Pyrazolone Derivatives Research Articles

Highly Tunable 4-Phosphoryl Pyrazolone Receptors for Selective Rare-Earth Separation

Highly selective rare-earth separation has become increasingly important due to the indispensable role of these elements in various cutting-edge technologies including clean energy. However, the similar physicochemical properties of rare-earth elements (REEs) render their separation very challenging, and the development of new selective receptors for these elements is potentially of very considerable economic and environmental importance. Herein, we report the development of a series of 4-phosphoryl pyrazolone receptors for the selective separation of trivalent lanthanum, europium, and ytterbium as the representatives of light, middle, and heavy REEs, respectively. X-ray crystallography studies were employed to obtain solid-state structures across 11 of the resulting complexes, allowing comparative structure-function relationships to be probed, including the effect of lanthanide contraction that occurs along the series from lanthanum to europium to ytterbium and which potentially provides a basis for REE ion separation. In addition, the influence of ligand structure and lipophilicity on lanthanide binding and selectivity was systematically investigated via n-octanol/water distribution and liquid-liquid extraction (LLE) studies. Corresponding stoichiometry relationships between solid and solution states were well established using slope analyses. The results provide new insights into some fundamental lanthanide coordination chemistry from a separation perspective and establish 4-phosphoryl pyrazolone derivatives as potential practical extraction reagents for the selective separation of REEs in the future.

Recent Developments on Synthesis of Organofluorine Compounds Using Green Approaches

Abstract: The synthesis of organofluorine compounds plays a vital role in the field of pharmaceuticals, agrochemicals, and materials since the fluorine-containing compounds have shown improved biological and physicochemical properties. Significant research has been directed towards synthesizing organofluorine compounds because organofluorine compounds have been displayed in several biological activities, including anticancer, antitumor, antihypertensive, antidepressant, anti-HIV and treatment of stroke. Due to several pharmaceutical applications of organofluorine compounds, numerous conventional as well as green synthetic methodologies have been developed for the synthesis of fluorine-containing compounds. However, particularly, the synthesis of organofluorine compounds using green approaches has been continuously attracting research interest since green approaches have several advantages, including the use of inexpensive and nontoxic reagents, catalytic, highly efficient, short reaction time, energy efficient, high reaction yields, and environmentally benign over the conventional methods. Among the green tools, the use of microwave-assisted synthesis, water, and ionic liquids as green solvent/reaction media, organocatalysts, photocatalysts, and solvent-free and catalyst-free reaction conditions have been exploited in the past decades for the synthesis of organofluorine compounds. In this review, we highlighted the recent developments in various green methods for the synthesis of organofluorine compounds via electrophilic fluorination for synthesis of various fluorohydrins, fluorinated acyclic & cyclic β -ketoesters, 1,3-dicarbonyl compounds, cyclic and acyclic ketones, α - cyanoesters, α-aryl-tetralones, α-amino acids, flavanones, and several fluorinated heterocycles such as fluorinated pyridine, pyrimidine, pyrrole, pyrazolone, benzofuran, indole, flavanone, and coumarin derivatives. In addition, some green methodologies have been highlighted for the synthesis of biologically active fluorinated compounds, including HIV-1 integrase inhibitors, 20-deoxy-20-fluorocamptothecin, fluorinated estrone, sclareolide, BMS- 204352 (MaxiPost), fluorinated naproxen and fluoxetine.

Electrochemical Oxidative Cross‐Coupling of Pyrazolones and Diselenides to Construct C‐Se Bonds

AbstractOrganoselenium compounds are important molecules owing to their value in medicinal chemistry, material chemistry and biochemistry. The selenation of pharmaceutical molecules is a promising way to find new drugs. Herein, we introduced an electrochemical oxidative cross‐coupling of pyrazolones and diselenides without transition‐metal catalyst and external oxidant. Various pyrazolones and diselenides were compatible, generating the desired products in up to 86% yield. Preliminary mechanistic investigation suggested that a radical/radical cross‐coupling process might be involved in this transformation. This method provides a green and convenient route for directly installing a selenium moiety into bioactive pyrazolone derivatives, which possesses great application potential.

The anticancer and EGFR-TK/CDK-9 dual inhibitory potentials of new synthetic pyranopyrazole and pyrazolone derivatives: X-ray crystallography, in vitro, and in silico mechanistic investigations

Treatment options for the management of breast cancer are still inadequate. This inadequacy is attributed to the lack of effective targeted medications, often resulting in the recurrence of metastatic disorders. Cumulative evidence suggests that epidermal growth factor receptor (EGFR-TK) and cyclin-dependent kinases-9 (CDK-9) overexpression correlates with worse overall survival in breast cancer patients. Pyranopyrazole and pyrazolone are privileged options for the development of anticancer agents. Inspired by this proven scientific fact, we report here the synthesis of two new series of suggested anticancer molecules incorporating both heterocycles together with their characterization by IR, 1H NMR, 13C NMR, 13C NMR-DEPT, and X-ray diffraction methods. An attempt to get the pyranopyrazole-gold complexes was conducted but unexpectedly yielded benzylidene-2,4-dihydro-3H-pyrazol-3-one instead. This unexpected result was confirmed by X-ray crystallographic analysis. All newly synthesized compounds were assessed for their anti-proliferative activity against two different human breast cancer cells, and the obtained results were compared with the reference drug Staurosporine. The target compounds revealed variable cytotoxicity with IC50 at a low micromolar range with superior selectivity indices. Target enzyme EGFR-TK and CDK-9 assays showed that compounds 22 and 23 effectively inhibited both biological targets with IC50 values of 0.143 and 0.121 µM, respectively. Molecular docking experiments and molecular dynamics simulation were also conducted to further rationalize the in vitro obtained results. Communicated by Ramaswamy H. Sarma

Optimization of BAX trigger site activator BTSA1 with improved antitumor potency and in vitro ADMET properties

Direct activation of the pro-apoptotic protein BAX represents a potential therapeutic strategy to trigger apoptosis in cancer. Herein, structural optimization of the reported BAX trigger site activator BTSA1 turned out into a series of pyrazolone derivatives, where compound 6d exhibited significantly enhanced antiproliferative effects and apoptosis induction ability compared to BTSA1. Mechanism of action studies revealed that compound 6d could initiate the BAX activation cascade, promoting BAX insertion into mitochondrial membranes and activating MOMP, ultimately leading to the release of cytochrome c and apoptosis. Furthermore, 6d showed significantly improved in vitro stability and CYPs profile compared to BTSA1. This work may lay a foundation to develop potent BAX trigger site activators for the treatment of BAX-expressing malignancies.

Synthesis and DFT supported spectroscopic characterization of a pyrazolone Schiff base complex of RuII-NO core

Due to the fact of fascinating properties of 4-aminoantipyrene and other pyrazolone derivatives, this work is mainly focused on the synthesis of Schiff base complex of Ru-NO core containing pyrazolone as the main ligand functionality. Several spectroscopic and spectrometric techniques in association with theoretical approach (DFT) have been applied to elucidate the structure of the complex. In addition to the characterization, parameters that decide to label the given compound as a significant nitric oxide releasing molecule (NORM) have been discussed. DFT based computational studies using LANL2DZ/B3LYP and 6-31 G(d,p)/B3LYP formalism, respectively for Ru and nonmetallic atoms of the complex have been used to deal with the NO-releasing phenomenon. From the results discussed herein it is evident that the complex can release NO at the cost of low energy radiation.

Squaramide-catalyzed asymmetric regioselective allylic alkylation of 4-aminopyrazolones with Morita-Baylis-Hillman carbonates.

An efficient squaramide-catalyzed asymmetric allylic alkylation of 4-aminopyrazolones with various MBH carbonates via different pathways has been described. This method provides access to a series of pyrazolone derivatives bearing a nitrogen-containing quaternary stereocenter in high yields with excellent enantioselectivities and regioselectivities under mild conditions. In addition, we utilized the target products to construct a range of bi-heterocyclic skeletons through [3 + 2] cycloadditions. These novel hybrid heterocycles would be promising candidates for drug-discovery programs and chemical biology.

Pyrazolone-type compounds (part II): in vitro and in silico evaluation of antioxidant potential; structure-activity relationship.

The pyrazolone class comprises a variety of hybrid compounds displaying diverse biological actions. Although studied for decades, these compounds are still of interest due to their facile chemical transformations. In our previous work, we presented the synthetic route of functionalised pyrazolone derivatives. The presence of pyrazolone structural motif in many drugs, such as edaravone, prompted us to investigate the antioxidant features of the selected compounds. In this paper, we provide an extensive in vitro and in silico description of the antioxidant properties of selected pyrazolone analogues. The obtained in vitro results revealed their great antiradical potency against the DPPH radical (IC50 values in the 2.6-7.8 μM range), where the best results were obtained for analogues bearing a catechol moiety. Density functional theory (DFT) was used to assess their antioxidant capacity from the thermodynamic aspect. Here, good agreement with in vitro results was achieved. DFT was employed for the prediction of the most preferable radical scavenging pathway, also. In polar solvents, the SPLET mechanism is a favourable scavenging route, whereas in nonpolar solvents the HAT is slightly predominant. Furthermore, antioxidant mechanisms were studied in the presence of relevant reactive oxygen species. The obtained values of the reaction enthalpies with the selected radicals revealed that HAT is slightly prevailing in polar solvents, while the SPLET mechanism is dominant in nonpolar solvents. Regarding the well-known antioxidant features of the drug edaravone, these findings represent valuable data for this pyrazolone class and could be used as the basis for further investigations.

Pyrazolone derivatives as potent and selective small-molecule SIRT5 inhibitors

Sirtiun 5 (SIRT5) is a NAD+-dependent protein lysine deacylase. It is emerging as a promising target for the development of drugs to treat cancer and metabolism-related diseases. In this study, we screened 5000 compounds and identified a hit compound 14 bearing a pyrazolone functional group as a novel SIRT5-selective inhibitor. Structure-based optimization of 14 resulted in compound 47 with an IC50 value of 0.21 ± 0.02 μM and a 100-fold improved potency. Compound 47 showed substantial selectivity for SIRT5 over SIRT1-3 and SIRT6. Biochemical studies suggest that 47 does not occupy the NAD + -binding pocket and acts as a substrate-competitive inhibitor. The identified potent and selective SIRT5 inhibitors allow further studies as research tools and therapeutic agents.

Computational and experimental investigation on biological and photophysical properties of high yielded novel aryl-substituted pyrazolone analogue

A series of new aryl-substituted pyrazolone derivatives 5(a-h) were synthesised via the Baylis-Hillman acetate reaction with pyrazolones and tested for antifungal, antibacterial, and antioxidant properties in vitro. Among the tested molecules 5d and 5e show good in vitro antifungal and antibacterial activities due to the presence of fluorine, which enhances the absorption rate by increasing lipid solubility and improves the pharmacological activity. It is also evident from the results obtained from structure-activity relationship (SAR) studies. Further, the photophysical properties of synthesized compounds were theoretically estimated using the ab-intio technique. The ground state optimization and HOMO–LUMO energy levels are calculated using the DFT-B3LYP-6-311 basis set. Using the theoretically estimated HOMO–LUMO value, global chemical reactivity descriptor parameters are estimated, and the result shows that compounds 5d and 5e have a higher electronegative and electrophilicity index than other molecules. Overall results suggest that, fluorine substituted pyrazolone derivatives show good photophysical, SAR, and biological properties.

Application of the pyrazolone derivatives as effective modulators in the opto-electronic networks

Materials engineering plays a pivotal role in the modern technologies and individual solutions for various applications. In this contribution we describe two pyrazolone-based organic chromophores that differ slightly in structure, but represent a significantly various spectroscopic response. Based on the quantum-chemical calculations, namely TD-DFT model, HOMO-LUMO maps estimation, we have implemented both derivatives in the 2nd and 3rd order nonlinear optical (NLO) experiments. Pyrazolone-based organic systems occurred to be sensitive and appealing all-optical modulators as well as SHG and THG signals generators. The presence of a small methoxy group or its lack in the dye structure directly affects the kinetics of photoinduced birefringence, and its magnification. Moreover, it allows to determine the ease modulation of higher harmonic of the light induction according to the provided experimental polarization spatial conditions. Such approach enables to design and implement individually adjusted organic components to the complex opto-electronic networks and highly effective photonic architectures.

New pyrazolone derivatives, synthesis, characterization, and neuroprotective effect against PTZ- induced neuroinflammation in mice.

The study was aimed at synthesis of the new derivatives of the pyrazolone nucleus, and their spectroscopic and pharmacological analysis and evaluation. Three series of compounds, with 2-picolinic acid (I a-d), 3-picolinic acid (II a-d), and 4-picolinic acid (III a-d) were synthesized and characterized by FT-IR, 1HNMR, 13C NMR, elemental, and melting points. The new compounds were then evaluated for their anti-oxidant, anti-inflammatory, and anti-epileptic potential. The hind paw edema model was used to screen anti-inflammatory potential, while the anticonvulsant effect was evaluated by employing the acute model of anti-epileptic activity. The in vivo anti-oxidant potential was determined through glutathione (GSH), glutathione-S-transferase (GST), catalase, and lipid peroxidase enzyme (LPO) assays. The expression of key biomarkers involved in inflammation and neuroprotection, including tumor necrotic factors alpha (TNF-α) and phosphorylated nuclear factor kappa B (NF-κB), was detected through enzyme-linked immunosorbent assay (ELISA) and Western blot analysis. The tested compounds showed anti-oxidant potential. The selected compounds exhibited good anti-inflammatory potential. The PTZ-induced elevation of these inflammatory mediators and oxidative stress were ameliorated significantly by the selected compound Ic. Results of molecular analysis (ELISA and Western blot analysis) for potent compound Ic showed a prominent inhibitory effect against neuroinflammatory mediators, including TNF-α and NF-κB. It is concluded that the derivative Ic ameliorated PTZ-induced seizures, oxidative stress, and inflammatory cascades by regulating the NF-κB/ TNF-α/ROS pathway.

Synthesis, biological evaluation, and molecular docking studies of novel diclofenac derivatives as antibacterial agents

In the recent years, interest in the synthesis of diclofenac derivatives has increased due to their exceptional biological activity. We present here the synthesis of some novel diclofenac derivatives through simple synthetic procedures, where the acylation of carbohydrazide compound 1 with chloroacetyl chloride in dioxane produced the compound 2. Chloroacetohydrazide compound 2 was further subjected to nucleophilic substitution reactions using different nucleophiles such as: hydrazine hydrate, thiosemicarbazide and p-aminobenzenesulfonamide to give the corresponding derivatives 3-5, respectively. Moreover, the reaction of the hydrazinyl compound 3 with active hydrogen species such as: ethyl acetoacetate and acetyl acetone in refluxed ethanol provided the corresponding pyrazolone derivatives 6 and 7, respectively. Furthermore, the reaction of previously reported diclofenac ester 8 with 1,2-diaminoethane gave the amino derivative 9. Finally, condensation reaction of the latter compound with benzaldehyde in dioxan furnished the corresponding Schiff's base compound 10, while its acylation with chloroacetyl chloride in dioxan produced 11. Different spectral (IR, NMR and Mass) and elemental analysis techniques were utilized to explore the structure of the synthesized compounds. All the synthesized compounds were tested for their in-vitro antibacterial activity against different strains of bacteria showing satisfactory results, and molecular docking study was performed to investigate the mode of action.

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.

Enantioselective Michael Addition of Pyrazolin-5-ones to Nitroalkenes Catalyzed by Novel Squaramide Organocatalyst

Abstract: A new tertiary amine-thiourea organocatalyst has successfully been developed and applied into the asymmetric Michael addition of pyrazolin-5-one to nitroalkenes. The catalyst system performed well with a low catalyst loading of 5 mol% under mild reaction conditions. A series of synthetically and pharmaceutically useful chiral pyrazolone derivatives was obtained in high yields (up to 95%) with good enantioselectivities (up to 88 % ee).

Synthesis and Computational Studies of pyrazole-chromeno[2,3-d]pyrimidines: As a novel Hg2+ fluorescent sensor

The synthesis of pyrazole-chromeno[2,3-d]pyrimidines through the three-component condensation reaction of salicylaldehyde, pyrazolone derivatives, and barbituric acid has been reported in the presence of Fe3O4@SiO2@Pr-SO3H under reflux conditions. Fe3O4@SiO2@Pr-SO3H as a heterogeneous magnetic catalyst is a green, effective and reusable magnetic nanoparticle, which can readily separate by an external magnet. The sensing ability of 4b was tested by adding various cations by fluorescence emission spectroscopy. It was shown outstanding Hg2+ fluorescence activity among various competing cations with a detection limit of 8.5 × 10−7 M. DFT results indicated two intramolecular O–H⋯O and C–H⋯O hydrogen bonds in the most stable configuration of the pyrazol-chromeno[2,3-d]pyrimidine. Natural bonding orbital analysis, Bader Atom in Molecule theory, and frequency analysis were employed to confirm the proposed intramolecular hydrogen bonds. The pyrazol-chromeno[2,3-d]pyrimidine complex with Hg2+ ion has two different Hg2+ coordination. The strongest interaction between ligand and metal is due to the delocalization of electrons from lone donor pairs of nitrogen and oxygen atoms to the empty LP* of transition metals as an acceptor.

Metal‐Free Aminomethylation of Pyrazolones: Direct Access to 4‐Aminomethylated Pyrazolones

AbstractA metal‐free aminomethylation of pyrazolones is accomplished with cyclic amines such as morpholine and piperazine analogues in the presence of (diacetoxyiodo)benzene at ambient temperature. Various sensitive functional groups can be compatible under the reaction conditions. Preliminary mechanistic investigation reveals that morpholine or piperazine analogues are likely to be the source of methylene group. This method provides a straightforward route for the preparation of 4‐aminomethylated pyrazolone derivatives under mild conditions.

Pharmacophore-Based Virtual Screening and Experimental Validation of Pyrazolone-Derived Inhibitors toward Janus Kinases.

Janus kinases (JAKs) are nonreceptor protein tyrosine kinases that play a role in a broad range of cell signaling. JAK2 and JAK3 have been involved in the pathogenesis of common lymphoid-derived diseases and leukemia cancer. Thus, inhibition of both JAK2 and JAK3 can be a potent strategy to reduce the risk of these diseases. In the present study, the pharmacophore models built based on the commercial drug tofacitinib and the JAK2/3 proteins derived from molecular dynamics (MD) trajectories were employed to search for a dual potent JAK2/3 inhibitor by a pharmacophore-based virtual screening of 54 synthesized pyrazolone derivatives from an in-house data set. Twelve selected compounds from the virtual screening procedure were then tested for their inhibitory potency against both JAKs in the kinase assay. The in vitro kinase inhibition experiment indicated that compounds 3h, TK4g, and TK4b can inhibit both JAKs in the low nanomolar range. Among them, the compound TK4g showed the highest protein kinase inhibition with the half-maximal inhibitory concentration (IC50) value of 12.61 nM for JAK2 and 15.80 nM for JAK3. From the MD simulations study, it could be found that the sulfonamide group of TK4g can form hydrogen bonds in the hinge region at residues E930 and L932 of JAK2 and E903 and L905 of JAK3, while van der Waals interaction also plays a dominant role in ligand binding. Altogether, TK4g, found by virtual screening and biological tests, could serve as a novel therapeutical lead candidate.

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.