Pyrazole Ring Research Articles

Synthesis of new heterocyclic systems fused at pyrazolo[3,4-c]-2,7-naphthyridine core

Efficient syntheses of new heterocyclic systems comprising pyrimido[1',2':1,5]pyrazolo[3,4-c]-2,7-naphthyridine, pyrazolo[3,4-c][1,2,4]triazolo[3,4-a]-2,7-naphthyridine and pyrazolo[3,4-c]tetrazolo[5,1-a]-2,7-naphthyridine cores were performed in two simple steps. In the first step, pyrazole ring was fused at the 2-chloro-3-cyanopyridine moiety by treatment with hydrazine. In the second step, pyrimidine part was fused at the thus formed 3-aminopyrazole moiety by heterocyclization with acetylacetone.

Indazole and its Derivatives in Cardiovascular Diseases: Overview, Current Scenario, and Future Perspectives.

Indazoles are a class of heterocyclic compounds with a bicyclic ring structure composed of a pyrazole ring and a benzene ring. Indazole-containing compounds with various functional groups have important pharmacological activities and can be used as structural motifs in designing novel drug molecules. Some of the indazole-containing molecules are approved by FDA and are already in the market. However, very few drugs with indazole rings have been developed against cardiovascular diseases. This review aims to summarize the structural and pharmacological functions of indazole derivatives which have shown efficacy against cardiovascular pathologies in experimental settings.

Visible-light-driven N and Fe co-doped carbon dots for peroxymonosulfate activation and highly efficient aminopyrine photodegradation

Low solar energy utilization, instability of Fe ions and Fe(III)/Fe(II) cycle difficulty are three main factors, limiting the photocatalytic activity of the Fe/peroxymonosulfate (PMS) system. Herein, based on the N and Fe co-doped carbon dots (N, Fe-CDs) synthesized by a facile one-pot hydrothermal method, a new Fe(III)/Fe(II) cycle system for PMS activation under visible light irradiation was proposed. The characterization experiments showed that Fe has been successfully doped to the sp2 graphitic structure and mainly existed as Fe-N and Fe-OH complexes, which played an important role in harvesting visible light, enhancing the stability of Fe ions and acting as active sites to accelerate electron transfer. Under visible light irradiation, the photogenerated electrons of N, Fe-CDs could be directly transferred to Fe (III) for Fe (II) formation via the ligand-to-mental charge transfer process, thus accelerating the Fe(III)/Fe(II) cycle. When N, Fe-CDs were used for activating PMS under visible light irradiation, aminopyrine could be efficiently degraded and mineralized to CO2 via the cleavage of pyrazole ring, demethylation, hydroxylation, decarbonylation and the cleavage of benzene ring. The produced O2− and 1O2 played the main roles in the whole photocatalytic reaction. The above results revealed that the novel N, Fe-CDs could effectively activate PMS under visible light irradiation for the degradation of pharmaceuticals in the polluted water.

Design, Synthesis, Pharmacodynamic and In Silico Pharmacokinetic Evaluation of Some Novel Biginelli-Derived Pyrimidines and Fused Pyrimidines as Calcium Channel Blockers.

Some new pyrimidine derivatives comprising arylsulfonylhydrazino, ethoxycarbonylhydrazino, thiocarbamoylhydrazino and substituted hydrazone and thiosemicarbazide functionalities were prepared from Biginelli-derived pyrimidine precursors. Heterocyclic ring systems such as pyrazole, pyrazolidinedione, thiazoline and thiazolidinone ring systems were also incorporated into the designed pyrimidine core. Furthermore, fused triazolopyrimidine and pyrimidotriazine ring systems were prepared. The synthesized compounds were evaluated for their calcium channel blocking activity as potential hypotensive agents. Compounds 2, 3a, 3b, 4, 11 and 13 showed the highest ex vivo calcium channel blocking activities compared with the reference drug nifedipine. Compounds 2 and 11 were selected for further biological evaluation. They revealed good hypotensive activities following intravenous administration in dogs. Furthermore, 2 and 11 displayed drug-like in silico ADME parameters. A ligand-based pharmacophore model was developed to provide adequate information about the binding mode of the newly synthesized active compounds 2, 3a, 3b, 4, 11 and 13. This may also serve as a reliable basis for designing new active pyrimidine-based calcium channel blockers.

Distal Ruthenaelectro-Catalyzed meta-C-H Bromination with Aqueous HBr.

While electrochemical ortho‐selective C−H activations are well established, distal C−H activations continue to be underdeveloped. In contrast, we herein describe the electrochemical meta‐C−H functionalization. The remote C−H bromination was accomplished in an undivided cell by RuCl3⋅3 H2O with aqueous HBr. The electrohalogenation proceeded under exogenous ligand‐ and electrolyte‐free conditions. Notably, pyrazolylarenes were meta‐selectively brominated at the benzenoid moiety, rather than on the electron‐rich pyrazole ring for the first time. Mechanistic studies were suggestive of an initial ruthenacycle formation, and a subsequent ligand‐to‐ligand hydrogen transfer (LLHT) process to liberate the brominated product.

Vibrational properties of the mononuclear Fe[HBpz3]2 spin crossover complex

Within this work, we report the results of nuclear inelastic scattering experiments of the low-spin phase of the iron(II) mononuclear SCO complex Fe[HBpz3]2 and density functional theory based calculations performed on a model molecule of the complex. We show that the calculated partial density of vibrational states based on the structure of a single iron(II) center which is linked by three pyrazole rings to borat is in good accordance with the experimentally obtained 57Fe-pDOS and assign the molecular vibrations to the prominent optical phonons.

Binding and Photocleavage Studies of Ru (II) Polypyridyl Complexes with DNA: An In Silico and Antibacterial activity

The global crisis of bacterial infections, search for an effective antibacterial is of utmost clinical significance. Experimental and computational approaches used to study the DNA binding of [Ru(A)2L] (ClO4)2.2H2O, where A=ancillary ligand; phen=1, 10 Phenanthroline (1), dmp=4,4’-dimethyl-1,10 -orthophenanthroline (2), bpy = bipyridyl (3) & dmb=4, 4’-dimethyl 2, 2’- bipyridine (4), Lis a novel intercalator ligand MPPIP=(2-(1-(2-methoxyphenyl)-1H-pyrazol-4-yl)-1H-imidazo [4,5-f][1,10]Phenanthroline) and their antibacterial activity. The synthesized complexes and their DNA affinity studies were executed by absorption, emission, and viscosity techniques to show binding via intercalation. The intrinsic binding constant, Kb indicates that the simple ancillary ligands (phen and bpy) are more robust binding. The 3D Conformational analysis shows slight distortion from octahedron geometry. The molecular descriptors calculated from the frontier molecular orbital energy gap, ΔE point that the complex of phen show higher binding with DNA. Further analysis of the molecular attributes show that the pyrazole ring of the intercalator Ligand is significant for DNA binding. Furthermore, the molecular docking studies of the Ru (II)-MPPIP complexes with DNA exhibit an inclination towards Guanine-rich sites by the Nitrogen of the pyrazole ring. Biological investigations establish that all the complexes were active against S. aureus and E. coli.

Pyrazole bridges ensure highly stable and insensitive bistetrazoles

• Insertion of a pyrazole-bridge between two tetrazole units increases the thermal stability. • Pyrazole-bridged bistetrazoles - high heats of formation, and nitrogen and insensitivity. • Mild, green halogenation at the 4-position was possible using Oxone® and halide salts. • Compounds 10 and 11 have good detonation properties relative to TATB and RDX. In the quest for efficient and thermally stable insensitive materials, the inclusion of a bridging molecule between symmetric or asymmetric azole units has recently emerged as a fruitful approach. However, the synthesis of new compounds with high density in combination with high thermal stability and insensitivity often occurs only with difficulty. Now a new class of pyrazole-bridged bistetrazole and bis(1-hydroxytetrazolyl) compounds was synthesized and fully characterized by NMR, IR spectroscopy, and elemental analysis. Thermal behavior was investigated by using differential scanning calorimetry (DSC), and thermal gravimetric analysis (TGA). The solid-state structures of the diammonium salt ( 9 ) based on 4-nitro-1 H -pyrazole, and 5,5′-(4-chloro-1 H -pyrazole-3,5-diyl)bis(1 H -tetrazole) ( 18 ) were determined by single-crystal X-ray diffraction. These pyrazole-bridged bistetrazole compounds exhibit excellent thermal stabilities with high decomposition temperatures, moderate heats of formation, high nitrogen content, and insensitivities to impact and friction. Additionally, introduction of a halogen atom at the 4-position of the pyrazole ring gives rise to a new active heterocycle which holds considerable promise as a suitable substrate for further transformation.

Synthesis of New Pyrazole Compounds via Diketonic Michael Adducts

Pyrazole ring containing heterocyclic molecules have been known to show biological activity. In this work, by realizing the cyclization reactions of diketonic Michael adducts, synthesis of new pyrazole compounds was accomplished. Diketonic Michael adducts were prepared in low-good yields by the addition reactions of acetylacetone to nitrovinyl arene compounds in the presence of piperidine. Pyrazole compounds were obtained in high yields via the cyclization reactions of these molecules. Structures of all the addition and the cyclization products were clarified by using 1H NMR, 13C NMR and HRMS techniques.

Crystal structures and Hirshfeld surface analysis of 5-amino-1-(4-meth-oxy-phen-yl)pyrazole-4-carb-ox-ylic acid and 5-amino-3-(4-meth-oxy-phen-yl)isoxazole.

The title compounds, C11H11N3O3, (I), and C10H10N2O2, (II), are commercially available and were crystallized from ethyl acetate solution. The dihedral angle between the pyrazole and phenyl rings in (I) is 52.34 (7)° and the equivalent angle between the isoxazole and phenyl rings in (II) is 7.30 (13)°. In the crystal of (I), the mol-ecules form carb-oxy-lic acid inversion dimers with an R(8) ring motif via pairwise O-H⋯O hydrogen bonds. In the crystal of (II), the mol-ecules are linked via N-H⋯N hydrogen bonds forming chains propagating along [010] with a C(5) motif. A weak N-H⋯π inter-action also features in the packing of (II). Hirshfeld surface analysis was used to explore the inter-molecular contacts in the crystals of both title compounds: the most important contacts for (I) are H⋯H (41.5%) and O⋯H/H⋯O (22.4%). For (II), the most significant contact percentages are H⋯H (36.1%) followed by C⋯H/H⋯C (31.3%).

Design, synthesis and biological activity of diamide compounds based on 3-substituent of the pyrazole ring†.

Diamide insecticides have attracted significant attention due to their high efficacy and low toxicity to non-target organisms since they were introduced to the market. In order to tackle the problems of insecticide resistance and ecological safety, 16 novel nitrobenzene substituted anthranilic diamides with ester, hydroxyl or sulfonyl at the 3-position of the pyrazole ring were designed and synthesized. All of these compounds possessed good activity against the ryanodine receptor (RyR) from Spodoptera frugiperda and relatively lower activity against mammalian RyR1, showing a better insect-selectivity compared to chlorantraniliprole in a cell-based assay. The molecular docking analysis predicted the binding conformations of these compounds, which showed a good correlation between the insecticidal activity and the binding scores. In vitro studies using a calcium imaging method demonstrated that the novel compounds could not only activate the RyR but may also target the dihydropyridine receptor on the plasma membrane of insect neurons, implicating a similar but not same mode of action. Substituted anthranilic diamides with an ester at the 3-position of the pyrazole ring exhibited a promising insecticidal activity and better insect-selectivity, which provided insight into the rational design of a new generation of effective diamide insecticides.

Discovery of ASP5878: Synthesis and structure–activity relationships of pyrimidine derivatives as pan-FGFRs inhibitors with improved metabolic stability and suppressed hERG channel inhibitory activity

Fibroblast growth factor receptor 3 (FGFR3) is an attractive therapeutic target for the treatment of bladder cancer patients harboring genetic alterations in FGFR3. We identified pyrimidine derivative ASP5878 (27) with improved metabolic stability and suppressed human ether-á-go-go related gene (hERG) channel inhibitory activity by the optimization of lead compound 1. Based on prediction of the metabolites of 1, an ether linker was introduced in place of the ethylene linker to improve metabolic stability. Moreover, conversion of the phenyl moiety into the pyrazole ring resulted in the suppression of hERG channel inhibitory activity, possibly due to the weaker π-π stacking interaction with Phe656 in the hERG channel by a reduction in π-electrical density of the aromatic ring. ASP5878 showed potent in vitro FGFR3 enzyme and cell growth inhibitory activity, and in vivo FGFR3 autophosphorylation inhibitory activity. Moreover, ASP5878 did not affect the hERG current up to 10 µM by in vitro patch-clamp assay, and a single oral dose of ASP5878 at 1, 10, and 100 mg/kg did not induce serious adverse effects on the central nervous, cardiovascular, and respiratory systems in dogs. Furthermore, ASP5878 exhibited lower total clearance than hepatic blood flow and high oral bioavailability in rats and dogs, and moderate brain penetration in rats.

Recent advances of heterocycle based anticancer hybrids

Abstract Cancer is one of the major causes of death across the world. Cancer is a broad word that encompasses a wide range of illnesses that can affect any part of the body. Cancer research has increased understanding of molecular biology and cellular biology, resulting in new cancer therapies. Despite of adverse effects, surgery, radiation, and anticancer medicines are the modern cancer treatments. Keeping in mind the excellent anticancer activity exhibited by various heterocyclics, various medicines with heterocyclic moiety have been developed to identify particular target regions. The chapter aims to discuss new discoveries in the field of anticancer pharmaceuticals comprising the thiazole, pyrazole, oxazole, and triazole rings over the last five years. The proposed anticancer drugs have a lot of future significance due to their high potency.

Organic Supramolecular Zippers with Ultralong Organic Phosphorescence by a Dexter Energy Transfer Mechanism.

Ultralong organic phosphorescence (UOP) materials glow persistently in the dark, which offers new exciting possibilities in the fields of anti-counterfeiting, photoelectric devices and biological imaging. However, the development of single-component UOP materials remains a great challenge. Herein, we develop a single component organic supramolecular zipper system with a lifetime up to 0.77 s. Owing to the introduction of a pyrazole ring into the diphenylsulfone group, the "V" shaped molecules were artfully self-assembled into supramolecular zippers via π-π and C-H⋅⋅⋅π interactions, that is not only of significance in highly efficient generation of triplet excitons but also facilitates a Dexter energy transfer process within supramolecular zippers, that are responsible for alleviating radiative and non-radiative deactivation decay of triplet excitons, to finally boost the UOP. This finding not only gives a new set of guidelines for the design of single-component UOP molecules but also reveals the UOP mechanism from a new perspective.

Organic Supramolecular Zippers with Ultralong Organic Phosphorescence by a Dexter Energy Transfer Mechanism

AbstractUltralong organic phosphorescence (UOP) materials glow persistently in the dark, which offers new exciting possibilities in the fields of anti‐counterfeiting, photoelectric devices and biological imaging. However, the development of single‐component UOP materials remains a great challenge. Herein, we develop a single component organic supramolecular zipper system with a lifetime up to 0.77 s. Owing to the introduction of a pyrazole ring into the diphenylsulfone group, the “V” shaped molecules were artfully self‐assembled into supramolecular zippers via π–π and C−H⋅⋅⋅π interactions, that is not only of significance in highly efficient generation of triplet excitons but also facilitates a Dexter energy transfer process within supramolecular zippers, that are responsible for alleviating radiative and non‐radiative deactivation decay of triplet excitons, to finally boost the UOP. This finding not only gives a new set of guidelines for the design of single‐component UOP molecules but also reveals the UOP mechanism from a new perspective.

Robust Nickel-Based Metal-Organic Framework for Highly Efficient Methane Purification and Capture.

Developing energy-efficient alternatives for methane (CH4) purification from natural gas and methane capture of coal-mine gas is of great significance and challenge in the chemical industry. Herein, we report a robust nickel-based metal-organic framework (MOF), Ni-BPZ, featuring one-dimensional (1D) rhombic channels decorated with abundant pyrazole rings. Ni-BPZ exhibits excellent separation performance toward both C2H6/CH4 and CH4/N2 binary mixtures. The C2H6/CH4 selectivity of Ni-BPZ is high, up to 50.2, exceeding those of most MOF adsorbents reported, and it simultaneously possesses a remarkable C2H6 uptake of 2.46 mmol/g at 298 K and 0.1 bar. The CH4/N2 selectivity of Ni-BPZ reaches 6.6, and its high CH4 uptake is 1.56 mmol/g, which is also superior to most high-performance CH4 adsorbents. The molecular simulation reveals that the uniform 1D rhombic channels with abundant pyrazole rings provide a high density of potential adsorption sites for efficient C2H6/CH4 and CH4/N2 separations.

Synthesis, crystal structure and Hirshfeld surface analysis of dimethyl 3-(3-bromo-phen-yl)-6-methyl-7-oxo-3,5,6,7-tetra-hydro-pyrazolo-[1,2-a]pyrazole-1,2-di-carboxyl-ate.

The title compound, C17H17BrN2O5, resulted from the 1,3-dipolar cyclo-addition reaction between dimethyl acetyl-enedi-carboxyl-ate and (3-bromo-benzyl-idene)-4-methyl-5-oxopyrazolidin-2-ium-1-ide in CHCl3. The dihedral angle between the pyrazole rings (all atoms) is 32.91 (10)°; the oxo-pyrazole ring displays an envelope conformation whereas the other pyrazole ring adopts a twisted conformation. The bromo-phenyl ring subtends a dihedral angle of 88.95 (9)° with the mean plane of its attached pyrazole ring. In the crystal, the mol-ecules are linked by C-H⋯O hydrogen bonds and aromatic π-π inter-actions with an inter-centroid distance of 3.8369 (10) Å. The Hirshfeld surface analysis and fingerprint plots reveal that the mol-ecular packing is governed by H⋯H (37.1%), O⋯H/H⋯O (31.3%), Br⋯H/H⋯Br (13.5%) and C⋯H/H⋯C (10.6%) contacts. The energy framework indicates that dispersion energy is the major contributor to the mol-ecular packing.

Synthesis of pyrazolo-enaminones, bipyrazoles and pyrazolopyrimidines and evaluation of antioxidant and antimicrobial properties

• New pyrazolo-enaminones have been synthesized in three steps from DHA in good yields. • The pyrazolo-enaminone 3h shows antioxidant properties comparable to Vitamin C. • Pyrazolopyridines were prepared by double condensation of the aminopyrazoles with keto-esters. • The pyrazoles 3b , 3d , 3e and the pyrazolopyridine 4b showed activity against Gram+ and Gram− bacteria. A novel pyrazolo-enaminones, bipyrazoles and bipyrazolopyridines from 1-(5-hydroxy-3-methyl-1-phenyl-1 H -pyrazol-4-yl)butane-1,3-dione and 4-methyl-2-phenyl-2 H -pyrazolo[3,4- b ]pyridine-3,6(3 aH ,7 H )-dione have been synthesized by assisted heating with microwave radiation without any catalyst. The pyridine and pyrazole ring formation has been developed from easily accessible enamino keto esters by formylation followed by intramolecular cyclization. The general applicability for the synthesis of the important pyrazolo-enaminones, bipyrazoles and pyrazolo-pyridines heterocycles was attributed to simplicity of operation, synthesis without catalyst, energy efficiency (shorter reaction time under microwave irradiation), good yields, more environmentally friendly and more cost-effective procedure. The antioxidant activity of new heterocyclic compounds was evaluated by free radical scavenging by DPPH assay. Several of these compounds showed good activity against both Gram-positive ( S. aureus ) and Gram-negative ( E. coli ) bacteria.

Computational screening for the identification of potent tubulin inhibitors as anticancer agents

Tubulin is a biological target for several multiple clinically used anticancer drugs which is responsible for chromosome segregation, cell shape maintenance, transport, motility, and organelle dispersion, among other things. For decades, anticancer medicines that target the microtubule, such as taxanes and vinca alkaloids, have formed the cornerstone of many chemotherapy regimens. However, these medicines have substantial drawbacks, prompting the development of new microtubule targeting compounds. The pyrazole ring system is a critical component of various tubulin inhibitors discovered in recent years. In the present study, a dataset of tubulin inhibitors have been downloaded from PubMed database and included for screening study by Glide module. The Lipinski rule of 5, high-throughput virtual screening, standard precision, and extra precision methodologies have been used for final screening of potent compounds against tubulin protein (PDB ID: 3E22). The docking studies of these inhibitors revealed a complementary fit in the allosteric site of Tubulin protein. Among all the selected inhibitors, Centaureldin and Chalcones MDL showed the highest docking scores of −7.76 and −6.21 kcal/mol, respectively, when compared with the cocrystal ligands of PDB-3E22. Postmolecular mechanics/generalized born surface area analysis of these potent inhibitors showed dG binding values −37.83 and −28.37 kcal/mol, respectively. On the basis of final screened compounds, we can further develop pharmacophore model and screened potential compounds against tubulin protein.

Challenging the Limits of the Oxygen Balance of a Pyrazole Ring

Challenging the Limits of the Oxygen Balance of a Pyrazole Ring