Pyrazolone Moiety Research Articles

Organocatalyzed Asymmetric Michael Addition of 4‐Monosubstituted‐pyrazol‐5‐ones to Enones: Construction of Vicinal Quaternary and Tertiary Stereocenters

AbstractPyrazolone moiety bearing an all‐carbon quaternary stereogenic center is frequent in biologically active products and pharmaceuticals. The catalytic route for the construction of quaternary carbon centers poses a formidable challenge . In this report, catalytic asymmetric Michael addition of 4‐monosubstituted‐pyrazol‐5‐ones to simple enones catalyzed by primary amine‐Brønsted acid composite has been developed. An array of pyrazolone derivatives bearing vicinal all carbon quaternary and tertiary stereocenters, were obtained in moderate to good diastereoselectivities (up to 92 : 8 dr) and good to excellent enantiomeric excess (up to 99 % ee). In addition, antipode for enantiomers of the pyrazolone derivatives were also realized in good to high stereoselectivities (up to 92 : 8 dr and up to 98 % ee).

Design, Synthesis, Characterization, and Antimicrobial Properties of New Azo Disperse Dyes Incorporating Quinazolinone-Pyrazolone Moieties and Their Applications for Dyeing of Polyester Fabrics

The current study outlines a straightforward and efficient method for creating new quinazolinone disperse dyes based on pyrazolone moieties, starting with quinazolinone and a variety of substituted pyrazolone as couplers. The synthesized dyes were characterized using a variety of spectroscopic and analytical methods. The synthesized dyes' ultraviolet–visible spectra showed bands brought on by several molecular transitions. We investigated in detail the multifunctional characteristics such color representation, dyeing duration, concentration, pH, buildup, and fastness properties of the dyed samples. Fastness properties and colorimetric data showed satisfactory results, demonstrating the effectiveness of these dyes in dyeing polyester fabrics. A pH of 5 and a dyeing temperature of 130 °C were the ideal conditions for dyeing polyester fabrics. Additionally, an ultraviolet protection factor test was performed on the dyed fabrics, and the results showed that these dyes provide the best UV protection. These dyes are suitable for industrial dyeing applications since they are easy to manufacture and scale up. Additionally, in-vitro testing was done to determine the dyes' antibacterial effectiveness against various bacteria and fungi. The antibacterial activity of the dyes was moderate to very good against both Gram-positive and Gram-negative bacteria, as well as fungi.

Synthesis, crystal structure, biological evaluation, in silico ADME properties, enzymatic target prediction and molecular docking studies of pyrazolone-azomethine analogs

A series of twelve azomethine analogs (3a-l) of 4-aminoantipyrine (4-AA) were prepared and characterized using FT-IR, 1HNMR and EI mass spectrometric analysis. Analog 3f was obtained as a single crystal, and X-ray diffraction (XRD) data indicated its adoption of a trans configuration around the central azomethine (CN) group, forming monoclinic P2(1)/n symmetry. The unit cell of 3f contains four molecules, and its crystal packing is stabilized through significant intermolecular host-guest CH⋯O, CH⋯π, and π⋯π interactions, resulting in a stacked supramolecular structure. In vitro bactericidal and fungicidal screening of analogs 3a-l was performed against twelve bacterial and five fungal strains, respectively. Most of the analogs demonstrated weak to moderate antimicrobial activities, specifically 3a, 3b, 3e and 3g exhibited highest activity against S. boydii, B. megaterium; S. sonnei and E. coli, respectively and 3c, 3d and 3l showed potent fungicidal activity against A. flavus, C. albicans, and N. crassa, respectively. The results indicate that the antimicrobial potency is largely dependent on the nature of the aromatic ring linked pyrazolone moiety via azomethine (CN) group. DPPH free radical scavenging assay revealed analogs 3e, 3l, 3g, 3k, 3h and 3d had IC50 values of 0.07, 1.19, 2.31, 2.57, 4.04 and 4.07 µg mL−1, respectively, comparable to that of the standard ascorbic acid (IC50 = 4.10 µg mL−1). Docking simulations were conducted to elucidate the binding mode of potent antibacterial analogs (3e and 3g) and antifungal analogs (3d and 3l) within the active sites of KAS (E. coli) and CYP 51 (C. albicans) receptors, respectively. The results revealed strong binding affinities between the studied molecules and the respective proteins. All the tested analogs fulfill the condition of Lipinski's rule of five (ROF) and Veber's rule, and the calculated ADMET profile indicated favorable drug-likeness, pharmacokinetic properties, and drug scores. Ligand-based enzymatic target predictions suggest that analogs 3a-l have potential as inhibitors of kinases, enzymes, proteases, or ligands for Family A GPCR. Finally, DFT calculations using the B3LYP/6-311G(d,p) level of theory provide insights into the FMO energies, global molecular reactivity, and biological properties of the azomethine analogs of 4-AA.

Synthesis, X-Ray Diffraction, Spectroscopic Characterization, Hirshfeld Surface Analysis, Molecular Docking Studies, and DFT Calculation of New Pyrazolone Derivatives

Pyrazolones derivatives are known for their pharmaceutical and therapeutic activities. In this regard, some new pyrazolone derivatives have been synthesized using cyclocondensation, nucleophilic substitution, and alkylation reactions. Their corresponding structures were elucidated using X-ray diffraction and NMR spectroscopic techniques. The experimental spectral data were compared with the predicted ones obtained at the B3LYP/6-311++G(d,p) level of theory. Geometrical parameters and chemical shifts are relatively well reproduced with correlation coefficients higher than 90%. The intercontacts in crystal units were investigated by the analysis of their corresponding Hirshfeld surfaces and fingerprint maps, which reveal that the major contacts are found for H…H intercontacts. Finally, the inhibition efficiency of the novel pyrazolone derivatives as SARS-CoV-2 Mpro is estimated by determining their binding affinities into the binding site of SARS-CoV-2 Mpro. The docking results reveal that the current pyrazolone derivatives may act as potent inhibitors of SARS-CoV-2 Mpro and that their inhibition efficiency may be strongly influenced by the substituted functional groups of pyrazolone moiety.

Molecular docking, HOMO-LUMO and quantum chemical computation analysis of anti-glyoximehydrazone derivatives containing pyrazolone moiety and their transition metal complexes

In this study, in order to obtain biologically active compounds, a series of anti-glyoximehydrazone ligands bearing vic-dioxime, hydrazone, and pyrazole moieties and their (O•••H–O) bridged nickel(II), cobalt(II) and copper(II) metal complexes were prepared. Further, the molecular docking studies were carried out on those ligands and their nickel(II), cobalt(II) and copper(II) metal complexes to analyze the interaction with EGFR Kinase domain complexed with tak-285 (PDB ID: 3POZ) and human androgen receptor T877A mutant (PDB ID:2OZ7). In addition, the compounds were optimized by using B3LYP/6-311G+(d,p) level of Density Functional Theory (DFT) to evaluate the HOMO–LUMO contours and quantum chemical parameters. Also, bioactivity analysis were performed.Metal complexes had higher binding affinities against 3POZ and 2OZ7. The most promising compounds for 3POZ were nickel(II) and copper(II) metal complexes. However, for the 2OZ7 target receptor, cobalt(II) and copper(II) metal complexes were the possible hit compounds. Furthermore, cobalt(II) metal complex of ligand two was found to be the most reactive one among others. Moreover, it had the highest ω which is related to a potent higher electrophilic character. It was determined that all the compounds had moderate bioactivity.In conclusion, nickel(II), cobalt(II), and copper(II) complexes could be powerful hit compounds for anti-cancer drug discovery studies.

Discovery of novel danshensu derivatives bearing pyrazolone moiety as potential anti-ischemic stroke agents with antioxidant activity

Neuroprotective agents with attenuation of oxidative stress by directly scavenging ROS and indirectly through Keap1-Nrf2 signal pathway activation may be a promising cerebral ischemic stroke therapeutic strategy. In this study, a series of novel danshensu derivatives bearing pyrazolone moieties with dual antioxidant effects were synthesized for the treatment of ischemic stroke. Most compounds exhibited considerable DPPH free radical scavenging ability and neuroprotective activity against H2O2-induced oxidative injury in PC12 neuronal cells, without cytotoxicity. Among these target compounds, Del03 displayed the strongest dose-dependent neuroprotective activity in vitro, directly downregulated intracellular ROS levels, and improved the oxidative stress parameters MDA, SOD, and LDH. Del03 also promoted Nrf2 translocation to the nucleus, subsequently increasing the expression of the Nrf2 downstream target HO-1. Molecular docking analysis revealed that Del03 could anchor to the key site of Keap1. Del03 possessed the ability to penetrate blood–brain barrier and displayed good ability on pharmacokinetic properties in rats Del03 possessed good BBB penetration efficiency, suitable pharmacokinetic properties in vivo. Del03 reduced cerebral infarction volume and promoted neurological function in a middle cerebral artery occlusion (MCAO) mouse model at a dose of 20 mg/kg by intravenous injection. The characteristics of Del03 detailed in this study demonstrate its potential as a therapeutic agent in the treatment of ischemic stroke.

Antiproliferative studies of transition metal chelates of a pyrazolone based hydrazone derivative

Pyrazolone derivatives play a significant role in the treatment of cancer. The synergic effect which emerges from the combination of pyrazolone moiety with hydrazone functionality was investigated. The objective of this study was to explore the antiproliferative potential of copper(II), cobalt(II), nickel(II) and zinc(II) metal chelates synthesized from pyrazolone based hydrazone derivative. The ligand and the metal chelates were characterized by various spectroscopic and analytical studies. The ligand was characterized by single crystal X-ray diffraction analysis.The results were in line with the spectroscopic methods. The geometry optimization of ligand and metal chelates were performed using density functional theory (DFT). The invitro cytotoxicity of ligand and metal chelates against different cancer cell lines was investigated by MTT assay. The cell-viability experiments showed that copper(II) complex is an efficient cytotoxic agent against HeLa cell line. Moreover, possible inhibition mechanism of synthesized compounds was evaluated in silico against HPV16-E6 receptor. Communicated by Ramaswamy H. Sarma

Synthesis and biological evaluation of azetidinone derivatives with pyrazolone moiety

A Schiff base has been prepared by the reaction of 4-acetyl-5-methyl-2-(4-methylphenyl)-2,4-dihydro-3 H -pyrazole-3-one with different substituted amines. Treatment of this Schiff base with chlorobactyl chloride affords the corresponding azetidinone in good yield. All the new compounds have been characterized by IR, 1 H NMR, GC-MS and elemental analysis. The antibacterial activity of these compounds has been determined with the reference of standard drug.

Heterocyclic Schiff base derivatives containing pyrazolone moiety: Synthesis, characterization, and in vitro biological studies

AbstractIn this study, some pyrazolone‐based Schiff base derivatives 2a‐e (except 2a) were synthesized for the first time and structurally illuminated by some spectroscopic techniques (1H, 13C NMR, FT‐IR) and elemental analysis. All synthesized molecules were screened for their anticancer and antioxidant activities, as well as AChE, BChE, and tyrosinase inhibitory properties. The obtained results exhibited that compounds 1b (IC50 = 9.497 μΜ) and 2a (IC50 = 30.49 μΜ) significantly decreased the proliferation of HeLa cells. On the other hand, the apoptotic effects of these two compounds were investigated with acridine orange/propidium iodide double staining. The apoptotic cell ratios of the molecules treated with these two compounds were determined as 60 and 64%. Compound 2b (IC50 = 17.95 ± 0.47 μΜ) was determined to be a very active substance in the ABTS assay. Compound 2e (A0.5 = 43.75 ± 0.62 μM) indicated the closest antioxidant activity to the standard compound α‐TOC (A0.5 = 50.58 ± 0.39 μM) in the cupric reducing antioxidant capacity (CUPRAC) assay. In inhibition studies of enzymes, it was determined that compound 2c had a very active molecule in AChE, BChE, and tyrosinase inhibitory activities with 82.79 ± 1.03, 91.39 ± 1.06, and 92.60 ± 1.80% inhibition, respectively. It was determined that the target molecules 2a‐e showed better antioxidant and enzyme inhibitory activities than those of ester derivatives 1a‐e.

Catalytic asymmetric construction of C-4 alkenyl substituted pyrazolone derivatives bearing multiple stereoelements.

An organocatalytic asymmetric process was reported for the sterically precise construction of C-4 alkenyl substituted pyrazolone derivatives bearing multiple stereoelements. A series of interesting products featuring the union of a centrally chiral pyrazolone moiety and an axially chiral styrene unit were obtained in high yield with excellent diastereoselectivity and enantioselectivity (up to 99% ee, >20 : 1 dr). The process has the characteristics of mild reaction conditions, simple operation and broad substrate scope. The result of gram-scale reaction indicates that the reaction has good practicability.

Synthesis and molecular docking study of new pyrazole derivatives as potent anti-breast cancer agents targeting VEGFR-2 kinase.

Based on the previous studies that revealed the valuable role of pyrazole scaffold in cancer management and VEGFR-2 inhibition, a new set of pyrazole conjugated with pyrazoline, triazolopyrimidine and pyrazolone moieties were synthesized and investigated for their anticancer efficiency against human breast cancer MCF-7. The anticancer screening revealed the significant sensitivity of breast carcinoma towards compounds 4b, 5c, 6c, 7b, 7c and 12c with IC50 values ranging from 16.50 - 26.73µM in comparison with tamoxifen (IC50=23.31µM). Moreover, the new analogues were further examined for their VEGFR-2 inhibitory activity, among the tested derivatives 5c, 6c, 7b, 7c and 12c displayed prominent inhibitory efficiency versus VEGFR-2 kinase with % inhibition ranging from 70 to 79%. Compounds 6c, 7c and 12c revealed inhibitory efficiency in nanomolar level with IC50 (913.51, 225.17 and 828.23nM, respectively) comparing to sorafenib (IC50=186.54nM). Flow cytometric analysis revealed that the promising compound 12c prompted pre-G1 apoptosis and cell growth cessation at G2/M phase and stimulated apoptosis via activation of caspase-3. Moreover, molecular docking study of the promising derivatives was performed to highlight their binding modes and interactions with the amino acid residues of VEGFR-2 enzyme.

Structure-Activity Relationship of Phenylpyrazolones against Trypanosoma cruzi.

Chagas disease is a neglected parasitic disease caused by the parasitic protozoan Trypanosoma cruzi and currently affects around 8 million people. Previously, 2‐isopropyl‐5‐(4‐methoxy‐3‐(pyridin‐3‐yl)phenyl)‐4,4‐dimethyl‐2,4‐dihydro‐3H‐pyrazol‐3‐one (NPD‐0227) was discovered to be a sub‐micromolar inhibitor (pIC50=6.4) of T. cruzi. So far, SAR investigations of this scaffold have focused on the alkoxy substituent, the pyrazolone nitrogen substituent and the aromatic substituent of the core phenylpyrazolone. In this study, modifications of the phenyldihydropyrazolone scaffold are described. Variations were introduced by installing different substituents on the phenyl core, modifying the geminal dimethyl and installing various bio‐isosteres of the dihydropyrazolone group. The anti T. cruzi activity of NPD‐0227 could not be surpassed as the most potent compounds show pIC50 values of around 6.3. However, valuable additional SAR data for this interesting scaffold was obtained, and the data suggest that a scaffold hop is feasible as the pyrazolone moiety can be replaced by a oxazole or oxadiazole with minimal loss of activity.

Grafting of multiwalled carbon nanotubes with pyrazole derivatives: characterization, antimicrobial activity and molecular docking study.

IntroductionIt is well known that the grafted multiwalled carbon nanotubes (MWCNTs) have antibacterial activity and lower cytotoxicity. Moreover, pyrazole derivatives have a broad spectrum of biological activity due to their fertile template for many medicinal drugs. On view of these findings we report herein the hybridization between MWCNTs and some pyrazole derivatives as antibacterial agents.Materials and methodsPyrazole and pyrazolone derivatives were grafted onto the surface of carboxylated MWCNTs via the reaction of carboxylated MWCNTs and the diazonium salts of pyrazoles and pyrazolones using mixed acid treatment. The insertion of the pyrazole and pyrazolone moieties was characterized by Fourier transform infrared (FTIR) spectroscopy, energy dispersion spectroscopy, transmission electron microscopy, X-ray diffraction and thermogravimetric (TGA).ResultsThe results indicate that pyrazole and pyrazolone moieties successfully attached on carboxylated MWCNTs surface. The neat pyrazole and pyrazolone derivatives and their corresponding carbon nanotubes were tested against Staphylococcus aureus, Bacillus subtilus, Escherichia coli, and Candida albicans bacteria, and Aspergillusniger fungi. The results showed that the grafted carbon nanotubes of pyrazole and pyrazolone derivatives have better antimicrobial activity than the neat pyrazole and pyrazolone derivatives. The molecular docking studies were performed on the most potent antimicrobial compounds to investigate the existence of the interactions between the most active inhibitors and Farnesyl pyrophosphate synthase (FPPS).ConclusionThe surface of the carboxylated MWCNTs was successfully grafted with some pyrazole derivatives. The antibacterial activity was investigated for the newly synthesized compounds and indicated that the grafted MWCNTs have good antibacterial activity toward some pathogenic types of bacteria.

Synthesis and antimicrobial evaluation of some new bicyclopyrazolone‐based thiopyran ring systems

A series of bicyclopyrazolones were synthesized from the condensation reaction of methyl 4‐oxotetrahydro‐2H‐thiopyran‐3‐carboxylate with hydrazine derivatives in ethanol. All synthesized products were characterized by FT‐IR, 1H, and 13C NMR spectral data, elemental analyses, and mass spectrometry. The antibacterial and antifungal activities of these compounds were evaluated against Staphylococcus aureus and Bacillus subtilis as Gram‐positive bacteria, Escherichia coli and Pseudomonas aeruginosa as Gram‐negative bacteria, and the fungus Candida albicans. The results revealed that bicyclopyrazolones including an aryl or aryl sulfonyl group in the N‐2 position of the pyrazolone moiety are the most effective against all the microorganisms studied in this work.

Detection of Biothiols with a Fast‐Responsive and Water‐Soluble Pyrazolone‐Based Fluorogenic Probe

Non‐protein thiols such as GSH, Hcy, or Cys, are present at different concentration levels in the body depending on the thiol species and their localization (plasma, cell, urine etc···). They play vital roles in controlling redox‐mediated biological processes, and abnormal levels of biothiols are related to a variety of syndromes. In few years, fluorometric methods have gain increasing attention enabling a rapid, sensitive and spatiotemporal detection of biothiols. Herein, is reported a novel two‐step access to a water‐soluble fluorogenic probe based on the 7‐aminocoumarin dye conjugated to a pyrazolone moiety. Upon the addition of biothiols, the fluorescence is turned‐on at 485 nm by a reversible thio‐Michael addition process, which enables the detection of biothiols in the low nanomolar range.

Synthesis, thermal, spectral, antimicrobial and cytotoxicity profile of the Schiff bases bearing pyrazolone moiety and their Cu(II) complexes

A series of Schiff bases resulted in the [1 + 1] condensation of 8-alkyl-2-hydroxy-tricyclo[7.3.1.02.7]-tridecan-13-one with the 4-amino-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one, and their complexes CuL(CH3COO)2·nH2O were synthesized. The compounds were characterized by microanalytical, ESI–MS, NMR, IR, electronic and EPR spectra. Based on the ESI–MS and IR spectra, a mononuclear structure with both Schiff base and acetate as chelate was proposed for complexes. An elongated rhombic stereochemistry was assigned considering electronic and EPR data. The thermal analyses have evidenced processes as water elimination, acetate decomposition as well as oxidative degradation of the Schiff base moiety. The bioevaluation of compounds in relation to planktonic and biofilm-embedded microbial cells, as well as to human cells, indicates an improved activity of complexes over ligands. The same tendency was observed for antioxidant activity.

Facile Synthesis of a New Class of Pyrazolone Attached Chromene Derivatives Showing Good Binding with β‐Lactoglobulin

AbstractA new class of compounds having both chromene and pyrazolone moieties in the structural motif has been developed starting from 2‐hydroxychalcones and pyrazolones using amberlyst‐15 as a heterogeneous catalyst. The methodology involves a domino sequence of Michael addition, cyclisation, dehydration and aerial oxidation. Most of the compounds thus synthesised show good binding with the carrier protein β‐lactoglobulin. Molecular docking study of the compound showing best binding with the protein has been carried out.

Design, synthesis, anti-inflammatory activity and molecular docking of potential novel antipyrine and pyrazolone analogs as cyclooxygenase enzyme (COX) inhibitors

As a part of a directed program for development of new active agents, novel heterocyclic derivatives with antipyrine and pyrazolone moieties -incorporated in- have been designed and synthesized. Starting with 4-arylidene-3-methyl-1-phenyl-5-pyrazolone derivative 2a,b novel Mannich bases derivatives have been synthesized and biologically evaluated for their anti-inflammatory activity. Furthermore, the activity of such compounds has been tested interestingly as COX-1 and COX-2 inhibitors. Structure elucidation of the synthesized compounds was attained by the use of elemental analysis, IR, 1H NMR, 13C NMR, and Mass spectrometry techniques. Compounds 3b, 3d and 4b represent the high % inhibition values for both COX-1 and COX-2. On the other hand, compound 8 showed little selectivity against COX-2 while compound 10 showed good selectivity against COX-1 only. Structure activity relationship has been discussed and the results were confirmed by molecular docking calculations.

Synthesis, structural and spectroscopic studies of 1-phenyl-3-methyl-4-benzoyl-5-pyrazolone N(4)-methyl-N(4)-phenyl thiosemicarbazone and its cadmium(II) complex

Synthesis, spectral and single crystal XRD studies of a novel ligand 1-phenyl-3-methyl-4-benzoyl-5-pyrazolone N(4)-methyl-N(4)-phenylthiosemicarbazone and its cadmium(II) complex have been communicated in this work. The ligand crystallizes in triclinic system with space group P-1, a(Å)=7.8930(4), b(Å)=11.2019(5), c(Å)=13.0211(7); α(°)=96.175(3), β(°)=100.922(3)°, γ(°)=91.005(3)°, V(Å3)=1123.02(10), r(mg/m3)=1.306 and Z=2. Cadmium(II) complex crystallizes in the monoclinic crystal system with space group P21/c, unit cell dimensions a(Å)=9.6939(5), b(Å)=22.5183(11), c(Å)=21.2054(10); α(°)=90, β(°)=99.960(2), γ (°)=90, V(Å3)=4559.2(4) and Z=4. The packing of the molecules in the crystal lattice is stabilized by intermolecular hydrogen bonds. Spectroscopic data along with crystal structure, confirmed the involvement of azomethine nitrogen, thione sulphur and enolic oxygen of pyrazolone moiety in coordination with the metal ion.

Synthesis, characterization, crystal structure and theoretical studies of 4-[(E)-(3-chloro-4-hydroxyphenyl) diazenyl]-1, 5-dimethyl-2-phenyl-1, 2-dihydro-3H-pyrazol-3-one

Crystals of new heterocyclic azo compound of 4-aminoantipyrine, 4-[(E)-(3-chloro-4-hydroxyphenyl)diazenyl]-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one have been grown by slow evaporation method at room temperature and its structural characterization was performed by X- ray diffraction method. The spectroscopic characterization was also performed by FT-IR, UV–Vis, 13C and 1H NMR techniques. The compound crystallizes in the monoclinic CC space group with cell dimensions a = 12.4842 (13), b = 16.4492 (16), c = 8.3389 (8) and β = 102.698 (3)°. The phenyl ring attached to the pyrazolone moiety is disordered over two positions with an occupancy ratio 52:48. The components of the disorder were refined. DFT calculations have been performed by using B3LYP/6-311G (d,p) level basis set. The calculated vibrational frequency showed a red shift for CO and OH stretching. The natural bond orbital analysis of monomer, dimer and trimer structures reveals the absence of intramolecular hydrogen bonding; however intermolecular hydrogen bonding is observed. The cationic and anionic reactive sites of compound have been visualized on MEP surface.