Pyrazolone Compounds Research Articles

Diverse Pharmacological Potential of different Substituted Pyrazole Derivatives.

The chemistry of heterocyclic compounds has been a topic of research interest. Some five-membered heterocyclic compounds have been the subject of extensive research due to their different types of pharmacological effects. The five-membered nitrogen-containing heterocyclic compounds pyrazole, pyrazoline, and pyrazolone derivatives have a lot of interest in the fields of medical and agricultural chemistry due to their diverse spectrum of therapeutic activities. Various substituted pyrazole, pyrazoline, and pyrazolone compounds exhibited diverse pharmacological effects like Anti-microbial, anti-inflammatory, anti-tubercular, anti-fungal, anti-malarial, anti-diabetic, diuretic, anti-depressant, anticonvulsant, antioxidant, anti-leishmanial, antidiabetic, and antiviral, etc. In recent decades, the synthesis of numerous pyrazole, pyrazoline, and pyrazolone derivatives by different synthetic methods as well as research into their chemical and biological behavior have become more important. This review focuses on synthetic methods of the pyrazole, pyrazoline, and pyrazolone derivatives, which have significant biological properties and a variety of applications.

Energetic features of H-bonded and antiparallel π-stacked supramolecular assemblies in pyrazolones: Experimental, computational and biological analyses

The work presented herein outlines a straightforward synthetic route to produce a series of pyrazolone compounds, which are significant in both coordination chemistry and pharmaceutical research. These heterocyclic compounds were thoroughly characterized using FTIR, 1H and 13C NMR spectroscopy, and their molecular structures were conclusively determined through X-ray crystallography. The resulting supramolecular architectures feature a variety of noncovalent interactions, including conventional NH…O and CH…O hydrogen bonds, CH…halogen contacts, CH…N interactions, and offset π-π stacking. Density Functional Theory (DFT) calculations, alongside Molecular Electrostatic Potential (MEP) surface analysis and Quantum Theory of Atoms in Molecules (QTAIM)/Non-Covalent Interaction (NCI) plot methodologies, were employed to probe these interactions further. This analysis highlighted the significance of both CH…O and NH…O hydrogen bonds and revealed the critical role of antiparallel π-stacking interactions, particularly within chlorophenyl and benzonitrile substituted pyrazolones, underscoring their stabilizing effects on the molecular structure. Biological assessment against urease enzyme unveiled compound 3a as the lead inhibitor with an IC50 value of 0.71 ± 0.09 μM and 31-folds strong inhibition than thiourea, thus making pyrazolone heterocycles as potential drug candidates.

Pyrazolone compounds could inhibit CES1 and ameliorates fat accumulation during adipocyte differentiation

Carboxylesterase 1 (CES1), a member of the serine hydrolase superfamily, is involved in a wide range of xenobiotic and endogenous substances metabolic reactions in mammals. The inhibition of CES1 could not only alter the metabolism and disposition of related drugs, but also be benefit for treatment of metabolic disorders, such as obesity and fatty liver disease. In the present study, we aim to develop potential inhibitors of CES1 and reveal the preferred inhibitor structure from a series of synthetic pyrazolones (compounds 1–27). By in vitro high-throughput screening method, we found compounds 25 and 27 had non-competitive inhibition on CES1-mediated N-alkylated d-luciferin methyl ester (NLMe) hydrolysis, while compound 26 competitively inhibited CES1-mediated NLMe hydrolysis. Additionally, Compounds 25, 26 and 27 can inhibit CES1-mediated fluorescent probe hydrolysis in live HepG2 cells with effect. Besides, compounds 25, 26 and 27 could effectively inhibit the accumulation of lipid droplets in mouse adipocytes cells. These data not only provided study basis for the design of newly CES1 inhibitors. The present study not only provided the basis for the development of lead compounds for novel CES1 inhibitors with better performance, but also offered a new direction for the explore of candidate compounds for the treatment of hyperlipidemia and related diseases.

Antimicrobial Properties Of Pyrazolone Compounds With Their Qsar Investigations

The present paper reports the analysis and the antimicrobial activity viz. antifungal activity of some pyrazolone compounds which were performed against Alternaria solani using disc diffusion method on nutrient agar and nutrient broth media. The compounds were characterized by elemental analysis and spectral studies. Result of antimicrobial screening indicated that compounds 4-Amino antipyrine thiosemicarbazone, 1-(2-Chloro-5-sulfophenyl)-3-methyl-5-pyrazolone and 1-(4 -Sulfoamidophenyl)-3-methyl-5-pyrazolone were found to be the most potent/active against A. solani. Correlation studies between different computed properties of the compounds with their biological activity, QSAR (Quantitative Structure Activity Relationship) investigations with a stepwise linear regression analysis were conducted. The studies are carried out using Hyperchem 8.0 version software using AM1, PM3, MNDO and ZINDO methods. Selected QSAR/ 3D-QSAR equations including different physical parameters of these series are reported.

N-Heterocyclic Carbene (NHC)-Catalyzed [3+2] Cycloaddition to Highly Diastereoselective Synthesis of Spirooxindole Dihydrofuran Fused Pyrazolone Compounds

N-Heterocyclic Carbene (NHC)-Catalyzed [3+2] Cycloaddition to Highly Diastereoselective Synthesis of Spirooxindole Dihydrofuran Fused Pyrazolone Compounds

Multicomponent approach to the synthesis and spectral characterization of some 3,5-pyrazolididione derivatives and evaluation as anti-inflammatory agents

Pyrazolones are a class of heterocyclic compounds that contain a pyrazole ring fused to a ketone group. Recent scientific research has focused extensively on the potential anti-inflammatory properties of pyrazolone compounds due to their diverse pharmacological effects in alleviating inflammation and reducing fever. This motivated us to focus on the preparation of these derivatives in a simple and eco-friendly manner. A convenient new green methodology was modified for the preparation of 1-phenyl-3,5-pyrazolidinedione by the sonicated MCR of diethyl malonate, phenylhydrazine, and a catalytic amount imidazole as homogenous organic catalyst in water green solvent in a good yield. On the other hand, some of 4-arylidinepyrazolidinedione derivatives are prepared in the same manner via the treatment of a mixture of diethyl malonate, phenylhydrazine, aromatic aldehydes, and a catalytic amount of imidazole in an aqueous medium. Our target synthesized pyrazolidinediones were elucidated via elemental and several spectral analyses. Due to the importance of pyrazolidinediones in the field of treating inflammation and relieving pain, a number of prepared compounds were chosen to test their efficacy as anti-inflammatory agents using carrageenan-induced foot edema in rats and compare the results with indomethacin, the standard drug. We found that the majority of derivatives yield promising results spanning from good to wonderful, so derivatives (15k, 15b, 15h, 15a, and 15j) yield the best results while derivative (15i) yields an average result. As for the derivative (15f), it yields the lowest results compared to the standard drug. This is due to the difference in the structural composition of these derivatives, which increases the likelihood of their use as anti-inflammatory derivatives.

In-Silico QSAR Studies of Some Pyrazolone Compounds

In-silico studies are fascinating the workers/scientists working in the field of drugs designing. The present paper includes QSAR studies related to some novel substituted pyrazolone derivatives. A series of seven pyrazolone compounds is taken for these studies. All the compounds were evaluated for antimicrobial activity against six different microbes viz. bacterial and fungal microbes. Their reported antimicrobial activities were used for Quantitative Structure Activity Relationship (QSAR) studies. The correlation between different computed molecular descriptor of the compounds with their reported biological activities has also been studied and reported in the paper.

Enhancement by pyrazolones of colistin efficacy against mcr-1-expressing E. coli: an in silico and in vitro investigation.

Owing to the emergence of antibiotic resistance, the polymyxin colistin has been recently revived to treat acute, multidrug-resistant Gram-negative bacterial infections. Positively charged colistin binds to negatively charged lipids and damages the outer membrane of Gram-negative bacteria. However, the MCR-1 protein, encoded by the mobile colistin resistance (mcr) gene, is involved in bacterial colistin resistance by catalysing phosphoethanolamine (PEA) transfer onto lipid A, neutralising its negative charge, and thereby reducing its interaction with colistin. Our preliminary results showed that treatment with a reference pyrazolone compound significantly reduced colistin minimal inhibitory concentrations in Escherichia coli expressing mcr-1 mediated colistin resistance (Hanpaibool et al. in ACS Omega, 2023). A docking-MD combination was used in an ensemble-based docking approach to identify further pyrazolone compounds as candidate MCR-1 inhibitors. Docking simulations revealed that 13/28 of the pyrazolone compounds tested are predicted to have lower binding free energies than the reference compound. Four of these were chosen for in vitro testing, with the results demonstrating that all the compounds tested could lower colistin MICs in an E. coli strain carrying the mcr-1 gene. Docking of pyrazolones into the MCR-1 active site reveals residues that are implicated in ligand-protein interactions, particularly E246, T285, H395, H466, and H478, which are located in the MCR-1 active site and which participate in interactions with MCR-1 in ≥ 8/10 of the lowest energy complexes. This study establishes pyrazolone-induced colistin susceptibility in E. coli carrying the mcr-1 gene, providing a method for the development of novel treatments against colistin-resistant bacteria.

SYNTHESIS, DOCKING STUDY, AND BIOLOGICAL EVALUATION OF 4-AMINOANTIPYRINE-ISONIAZID DERIVATIVES AS A HYBRID ANTIBACTERIAL AND ANALGESIC AGENTS

Background: 4-aminoantipyrine is one of the pyrazolone derivatives, it has been exposed to a large range of biological activities as an antimicrobial, analgesic, antiviral, anti-inflammatory, and anticancer compound. One of the important derivatives is the hybrid pyrazolone which includes two organic or inorganic drugs attached to give new pharmaceutical agents which may be the same or different activity from the original drugs. Aim: This research aimed to synthesize novel compounds derived from 4-aminoantipyrine and test their biological activity. Methods: Synthesis of 4-aminoantipyrine derivatives, which contain structurally two heterocyclic moieties, pyrazolone with oxadiazole, triazole, or tetrazole rings. The structures of the compounds were identified by 1H-NMR and FT-IR spectroscopy. The in vitro, developed compounds were screened for their analgesic activity and antibacterial activity against medically important gram (+) and gram (-) bacterial strains. Results: The antibacterial evaluation tests showed that some compounds gave good activity and others had no activity. The analgesic activity referred that the synthesized compounds had promising potency. The free binding energy (S) of the compounds with the protein 6B73 were ?4.90 to ?8.76 kcal/mol, whereas free energy (S) with the protein 5C1M gave ?4.94 to ?9.21 kcal/mol. Discussion: Among the tested compounds, it was found that compounds 1a, 4b, and 5a had more potent antibacterial activity. The analgesic activity showed that compounds 1b, 4b, and 5a gave the best activity using hot plate methods compared with the standard drug. On the other hand, compounds 1a, 4b, and 5b gave good activity using the writhing test method. Conclusions: Potent, good, or moderate analgesic and antibacterial agents were synthesized using simple and high-yield chemical reactions. The chemical reactions include the synthesis of hybrid antibacterial and analgesic agents using pyrazolone compounds.

Catalytic and Multicomponent Reactions for Green Synthesis of Some Pyrazolone Compounds and Evaluation as Antimicrobial Agents.

A green synthetic approach and facile method was developed to produce pyrazole compounds (6a–d) by the reaction of ethyl acetoacetate (1), hydrazines (2a–d), and catalytic imidazole (3) in aqueous media. 4-Dicyanomethylene-2-pyrazoline-5-one derivatives (14a–d) were synthesized through the reaction of 2-pyrazoline-5-one derivatives (6a–d) with tetracyanoethylene (TCE) (7) by using catalytic imidazole (3) in an aqueous medium. Moreover, the 4-dicyanomethylene derivative (16) was obtained via treatment of 1-phenyl-3,5-pyrazolidinedione (15) with TCE (7). The spiropyrazoleoxirane derivatives (18 and 20) were prepared by treating the precursor 4-dicyanomethylene-2-pyrazoline-5-one derivative (14b) with hydrogen peroxide in various polar solvents under alkaline conditions. The spiropyrazole oxirane derivative (18) was used as a precursor for the design of functionalized pyrazolone derivatives (24 and 27a, b). The chemical structure of the novel designed derivatives was ascertained based on elemental analyses, mp, thin-layer chromatography, and spectral analyses. Furthermore, some of the synthesized derivatives were examined against different pathogenic bacterial and fungal strains. Their results demonstrated that some of them revealed notable antimicrobial activities.

590 Biological and in-silico characterization of pyrazole and pyrazolone derivatives: Identifies novel anti-skin cancer, antioxidant and tyrosinase inhibitory agents

The psychosocial burden akin to cutaneous conditions such as cancer and hyperpigmentation disorders, make their management very sensitive. Current therapeutic interventions, are associated with side-effects, cost, invasiveness and bioavailability issues. Herein, 26 new pyrazole and pyrazolone compounds were synthesized via microwave-assisted reactions and their pharmacokinetic parameters ADMET predicted by in-silico methods. In addition, these compounds were evaluated for their anti-proliferative, antioxidant, anti-tyrosinase effects.

1,3-diarylpyrazolones as potential anticancer agents for non-small cell lung cancer: Synthesis and antiproliferative activity evaluation.

A series of pyrazolone compounds with different substitution patterns have been synthesized using microwave-assisted methods and evaluated their in vitro antiproliferative activity against human lung adenocarcinoma cell lines (A549 and NCI-H522). Among the tested compounds, the pyrazolone P7 exhibited high antiproliferative activity against both A549 and NCIH522 cancer cell lines while being 10 times less cytotoxic to non-cancerous cells. Moreover, our compounds P7 and P11 exhibited higher antiproliferative activity and selectivity against A549 and NCIH522 cells compared with the clinically approved drugs Afatinib and Gefitinib. The cell cycle analysis showed that the compound P7 and P11 arrests the cell cycle at G0/G1 phase, whereas the compounds P13 and P14 involved in G2/M phase arrest. The results from antiproliferative activity screening, cell cycle analysis, and kinase profiling indicate that the suitably substituted 1,3-diarylpyrazolones exhibit high antiproliferative activity against non-small cell lung cancer cells.

Design and synthesis of pyrazolone-based compounds as potent blockers of SARS-CoV-2 viral entry into the host cells

SARS-CoV-2 are enveloped positive-stranded RNA viruses that replicate in the cytoplasm. It relies on the fusion of their envelope with the host cell membrane to deliver their nucleocapsid into the host cell. The spike glycoprotein (S) mediates virus entry into cells via the human Angiotensin-converting enzyme 2 (hACE2) protein located on many cell types and tissues' outer surface. This study, therefore, aimed to design and synthesize novel pyrazolone-based compounds as potential inhibitors that would interrupt the interaction between the viral spike protein and the host cell receptor to prevent SARS-CoV 2 entrance into the cell. A series of pyrazolone compounds as potential SARS-CoV-2 inhibitors were designed and synthesized. Employing computational techniques, the inhibitory potentials of the designed compounds against both spike protein and hACE2 were evaluated. Results of the binding free energy from the in-silico analysis, showed that three compounds (7i, 7k and 8f) and six compounds (7b, 7h, 7k, 8d, 8g, and 8h) showed higher and better binding high affinity to SARS-CoV-2 Sgp and hACE-2, respectively compared to the standard drugs cefoperazone (CFZ) and MLN-4760. Furthermore, the outcome of the structural analysis of the two proteins upon binding of the inhibitors showed that the two proteins (SARS-CoV-2 Sgp and hACE-2) were stable, and the structural integrity of the proteins was not compromised. This study suggests pyrazolone-based compounds might be potent blockers of the viral entry into the host cells.

Discovery of pyrazolones as novel carboxylesterase 2 inhibitors that potently inhibit the adipogenesis in cells

Carboxylesterase 2 (CES2) is one of the most important Phase I drug metabolizing enzymes in the carboxylesterase family. It plays crucial roles in the bioavailability of oral ester prodrugs and the therapeutic effect of some anticancer drugs such as irinotecan (CPT11) and capecitabine. In addition to the well-known roles of CES2 in xenobiotic metabolism, the enzyme also participates in endogenous metabolism and the production of lipids. In this study, we synthesized a series of pyrazolones and assayed their inhibitory effects against CES2 in vitro. Structure-activity relationship analysis of these pyrazolones reveals that the introduction of 4-methylphenyl unit (R1), 4-methylbenzyl (R2) and cyclohexyl (R3) moieties are beneficial for CES2 inhibition. Guided by these SARs results, 1-cyclohexyl-4-(4-methylbenzyl)-3-p-tolyl-1H- pyrazol-5(4H)-one (27) was designed and synthesized. Further investigations demonstrated that the compound 27 exhibited stronger CES2 inhibition activity with a lower IC50 value (0.13 μM). The inhibition kinetic study demonstrated that compound 27 inhibited the hydrolysis of CES2-fluorescein diacetate (FD) through non-competitive inhibition. In addition, the molecular docking showed that the core of pyrazolone, the cyclohexane moiety, 4-methylbenzyl and 4-methylphenyl groups in compound 27 all played important roles with the amino acid residues of CSE2. Also, compound 27 could inhibit adipocyte adipogenesis induced by mouse preadipocytes. In brief, we designed and synthesized a novel pyrazolone compound with a strong inhibitory ability on CES2 and could inhibit the adipogenesis induced by mouse preadipocytes, which can be served as a promising lead compound for the development of more potent pyrazolone-type CES2 inhibitors, and also used as a potential tool for exploring the biological functions of CES2 in human being.

Synthesis and Evaluation of Biological Activity of Pyrazolone Compounds

Synthesis and Evaluation of Biological Activity of Pyrazolone Compounds

Synthesis of New Derivatives of Pyrazolone Compounds

Synthesis of New Derivatives of Pyrazolone Compounds

Finding potent inhibitors for COVID-19 main protease (Mpro): an in silico approach using SARS-CoV-3CL protease inhibitors for combating CORONA

SARS-CoV-2 is liable for the worldwide coronavirus disease (COVID-19) exigency. This pandemic created the need for all viable treatment strategies available in the market. In this scenario, computer-aided drug design techniques can be efficiently applied for the quick identification of promising drug repurposing candidates. In the current study, we applied the molecular docking approach in conjugation with molecular dynamics (MD) simulations to find out potential inhibitors against Mpro of SARS-CoV-2 from previously reported SARS-3CL protease inhibitors. Our results showed that N-substituted isatin derivatives and pyrazolone compounds could be used as a potent inhibitor and may possess an anti-viral activity against SARS-CoV-2. However, further experimental investigation and validation of the selected hits are required to find out their suitability for clinical trials. Communicated by Ramaswamy H. Sarma

Application of Pyrazolone Compounds in Catalytic Asymmetric Reactions

Application of Pyrazolone Compounds in Catalytic Asymmetric Reactions

Experimental and theoretical study on structure-tautomerism among edaravone, isoxazolone, and their heterocycles derivatives as antioxidants

Edaravone is a heterocyclic pyrazolone compound. It has pronounced effect against free radicals, however renal and hepatic disorders have been reported. Isoxazolones are considered bioisosteric analogues of pyrazolones and may have comparable properties. Thus, we investigated the structural and electronic influences for edaravone, isoxazolone, and their tautomers on antioxidant process. Structure and tautomerism study among edaravone, isoxazolone and their heterocycles derivatives were related to antioxidant mechanisms by using the hybrid DFT method B3LYP with the basis sets 6-31++G(2d,2p). The CH tautomer was the most stable and energetically favored among them. Intramolecular NHN hydrogen bonds and polar medium were responsible for the low energy differences among all possible tautomers. NH tautomers in both systems proved to be better antioxidant by SET (single electron transfer), while OH tautomers were better antioxidant on HAT (homolytic hydrogen atom transfer) mechanism. Theoretical calculation showed that edaravone is more potent than phenylisoxazolone, however, both has similar antioxidant scavenging on experimental DPPH. The carbonyliminic system played a very important role in the antioxidant activity for both studied classes.

The catalytic asymmetric synthesis of CF3-containing spiro-oxindole-pyrrolidine-pyrazolone compounds through squaramide-catalyzed 1,3-dipolar cycloaddition.

Pharmaceutically important compounds were synthesized through the organocatalytic 1,3-dipolar cycloaddition reaction. In the presence of a cinchonine-derived squaramide catalyst, the cycloaddition of N-2,2,2-trifluoroethylisatin ketimines with α,β-unsaturated pyrazolones gave a spiro-pyrrolidine-linked oxindole and pyrazolone compound bearing four consecutive stereocenters and two vicinal spiroquaternary chiral centers, in excellent yields and stereoselectivities.