Pyrazolone-Based Zn(II) Complexes Display Antitumor Effects in Mutant p53-Carrying Cancer Cells.

The synthesis and characterization of nine Schiff bases of pyrazolone ligands HLn (n = 1-9) and the corresponding zinc(II) complexes 1-9 of composition [Zn(Ln)2] (n = 1-9) are reported. The molecular structures of complexes 2, 3, 4, 8, and 9 were determined by single-crystal X-ray diffraction analysis, highlighting in all cases a distorted tetrahedral geometry around the Zn(II) ion. Density functional theory studies are performed on both the HLn ligands and the derived complexes. A mechanism of dissociation and hydrolyzation of the coordinated Schiff base ligands is suggested, confirmed experimentally by powder X-ray diffraction study and photophysical studies. Complexes 1-9 were investigated in vitro as anticancer agents, along with mutant p53 (mutp53) protein levels in human cancer cell lines carrying R175H and R273H mutp53 proteins. Only those complexes with the highest Zn(II) ion release via dissociation have shown a significant cytotoxic activity with reduction of mutp53 protein levels.

Highly efficient synthesis of isoxazolones and pyrazolones using g-C3N4·OH nanocomposite with their in silico molecular docking, pharmacokinetics and simulation studies.

An environmentally friendly, versatile multicomponent reaction for synthesizing isoxazol-5-one and pyrazol-3-one derivatives has been developed, utilizing a freshly prepared g-C3N4·OH nanocomposite as a highly efficient catalyst at room temperature in aqueous environment. This innovative approach yielded all the desired products with exceptionally high yields and concise reaction durations. The catalyst was well characterized by FT-IR, XRD, SEM, EDAX, and TGA/DTA studies. Notably, the catalyst demonstrated outstanding recyclability, maintaining its catalytic efficacy over six consecutive cycles without any loss. The sustainability of this methodology was assessed through various eco-friendly parameters, including E-factor and eco-score, confirming its viability as a green synthetic route in organic chemistry. Additionally, the gram-scale synthesis verifies its potential for industrial applications. The ten synthesized compounds were also analyzed via a PASS online tool to check their several pharmacological activities. The study is complemented by in silico molecular docking, pharmacokinetics, and molecular dynamics simulation studies. These studies discover 5D as a potential candidate for drug development, supported by its favorable drug-like properties, ADMET studies, docking interaction, and stable behavior in the protein binding cavity.

Pyrazolone-Protein Interaction Enables Long-Term Retention Staining and Facile Artificial Biorecognition on Cell Membranes.

Cell membrane genetic engineering has been utilized to confer cell membranes with functionalities for diagnostic and therapeutic purposes but concerns over cost and variable modification results. Although nongenetic chemical modification and phospholipid insertion strategies are more convenient, they still face bottlenecks in either biosafety or stability of the modifications. Herein, we show that pyrazolone-bearing molecules can bind to proteins with high stability, which is mainly contributed to by the multiple interactions between pyrazolone and basic amino acids. This new binding model offers a simple and versatile noncovalent approach for cell membrane functionalization. By binding to cell membrane proteins, pyrazolone-bearing dyes enabled precise cell tracking in vitro (>96 h) and in vivo (>21 days) without interfering with the protein function or causing cell death. Furthermore, the convenient anchor of pyrazolone-bearing biotin on cell membranes rendered the biorecognition to avidin, showing the potential for artificially creating cell targetability.

Structural characterization and keto-enol tautomerization of 4-substituted pyrazolone derivatives with DFT approach.

The synthesis of two pyrazolone derivative compounds, PYR-I(4-Acetyl-1-(4-chlorophenyl)-3-isopropyl-1H-pyrazol-5(4H)-one) and PYR-II1-(4-Chlorophenyl))-3-isopropyl-5-oxo-4,5-5-dihydro-1H-pyrazole-4-carbaldehyde, their characterization by FT-IR, NMR, UV-Vis and GC-MS techniques, and the evaluation of the keto-enol tautomerization process of the structures along with the DFT approach and spectral data were reported in this paper. Spectral findings indicated that PYR-I was stable at the keto state. The IR spectrum recorded in solid form showed that the PYR-II structure was stable in the enol state, while the NMR spectrum in the solution medium showed that it was stable in the keto state. DFT-based analyses were realized with the B3LYP hybrid functional and the 6-311++G(d,p) basis set. The modelled keto, transition and enol state molecular geometries of structures were optimized in the gas phase and different solvent media and the total energy and dipole moment values were investigated at the specified theoretical level. The possible keto-enol tautomerism mechanism of the structures was evaluated through some thermodynamic parameters such as the difference in free Gibbs energy (ΔG), enthalpy (ΔH), entropy (ΔS), and predictive tautomeric equilibrium constants (Keq), acidity constants (pKa) and percentages of tautomers at 298.15 K and 1 atm pressure. The results of these analyses based on the DFT approach indicated that the keto-enol tautomer equilibrium heavily favours the keto form for PYR-I and the enol form for PYR-II in all cases. Moreover, natural bond orbital (NBO) analysis was performed for the tautomers, and the chemical reactivity profiles of the most stable tautomers were examined with the values of frontier molecular orbital energy and some reactivity descriptors.

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.

Activity of pyridyl-pyrazolone derivatives against Trypanosoma cruzi.

New affordable drugs are needed for the treatment of infection with the protozoan parasite Trypanosoma cruzi responsible for the Chagas disease (CD). Only two old drugs are currently available, nifurtimox and benznidazole (Bz) but they exhibit unwanted side effects and display a weak activity in the late chronic phase of the disease. In this context, we evaluated the activity of a series of aryl-pyrazolone derivatives against T cruzi, using both bloodstream trypomastigote and intracellular amastigote forms of the parasite. The test compounds originate from a series of anticancer agents targeting the immune checkpoint ligand PD-L1 and bear an analogy with known anti-trypanosomal pyrazolones. A first group of 6 phenyl-pyrazolones was tested, revealing the activity of a single pyridyl-pyrazolone derivative. Then a second group of 8 compounds with a common pyridyl-pyrazolone core was evaluated. The in vitro testing process led to the identification of two non-cytotoxic and highly potent molecules against the intracellular form of T. cruzi, with an activity comparable to Bz. Moreover, one compound revealed an activity largely superior to that of Bz against bloodstream trypomastigotes, while being non-cytotoxic (selectivity index >1000). Unfortunately, the compound showed little activity in vivo, most likely due to its very limited plasma stability. However, the study opens novel perspectives for the design of new anti-trypanosomal products and the mechanism of action of the compounds is discussed.

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.

Squaramide-Catalyzed Asymmetric Mannich Reaction between 1,3-Dicarbonyl Compounds and Pyrazolinone Ketimines: A Pathway to Enantioenriched 4-Pyrazolyl- and 4-Isoxazolyl-4-aminopyrazolone Derivatives.

A series of N-Boc ketimines derived from pyrazolin-5-ones have been used as electrophiles in enantioselective Mannich reactions with different 1,3-dicarbonyl compounds. This method provides a direct pathway to access the 4-amino-5-pyrazolone derivatives bearing a quaternary substituted stereocenter and containing two privileged structure motifs, the ß-diketone and pyrazolinone substructures. The adducts were obtained in excellent yields (up to 90%) and enantioselectivities (up to 94:6 er) by employing a very low loading of 2 mol% of a quinine-derived bifunctional squaramide as an organocatalyst for a wide range of substrates. In addition, the utility of the obtained products was demonstrated through one step transformations to enantioenriched diheterocyclic systems (4-pyrazolyl-pyrazolone and 4-isoxazolyl-pyrazolone), potentially promising candidates for drug discovery.

Role of hydrazone substituents in determining the nuclearity and antibacterial activity of Zn(II) complexes with pyrazolone-based hydrazones.

Hydrazones and their metal derivatives are very important compounds in medicinal chemistry due to their reported variety of biological activities, such as antibacterial, antifungal and anticancer action. Five hydrazone-pyrazolone ligands H2Ln (n = 1-5) were prepared and fully characterized and their tautomerism was investigated in the solid state and solution. Five zinc(II) complexes 1-5 of composition [Zn(HLn)2] (n = 1 and 2), [Zn(HLn)2(H2O)2] (n = 3 and 5) and [Zn(HL4)2]n were synthesized and characterized by elemental analysis, IR, 1H, 19F, 13C, and 15N NMR spectroscopy, and ESI mass spectrometry. In addition, the structures of two ligands and three complexes were determined by single-crystal X-ray diffraction. The ligands H2L2 and H2L4 exist both in the NH,NH tautomeric form. Complexes 1 and 2 are mononuclear compounds, while complex 4 is a one-dimensional coordination compound. Density functional theory (DFT) calculations were carried out on proligands, their anions and all zinc complexes, confirming the experimental results, supporting IR and NMR assignments and giving proofs of the mononuclear diaqua structure of complexes 3 and 5. The antibacterial activity of the free ligands and the Zn(II) complexes was established against Escherichia coli and Staphylococcus aureus, and a strong efficiency has been found for Zn(II) complexes, particularly for the polynuclear 4 and the mononuclear diaqua complex 5, the latter containing a ligand with aliphatic and fluorinated substituents able to compromise the permeability of and disrupt the bacterial cell membrane.

Catalytic asymmetric Michael/cyclization reaction of 3-isothiocyanato thiobutyrolactone: an approach to the construction of a library of bispiro[pyrazolone-thiobutyrolactone] skeletons.

Here, we demonstrate the first example of 3-isothiocyanato thiobutyrolactone serving as a useful building block in the Michael/cyclization reaction with alkylidene pyrazolones for the enantioselective construction of optically active structural bispiro[pyrazolone-thiobutyrolactone] skeletons containing three contiguous stereocenters with two spiroquaternary stereocenters. These products were smoothly afforded in up to 90% yield, >20 : 1 dr and >99% ee with chiral squaramide as the catalyst under mild conditions. Notably, this is also the first example of the merger of a spirocyclic pyrazolone scaffold with a spirocyclic thiobutyrolactone scaffold, potentially useful in medicinal chemistry.

Recent advances in the applications of pyrazolone derivatives in enantioselective synthesis.

Pyrazolones and pyrazoles, featuring nitrogen-nitrogen bonds, are two of the most important classes of heterocycles, owing to their widespread occurrence in medicinal chemistry and functional materials. The last decade has witnessed a rapid increase in the construction of chiral pyrazolone and pyrazole derivatives, with the application of pyrazolone derivatives as powerful synthons. Since our last review in 2018, a large number of new achievements has emerged in this area, requiring a timely update. Thus, this review summarizes these elegant achievements based on the multiple reactive sites of different pyrazolone synthons. In addition, important mechanisms and interesting biological investigations relating to the corresponding products are also discussed.

Novel benzofurane-pyrazole derivatives with anti-inflammatory, cyclooxygenase inhibitory and cytotoxicity evaluation.

Novel benzofurane-pyrazolone hybrids have been synthesized for evaluating their anti-inflammatory and cytotoxic properties. 4-(2-chloroacetyl)-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one were reacted with α-hydroxy aldehyde or α-hydroxy ketone derivatives to obtain nine novel pyrazolone derivatives. Structures were successfully elucidated by 1H NMR, 13C NMR, IR and HRMS. Enzyme inhibitory activity was measured on cyclooxygenases (COXs) as considered to address anti-inflammatory activity. Compound 2 showed the highest activity on both COX-1 and COX-2 subtypes with 12.0 µM and 8.0 µM IC50, respectively. This activity was found close to indomethacin COX-2 inhibition measured as 7.4 µM IC50. Rest of the compounds (1, 3-9) showed 10.4-28.1 µM IC50 on COX-2 and 17.0-35.6 µM IC50 on COX-1 (Compound 1 has no activity on COX-1). Tested compounds (1-9) showed activity on NO production. Only compound was the 4, which showed a low inhibition on IL-6 levels. Cell viability was up to 60% at 100 µM for all compounds (1-9) on RAW 264.7 and NIH3T3 cell lines, thus compounds were reported to be noncytotoxic.

Discovery of Pyrazolo[3,4-d]pyridazinone Derivatives as Selective DDR1 Inhibitors via Deep Learning Based Design, Synthesis, and Biological Evaluation.

Alterations of discoidin domain receptor1 (DDR1) may lead to increased production of inflammatory cytokines, making DDR1 an attractive target for inflammatory bowel disease (IBD) therapy. A scaffold-based molecular design workflow was established and performed by integrating a deep generative model, kinase selectivity screening and molecular docking, leading to a novel DDR1 inhibitor compound 2, which showed potent DDR1 inhibition profile (IC50 = 10.6 ± 1.9 nM) and excellent selectivity against a panel of 430 kinases (S (10) = 0.002 at 0.1 µM). Compound 2 potently inhibited the expression of pro-inflammatory cytokines and DDR1 autophosphorylation in cells, and it also demonstrated promising oral therapeutic effect in a dextran sulfate sodium (DSS)-induced mouse colitis model.

Synthesis, biological evaluation, molecular modeling, and structural analysis of new pyrazole and pyrazolone derivatives as N-formyl peptide receptors agonists.

N-formyl peptide receptors (FPR1, FPR2, and FPR3) play key roles in the regulation of inflammatory processes, and recently, it was demonstrated that FPR1 and FPR2 have a dual role in the progression/suppression of some cancers. Therefore, FPRs represent an important therapeutic target for the treatment of both cancer and inflammatory diseases. Previously, we identified selective or mixed FPR agonists with pyridazinone or pyridinone scaffolds showing a common 4-(bromophenyl)acetamide fragment, which was essential for activity. We report here new pyrazole and pyrazolone derivatives as restricted analogues of the above 6-membered compounds, all exhibiting the same 4-bromophenylacetamide side chain. Most new products had low or absent FPR agonist activity, suggesting that the pyrazole nucleus was not appropriate for FPR agonists. This hypothesis was confirmed by molecular modeling studies, which highlighted that the five-membered scaffold was responsible for a worse arrangement of the molecules in the receptor binding site.

Structure-based modification of pyrazolone derivatives to inhibit mTORC1 by targeting the leucyl-tRNA synthetase-RagD interaction.

The enzyme leucyl-tRNA synthetase (LRS) and the amino acid leucine regulate the mechanistic target of rapamycin (mTOR) signaling pathway. Leucine-dependent mTORC1 activation depends on GTPase activating protein events mediated by LRS. In a prior study, compound BC-LI-0186 was discovered and shown to interfere with the mTORC1 signaling pathway by inhibiting the LRS-RagD interaction. However, BC-LI-0186 exhibited poor solubility and was metabolized by human liver microsomes. In this study, in silico physicochemical properties and metabolite analysis of BC-LI-0186 are used to investigate the addition of functional groups to improve solubility and microsomal stability. In vitro experiments demonstrated that 7b and 8a had improved chemical properties while still maintaining inhibitory activity against mTORC1. The results suggest a new strategy for the discovery of novel drug candidates and the treatment of diverse mTORC1-related diseases.

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.

A novel class of selective non-nucleoside inhibitors of human DNA methyltransferase 3A.

Screening of a small chemical library (Medicines for Malaria Venture Pathogen Box) identified two structurally related pyrazolone (inhibitor 1) and pyridazine (inhibitor 2) DNMT3A inhibitors with low micromolar inhibition constants. The uncompetitive and mixed type inhibition patterns with DNA and AdoMet suggest these molecules act through an allosteric mechanism, and thus are unlikely to bind to the enzyme's active site. Unlike the clinically used mechanism based DNMT inhibitors such as decitabine or azacitidine that act via the enzyme active site, the inhibitors described here could lead to the development of more selective drugs. Both inhibitors show promising selectivity for DNMT3A in comparison to DNMT1 and bacterial DNA cytosine methyltransferases. With further study, this could form the basis of preferential targeting of de novo DNA methylation over maintenance DNA methylation.

Design, Synthesis, and Structure-Activity Relationship Study of Pyrazolones as Potent Inhibitors of Pancreatic Lipase.

Pancreatic lipase (PL), a key target for the prevention and treatment of obesity, plays crucial roles in the hydrolysis and absorption of in dietary fat. In this study, a series of pyrazolones was synthesized, and their inhibitory effects against PL were assayed by using 4-methylumbelliferyl oleate (4-MUO) as optical substrate for PL. Comprehensive structure-activity relationship analysis of these pyrazolones led us to design and synthesize a novel compound P32 (5-(naphthalen-2-yl)-2-phenyl-4-(thiophen-2-ylmethyl)-2,4-dihydro-3H-pyrazol-3-one) as a potent mixed-competitive inhibitor of PL (IC50 =0.30 µM). In addition, P32 displayed some selectivity over other known serine hydrolases. A molecular docking study for P32 demonstrated that the inhibitory activity of P32 towards PL could be attributed to the π-π interactions of 2-naphthyl unit (R1 ) and hydrophobic interactions of phenyl moiety (R3 ) with the active site of PL. Thus, P32 could serve as promising lead compound for the development of more efficacious and selective pyrazolones-type PL inhibitors for biomedical applications.

New substituted pyrazolones and dipyrazolotriazines as promising tyrosyl-tRNA synthetase and peroxiredoxin-5 inhibitors: Design, synthesis, molecular docking and structure-activity relationship (SAR) analysis.

New substituted pyrazolone and dipyrazolotriazine derivatives have been synthesized, designed and well characterized as promising dual antimicrobial/antioxidant agents to overcome multidrug resistant bacteria (MDR), oxidative stress and their related diseases. Among all strains, S. aureus was found to be the most susceptible for all compounds except 10b and 12b. Out of the three investigated series, sulfonamide analogues 5a-c displayed excellent antibacterial activity with 5b (MIC = 7.61 µM) and 5a (MIC = 8.98 µM) displaying activity that exceeds the reference drug tetracycline (MIC = 11.77 µM). The same sulfonamide derivatives 5a-c demonstrates high ABTS scavenging capacity comparable to standard. Moreover, the structure-activity relationship (SAR) revealed that benzenesulfonamide is a crucial group for enhancing activity. Molecular docking studies of the potent analogues were performed by targeting the crystal structures of S. aureus tyrosyl-tRNA synthetase and human peroxiredoxin-5 enzymes and the obtained results supported well the in vitro data revealing stronger binding interactions. Pharmacokinetics prediction together with modeling outcomes suggests that our sulfonamide derivatives may serve as useful lead compounds for the treatment of infectious disease.

A Therapeutic Journey of 5-Pyrazolones as a Versatile Scaffold: A Review.

A sizeable proportion of currently marketed drugs come from heterocycles. The heterocyclic moiety 5-pyrazolone is well known five-membered ring containing nitrogen. Derivatives of this wonder nucleus have exhibited activities as diverse as antimicrobial, anti-inflammatory, analgesic, antidepressant, anticonvulsant, antidiabetic, antihyperlipidemic, antiviral, antitubercular, antioxidant, anticancer and antiviral, including action against severe acute respiratory syndrome (SARS) or 3C protease inhibitor. A number of drugs based on this motif have already made it to the market. Standard texts and literature on medicinal chemistry cite different approaches for the synthesis of 5- pyrazolones. The present review provides an insight view to 5-pyrazolone synthesis, their biological profile and structure-activity relationship studies.