HeLa) to confirm the apoptotic mechanism of cell death, predominantly in IMR-32. The DNA cleavage studies were then performed in the presence of the synthesized compounds to verify the influence of ligand structural features in their nuclease activity. Complex 2 was able to cause double-strand DNA scissions both in an oxidizing and reducing environment, whereas complex 1 broke the single-strand DNA in a reducing environment only, suggesting its potential anticancer therapeutics. To shed a better understanding of DNA-substrate interaction, a molecular docking study was performed.

Study on Synthesis and Antifungal Activity of Novel Benzamides Containing Substituted Pyrazole Unit

Study on Synthesis and Antifungal Activity of Novel Benzamides Containing Substituted Pyrazole Unit

Aggregation-induced luminescence enhancement, anion sensing, solvent-selective fluorescence quenching of arylpyrazoline fluorescent probe

28 Novel pyrazoline compounds containing pyrazole units have been synthesized and characterized. The crystal structures of C1 and B6 showed that these pyrazoline derivatives could form 3D layered structures through face-to-face stacking of aromatic rings, and they were more inclined to form H-type aggregation in poor solvent. Compound C4 was selected as the standard sample to study their properties of aggregation-induced emission enhancement (AIEE) and reversible mechanical chromoluminescence (MFC) behaviors in THF/cyclohexane. And the results suggested the formation of H-type aggregation, and the RIR and RIV phenomenon in the aggregated state led to strong fluorescence emission behavior in high fc solvent. The analysis of fluorescence emission spectroscopy indicated that the fluorescence emission of C4 could be selectively quenched by chloroform. Meanwhile, compound C4 can selectively recognize NO3− in CH2Cl2. The studies of fluorescence quenching mechanism showed that compound C4 could be oxidized by oxygen in the air to form a new compound C4-1 in CHCl3 solvent or in the presence of NO3−, leading to the fluorescence quenching of C4. Density functional theory calculations also confirmed the results.

Synthesis of Energetic 7-Nitro-3,5-dihydro-4H-pyrazolo[4,3-d][1,2,3]triazin-4-one Based on a Novel Hofmann-Type Rearrangement.

Rearrangement reactions are efficient strategies in organic synthesis and contribute enormously to the development of energetic materials. Here, we report on the preparation of a fused energetic structure of 7-nitro-3,5-dihydro-4H-pyrazolo[4,3-d][1,2,3]triazin-4-one (NPTO) based on a novel Hofmann-type rearrangement. The 1,2,3-triazine unit was introduced into the fused bicyclic skeleton from a pyrazole unit for the first time. The new compound of NPTO was fully characterized using multinuclear NMR and IR spectroscopy, elemental analysis as well as X-ray diffraction studies. The thermal behaviors and detonation properties of NPTO were investigated through a differential scanning calorimetry (DSC-TG) approach and EXPLO5 program-based calculations, respectively. The calculation results showed similar detonation performances between NPTO and the energetic materials of DNPP and ANPP, indicating that NPTO has a good application perspective in insensitive explosives and propellants.

Nucleophilic Catalyzed Structural Binary Cleavage of a Fused [5,5]-Bicyclic Compound.

Structural binary cleavage of 3,7-diamino-2,6-dinitro-1H,5H-pyrazolo-[1,2-a]pyrazole-1,5-dione 3, under nucleophilic conditions, leads to the formation of a monocyclic pyrazole unit of 5-amino-4-nitro-1,2-dihydro-3H-pyrazol-3-one, 4. Additionally, various salts of the pyrazole ring were synthesized and fully characterized. Detonation properties and mechanical sensitivities of 4 and other new compounds are remarkably improved compared to 3. This simple and efficient strategy is highly desirable for future studies on the development of insensitive and high performing materials.

Hantzsch synthesis of bis(pyrido[2,3-d:6,5-d']dipyrimidines), bis(pyrimido[4,5-b]quinolines), and bis(benzo[4,5]imidazo[2,1-b]quinazolines) linked to pyrazole units as novel hybrid molecules

Bis(1-phenylpyrazole-4-carboxaldehydes) were utilized as versatile precursors to novel series of bis(pyrido[2,3-d:6,5-d']dipyrimidines), bis(pyrimido[4,5-b]quinolines), and bis(benzo[4,5]imidazo[2,1-b]quinazolines) derivatives which are linked to pyrazole units.

Chiral Cobalt(II) Complex Catalyzed Asymmetric [2,3]-Sigmatropic Rearrangement of Allylic Selenides with α-Diazo Pyrazoleamides

Organoselenium compounds, due to their high structural diversity, special function, and biological activities, have drawn attention in synthetic chemistry. Herein, a novel example of chiral N,N′-di...

Enhancing Tris(pyrazolyl)borate-Based Models of Cysteine/Cysteamine Dioxygenases through Steric Effects: Increased Reactivities, Full Product Characterization and Hints to Initial Superoxide Formation.

The design of biomimetic model complexes for the cysteine dioxygenase (CDO) and cysteamine dioxygenase (ADO) is reported, where the 3‐His coordination of the iron ion is simulated by three pyrazole donors of a trispyrazolyl borate ligand (Tp) and protected cysteine and cysteamine represent substrate ligands. It is found that the replacement of phenyl groups—attached at the 3‐positions of the pyrazole units in a previous model—by mesityl residues has massive consequences, as the latter arrange to a more spacious reaction pocket. Thus, the reaction with O2 proceeds much faster and afterwards the first structural characterization of an iron(II) η 2‐O,O‐sulfinate product became possible. If one of the three Tp‐mesityl groups is placed in the 5‐position, an even larger reaction pocket results, which leads to yet faster rates and accumulation of a reaction intermediate at low temperatures, as shown by UV/Vis and Mössbauer spectroscopy. After comparison with the results of investigations on the cobalt analogues this intermediate is tentatively assigned to an iron(III) superoxide species.