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In this study, we successfully synthesized a pyrazole derivative, specifically 4-phenylpiperidin-4-ol substituted pyrazole (CHP), through the reaction of Grignard reagents in combination with pyrazole. This newly synthesized molecule was subjected to a comprehensive evaluation for both its photophysical and biological applications. Notably, CHP exhibited promising invitro antifungal and antibacterial activities, primarily attributed to the presence of the 4-phenylpiperidin-4-ol moiety and resulting component contributed to an enhanced absorption rate of lipids, thereby improving the pharmacological activity of CHP. This correlation between structure and function was further supported by the outcomes of structure-activity relationship studies. Additionally, we conducted in silico studies to examine the molecular interactions of the synthesized molecule with key proteins, including DNA Gyrase, Lanosterol 14 α-demethylase, and KEAP1-NRF2. The results unveiled robust binding interactions at specific sites within these proteins, indicating potential therapeutic relevance. Furthermore, the photophysical properties of the synthesized compounds were thoroughly investigated using the ab-initio technique. This involved the determination of ground state optimization and HOMO-LUMO energy levels, all calculated with the DFT-B3LYP-6-31G(d) basis set. The assessment of the theoretically estimated HOMO-LUMO value provided insights into the global chemical reactivity descriptors, revealing that the synthesized molecule boasts a highly electronegative and electrophilic index. Taken together, our findings suggest that pyrazole derivatives with 4-phenylpiperidin-4-ol substitutions exhibit promising applications in both photophysical and biological contexts. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Metamizole, or dipyrone, has been used for decades as a non-narcotic analgesic, providing pain relief from musculoskeletal disorders and antipyretic and antispasmolytic properties. Despite being in use since the 1920s, its mechanism of action still needs to be discovered. Despite causing fewer adverse effects when compared to other analgesics, its harmful effects on the blood and lack of evidence regarding its teratogenicity make the usage of the drug questionable, which has led to it being removed from the drug market of various countries. This narrative review aims to provide a detailed insight into the mechanism of action and efficacy, comparing its effectiveness and safety with other classes of drugs and the safety profile of metamizole. [ABSTRACT FROM AUTHOR]

A series of benzoquinoline-employing heterocycles was synthesized by treating 3-chlorobenzo[f]quinoline-2-carbaldehyde with N-phenyl-3-methylpyrazolone, 4-aminoacetophenone, 1,2-diaminoethane, and 2-cyanoethanohydrazide. Also, pyridine, chromene, α,β-unsaturated nitrile, thiosemicarbazone, and 1,2-bis-aryl hydrazine derivatives were prepared from the cyanoethanohydrazone obtained. The DFT calculations and experiment outcomes were consistent. In vitro screening of their antiproliferative efficacy was examined against HCT116 and MCF7 cancer cell lines. The pyrazolone 2 and cyanoethanohydrazone 5 derivatives exhibited the most potency, which was demonstrated by their molecular docking towards the CDK-5 enzyme. The binding energies of compounds 2 and 5 were − 6.6320 kcal/mol (with RMSD of 0.9477 Å) and − 6.5696 kcal/mol (with RMSD of 1.4889 Å), respectively, which were near to that of co-crystallized ligand (EFP). This implies a notably strong binding affinity towards the CDK-5 enzyme. Thus, pyrazolone derivative 2 would be considered a promising candidate for further optimization to develop new chemotherapeutic agents. In addition, the ADME (absorption, distribution, metabolism, and excretion) analyses displayed its desirable drug-likeness and oral bioavailability properties. [ABSTRACT FROM AUTHOR]

The goal of this study was directed to synthesize a novel class of annulated compounds containing difuro[3,2-c:3′,2′-g]chromene. Friedländer condensation of o-aminoacetyl derivative 3 was performed with some active methylene ketones, namely, 1,3-cyclohexanediones, pyrazolones, 1,3-thiazolidinones and barbituric acids, furnished furochromenofuroquinolines (4,5), furochromenofuropyrazolopyridines (6–8), furochromenofurothiazolopyridines (9,10) and furochromenofuropyridopyrimidines (11, 12), respectively. Also, condensation of substrate 3 with 5-amine-3-methyl-1H-pyrazole and 6-amino-1,3-dimethyluracil, as cyclic enamines, resulted in polyfused systems 13 and 14, respectively. In vitro antimicrobial efficiency of the prepared heterocycles against microbial strains exhibited variable inhibition action, where compound 3 was the most effective against all kinds of microorganisms. A significant cytotoxic activity was seen upon the annulation of the starting compound with thiazolopyridine (9 and 10) as well as pyridopyrimidine moieties (11, 12 and 14). The spectroscopic and analytical results were used to infer the structures of the novel synthesized compounds. [ABSTRACT FROM AUTHOR]

In the title compound, C12H11N3OS, the interplanar angle between the pyrazole and benzothiazole rings is 3.31 (7)°. In the three-dimensional molecular packing, the carbonyl oxygen acts as acceptor to four C--H donors (with one H…O as short as 2.25 Å), while one methyl hydrogen is part of the three-centre system H…(S, O). A double layer structure parallel to (...01) can be recognized as a subsection of the packing. [ABSTRACT FROM AUTHOR]

In this study, we successfully synthesized ethyl 2-(3-methoxybenzyl) acrylate-substituted pyrazolones derivative (EMH) through the reaction of Baylis-Hillman acetate with pyrazolones. We conducted comprehensive screenings to evaluate its invitro antifungal, antibacterial, and antioxidant properties. The molecule demonstrated notable in vitro antifungal and antibacterial activities attributed to the presence of anisole, enhancing absorption rates through increased lipid solubility and improving pharmacological effects. Structure-activity relationship (SAR) studies supported these findings. Additionally, insilico studies delved into the molecular interactions of the synthesized molecule with DNA Gyrase, Lanosterol 14 alpha demethylase, and KEAP1-NRF2 proteins, revealing strong binding interactions at specific sites. Furthermore, we employed ab-initio techniques to theoretically estimate the photophysical properties of the compounds. Ground state optimization, dipole moment, and HOMO-LUMO energy levels were calculated using the DFT-B3LYP-6-31G(d) basis set. The theoretical HOMO-LUMO values indicated high electronegativity and electrophilicity index. NBO analysis confirmed the presence of intermolecular ON...H hydrogen bonds resulting from the interaction of the lone pair of oxygen with the anti-bonding orbital. Overall, our results suggest that anisole-substituted pyrazolones derivatives exhibit promising applications in both photophysical and biological domains.

A new azo dye was produced by mixing 1-(4-sulfophenyl)-3-methyl-5-pyrazolone with diazonium salt from luminol. The produced dye was assessed using the FT-IR, ¹HNMR, and UV-Visible spectroscopy techniques. This dye was dissolved in five polar solvents, and its UV-visible absorption spectra were measured and spectroscopically analysed at room temperature. Additionally, an atomic force microscope (AFM) was used to measure the enhancement of CO3O4 and ZrO2 nanoparticles in luminol azo 1-(4 -sulfophenyl)-3-methyl-5- pyrazolone solutions in aqueous solution. [ABSTRACT FROM AUTHOR]

An electrochemical/I– dual-catalyzed access to sulfonated pyrazoles from pyrazolones and sodium sulfites under external oxidant-free conditions has been developed. This established electrochemical reaction works smoothly under external oxidant-free conditions and has the advantages of good functional group tolerance, easy to gram-scale synthesis, delivering up to 95% yield for 35 examples.

A chiral sulfonamide-phosphine catalyzed regio- and enantioselective (3 + 3)-annulation of 2-(4H-benzo[d][1,3]oxazin-4-yl)acrylates with 2,4-dihydro-3H-pyrazol-3-ones has been established, affording a wide range of such 1,4,5,6-tetrahydropyrano [2,3-c]pyrazole-containing carboxylates in generally high yields (61–96%) with high diastereo- and enantioselectivities (8:1->20:1 dr, 85–95% ee). Based on several control experiments, a reaction mechanism was proposed. Importantly, the work represents the first example of using benzoxazinyl acrylates as three-atom synthons, which enriches the chemistry of benzoxazinyl acrylates.

Under the catalysis of Rh2(OAc)4 (10 mol%) and binapbisphosphine ligand (±)-L3 (20 mol%) in DCE at 80 °C, the cascade cyclization of diazoimides with alkylidenepyrazolones underwent stereoselectively (dr > 20:1), affording pyrazole-fused oxa-bridged oxazocines in reasonable chemical yields. The chemical structure and relative configuration of title products were firmly identified by X-ray diffraction analysis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The pyrazolone-based 4-(furan-2-yl)benzoic acids have been synthesized and studied as xanthine oxidase inhibitors. This enzyme is one of the therapeutic targets for the treatment of hyperuricemia and related diseases. The compounds studied have found to exhibit low micromolar IC50 values relative to the enzyme in vitro, depending on substituents in position 3 of the pyrazolone ring. However, the inhibitory effects observed are reduced in the presence of bovine serum albumin or Tween-80. Among the pyrazolone derivatives synthesized, 4-(5-((3-methyl-5-oxo-1-phenyl-1,5-dihydro-4H-pyrazol-4-ylidene)methyl)furan2-yl)benzoic acid has been found to be the most potent inhibitor of xanthine oxidase. Kinetic results have shown that this compound is a mixed-type inhibitor with higher affinity to the free enzyme than to the enzyme-substrate complex. The results of the molecular docking and molecular dynamics show that the carboxylic group of the inhibitor can form a salt bridge with Arg880 and a hydrogen bond with Thr1010. These interactions can be key factors in the enzyme-inhibitor complex stabilization [ABSTRACT FROM AUTHOR]

A preparative approach to thiazole-containing chromone derivatives has been developed by modifying the corresponding aldehydes with their further transformation into propenone derivatives, and finally introducing them into the Algar-FlynnOyamada reaction. Several methods for obtaining propenones have been analyzed, and the most effective and practically convenient one has been found. The thiazole-containing analogs of chromones obtained have a great potential as probes for a wide range of studies. [ABSTRACT FROM AUTHOR]

The desymmetrization of N-pyrazolyl maleimides was realized through an asymmetric Michael addition by using pyrazolones under mild conditions, leading to the formation of a tri-N-heterocyclic pyrazole–succinimide–pyrazolone assembly in high yields with excellent enantioselectivities (up to 99% yield, up to 99% ee). The use of a quinine-derived thiourea catalyst was essential for achieving stereocontrol of the vicinal quaternary–tertiary stereocenters together with the C–N chiral axis. Salient features of this protocol included a broad substrate scope, atom economy, mild conditions and simple operation. Moreover, a gram-scale experiment and derivatization of the product further illustrated the practicability and potential application value of this methodology. [ABSTRACT FROM AUTHOR]

Among the methods used for the synthesis of functionalized heterocyclic compounds, photochemistry has gained immense popularity due to the reactivity of intermediates in photoinduced reactions. In this study, we report on the effect of diaryl disulfides as hydrogen atom transfer catalysts on the photoinduced transformations of pyrazolo[1,2-a]pyrazolones. After excitation with visible light, these compounds are susceptible to C–N bond cleavage, followed by intermolecular hydrogen atom abstraction. By modifying the reaction conditions, we have developed two novel methods for the synthesis of highly substituted pyrazoles. [ABSTRACT FROM AUTHOR]

Orally-active anticancer small molecules targeting the PD-1/PD-L1 immune checkpoint are actively searched. Phenyl-pyrazolone derivatives with a high affinity for PD-L1 have been designed and characterized. In addition, the phenyl-pyrazolone unit acts as a scavenger of oxygen free radicals, providing antioxidant effects. The mechanism is known for the drug edaravone (1) which is also an aldehyde-reactive molecule. The present study reports the synthesis and functional characterization of new molecules (2–5) with an improved anti-PD-L1 activity. The leading fluorinated molecule 5 emerges as a potent checkpoint inhibitor, avidly binding to PD-L1, inducing its dimerization, blocking PD-1/PD-L1 signaling mediated by phosphatase SHP-2 and reactivating the proliferation of CTLL-2 cells in the presence of PD-L1. In parallel, the compound maintains a significant antioxidant activity, characterized using electron paramagnetic resonance (EPR)-based free radical scavenging assays with the probes DPPH and DMPO. The aldehyde reactivity of the molecules was investigated using 4-hydroxynonenal (4-HNE), which is a major lipid peroxidation product. The formation of drug-HNE adducts, monitored by high resolution mass spectrometry (HRMS), was clearly identified and compared for each compound. The study leads to the selection of compound 5 and the dichlorophenyl-pyrazolone unit as a scaffold for the design of small molecule PD-L1 inhibitors endowed with antioxidant properties. [ABSTRACT FROM AUTHOR]

Aim: A new simple, accurate, precise, Reverse Phase High-performance Liquid Chromatography method was developed and validated for the estimation of newly synthesized (4Z) 3 methyl 1 (4 nitrobenzoyl) 1H pyrazole 4,5 dione 4[(4fluorophenyl)hydrazone] derivative of pyrazolone. Materials and Methods: The chromatogram was run through Luna 5µ C18(2). 250 × 4.80 mm. 272817-7 HPLC column; mobile phase consisting of acetonitrile and water in the ratio 90:10 was pumped through the column at a flow rate of 0.8mL/min. Results: The optimized wavelength was 237 nm. The retention time of (4Z) 3 methyl 1 (4 nitrobenzoyl) 1H pyrazole 4,5 dione 4[(4fluorophenyl)hydrazone] was found to be 7.3 min. The percentage relative standard deviation was obtained as 0.3%. Conclusion: This method was accurate, precise, and sensitive; therefore, could be used for the quality control and bioanalytical evaluation of (4Z) 3 methyl 1 (4 nitrobenzoyl) 1H pyrazole 4,5 dione 4[(4fluorophenyl)hydrazone] in drug testing laboratory. [ABSTRACT FROM AUTHOR]

Knee injuries cause structural damage and acute inflammation that initiates the development of post-traumatic osteoarthritis (PTOA). NADPH oxidase 4 (Nox4), a member of a family of enzymes that generates reactive oxygen species (ROS), plays a pivotal role in normal development of the musculoskeletal system, but may increase ROS production to harmful levels after joint injury. The role of ROS in both normal joint homeostasis and injury is poorly understood, but inhibition of excessive ROS production by Nox4 after joint injury could be protective to the joint, decreasing oxidative stress, and initiation of PTOA. Knee injuries were simulated using inflammatory cytokines in cultured primary human chondrocytes and a non-invasive mouse model of PTOA in C57BL/6N and Nox4 knockout mice. There is an acute decrease in Nox4 activity within 24 h after injury in both systems, followed by a subsequent sustained low-level increase, a novel finding not seen in any other system. Inhibition of Nox4 activity by GKT137831 was protective against early structural changes after non-invasive knee injury in a mouse model. Nox4 knockout mice had significant differences in structural and mechanical properties of bone, providing further evidence for the role of Nox4 in development of joint tissues and biochemical response after joint injury. Nox4 plays a significant role in the acute phase after joint injury, and targeted inhibition of inflammation caused by Nox4 may be protective against early joint changes in the pathogenesis of PTOA. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2429-2436, 2019.

By reacting 2-chloro-N-aryl-acetamide with the potassium salt of p-formylbenzoic acid in DMF at reflux, a variety of new 2-oxo-2-(arylamino)ethyl 4-formylbenzoates were generated in good yields. The corresponding fused pyrans were obtained using a three-component reaction of the novel aldehydes with malononitrile and active methylene compounds, in particular, dimedone, pyrazolone, and 4-hydroxycoumarin, in the presence of a basic catalyst. A variety of spectra were used to confirm the structures of the new compounds. [ABSTRACT FROM AUTHOR]

Objective(s): The study was aimed at synthesis of the new derivatives of the pyrazolone nucleus, and their spectroscopic and pharmacological analysis and evaluation. Materials and Methods: 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 antiinflammatory 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-a) and phosphorylated nuclear factor kappa B (NF-κB), was detected through enzymelinked immunosorbent assay (ELISA) and Western blot analysis. Results: 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-a and NF-κB. Conclusion: It is concluded that the derivative Ic ameliorated PTZ-induced seizures, oxidative stress, and inflammatory cascades by regulating the NF-κB/TNF-a/ROS pathway. [ABSTRACT FROM AUTHOR]

[Display omitted] • By in vitro high-throughput screening method, we found three potential CES1 inhibitors (compounds 25, 26, 27) from series of synthetic pyrazolone; • Compounds 25 and 27 had non-competitive inhibition on CES1-mediated NLMe hydrolysis, while compound 26 competitively inhibited CES1-mediated NLMe hydrolysis. • These newly developed inhibitors can effectively inhibit intracellular CES1 activity and ameliorate the accumulation of lipid droplets in mouse adipocytes cells. 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. [ABSTRACT FROM AUTHOR]

The synthesis of two pyrazolone derivative compounds, PYR-I (4-Acetyl-1-(4-chlorophenyl)-3-isopropyl-1H-pyrazol-5(4H)-one) and PYR-II 1-(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 (K eq), acidity constants (p K a) 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. [Display omitted] • Characterization of 4-Substituted Pyrazolone Derivatives by, FT-IR, NMR, UV–Vis and GC-MS techniques. • Keto-enol tautomerization process of structures with the DFT approach and spectral data. • Reactivity profiles of structures based on the DFT approach. [ABSTRACT FROM AUTHOR]

Transient activation of biochemical reactions by visible light and subsequent return to the inactive state in the absence of light is an essential feature of the biochemical processes in photoreceptor cells. To mimic such light-responsiveness with artificial nanosystems, polymersome nanoreactors were developed that can be switched on by visible light and self-revert fast in the dark at room temperature to their inactive state. Donor-acceptor Stenhouse adducts (DASAs), with their ability to isomerize upon irradiation with visible light, were employed to change the permeability of polymersome membranes by switching polarity from a nonpolar triene-enol form to a cyclopentenone with increased polarity. To this end, amphiphilic block copolymers containing poly(pentafluorophenyl methacrylate) in their hydrophobic block were synthesized by reversible addition-fragmentation chain-transfer (RAFT) radical polymerization and functionalized either with a DASA that is based on Meldrum's acid or with a novel fast-switching pyrazolone-based DASA. These polymers were self-assembled into vesicles. Release of hydrophilic payload could be triggered by light and stopped as soon as the light was turned off. The encapsulation of enzymes yielded photoresponsive nanoreactors that catalyzed reactions only if they were irradiated with light. A mixture of polymersome nanoreactors, one that switches in green light, the other switching in red light, permitted specific control of the individual reactions of a reaction cascade in one pot by irradiation with varied wavelengths, thus enabling light-controlled wavelength-selective catalysis. The DASA-based nanoreactors demonstrate the potential of DASAs to switch permeability of membranes and could find application to switch reactions on and off, on demand, e.g., in microfluidics or in drug delivery.

Purpose: To synthesize novel pyrazolone fused thiazolidinone analogues and evaluate their efficiency as potent HER2 and EGFR inhibitors in human breast adenocarcinoma cells for anti-cancer activity. Method: In this study, several pyrazolone fused thiazolidinone analogues were synthesized, and characterized by elemental analysis, IR, ¹H-NMR, 13C-NMR, and mass spectroscopy, as well as tested for their in vitro cytotoxicity against breast cancer cell line (MCF-7) by MTT assay. A correlation study of the cytotoxicity was performed to obtain the Docking score using Schrodinger (Maestro) Version 9.6 Glide XP software. Result: A total of 10 compounds were synthesised and analysed for their physiochemical, spectral, and cytotoxic activity against breast cancer cell lines (MCF-7). Among the synthesised compounds, compound 4B5 showed significantly higher (p < 0.05) anticancer properties against MCF-7 cell lines with docking score of -6.614, and half-maximal concentration (IC50) value of 001.17 M compared to other synthesized compounds of the same categories. Conclusion: Novel pyrazolone-fused thiazolidinone analogues have been successfully synthesized. The synthesised compounds possess anti-cancer activity against the MCF-7 cell lines. This could potentially lead to the development of new anti-breast cancer agents. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

In silico evaluation of various regioisomeric 5- and 3-hydroxy-substituted alkyl 1-aryl-1H-pyrazole-4-carboxylates and their acyclic precursors yielded promising results with respect to their binding in the active site of dihydroorotate dehydrogenase of Plasmodium falciparum (PfDHODH). Consequently, four ethyl 1-aryl-5-hydroxy-1H-pyrazole-4-carboxylates and their 3-hydroxy regioisomers were prepared by two-step syntheses via enaminone-type reagents or key intermediates. The synthesis of 5-hydroxy-1H-pyrazoles was carried out using the literature protocol comprising acid-catalyzed transamination of diethyl [(dimethylamino)methylene]malonate with arylhydrazines followed by base-catalyzed cyclization of the intermediate hydrazones. For the synthesis of isomeric methyl 1-aryl-3-hydroxy-1H-pyrazole-4-carboxylates, a novel two-step synthesis was developed. It comprises acylation of hydrazines with methyl malonyl chloride followed by cyclization of the hydrazines with tert-butoxy-bis(dimethylamino)methane. Testing the pyrazole derivatives for the inhibition of PfDHODH showed that 1-(naphthalene-2-yl)-5-hydroxy-1H-pyrazole-4-carboxylate and 1-(naphthalene-2-yl)-, 1-(2,4,6-trichlorophenyl)-, and 1-[4-(trifluoromethyl)phenyl]-3-hydroxy-1H-pyrazole-4-carboxylates (~30% inhibition) were slightly more potent than a known inhibitor, diethyl α-{[(1H-indazol-5-yl)amino]methylidene}malonate (19% inhibition). [ABSTRACT FROM AUTHOR]

Background: A new, green and environmentally friendly protocol has been developed for the synthesis of tetrahydrodipyrazolopyridine derivatives. The structures of these products were determined in terms of melting point, FTIR, NMR and Mass spectroscopy. Results: The tetrahydrodipyrazolopyridine derivatives were synthesized in water through a catalyst-free pseudo-six-component reaction of hydrazine hydrate, ethyl acetoacetate, ammonium acetate and aldehyde at room temperature. Conclusions: This novel procedure has some advantages such as aqueous media, high yield and simple work-up. [ABSTRACT FROM AUTHOR]

Abstract Background Synthesize new complexes of Ag(I) to enhance efficacy or stability and also, pharmacological activities on the operation of pyrazolone's biological properties. Results Efficient and high yielding pathways starting from the versatile and readily available 3-methyl-1-phenyl-5-pyrazolone by Knoevenagel condensation of a sequence of 4-arylidene-3-methyl-1-phenyl-5-pyrazolone derivatives (2a-c) have been formed by the reaction of various substituted aromatic aldehydes Used as ligands to synthesize Ag(I) chelates. Synthesized compounds and their complexes have been characterized by elemental analysis, magnetic and spectroscopic methods (IR, 13C, 1HNMR, mass) and thermal analysis. The spectrophotometric determinations suggest distorted octaedral geometry for all complexes. Both ligands and their metal complexes have also been tested for their antibacterial and antifungal efficacy. Conclusions Newly synthesized compounds have shown potent antimicrobial activity. The results showed that the complex 's high activity was higher than its free ligands, and that Ag(I)-L3 had the highest activity.

In human breast cancers, the human epidermal development factor receptor-2 is a membrane tyrosine kinase that is overexpressed, and gene amplified. Pyrazolone fused heterocyclic moieties-thiazolidinone, carboxymethyl thiazolidinone, azetidinone are significant DNA-intercalating agents here human epidermal development factor receptor-2 amplification and over expression are linked to tumour cell proliferation and the pathway of instances in breast cancer. Few novel pyrazolone fused heterocyclic analogues are designed by in-silico-technique for their human epidermal development factor receptor-2 inhibition action. Docking patterns of compounds 4A1-4A10 are carried out against human epidermal development factor receptor-2 (PDB id-3RCD) by using Schrodinger suite 2016-2. Molecular docking study for the framed moieties 4A1-4A10 were performed by Glide XP module of Schrodinger suite. The affinity of binding as chosen based on the Glide score. Many compounds were showing good hydrophobic and hydrogen bonding communication and association in order to hinder human epidermal development factor receptor-2. The derivatives 4A1-4A10 have significant glide scores in the scope of -4.476 to - 6.234 compared with the standard Tamoxifen (-7.893). The in-silico screening properties are within the druglikeness. The results proved that this study gave a shred of evidence for the consideration of Pyrazolone fused heterocyclic analogues as potential human epidermal development factor receptor-2 inhibitors. Among the compounds, 4A1-4A10 with significant glide scores may produce significant anti-breast cancer activity and further in-vitro and in-vivo investigations may prove their therapeutic potential. The precursor phenyl hydrazine is reacted with ethylacetoacetate to give 5-methyl-2-phenyl-2,-dihydro-3H-pyrazol-one derivatives. Also, the reactivity of the precursor towards Schiff base derivatives of 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-one to give the hetero analogues of thiazolidinone derivatives was studied. [ABSTRACT FROM AUTHOR]

The [Ir]-catalysed carbenoid insertion and cyclization of N-arylpyrazolones has been carried out with α-diazotized Meldrum's acid to access tricyclic pyrazolone fused 1,4-dihydrocinnolin-3-one derivatives. Further, the selective reduction of these tricyclic derivatives has been studied under Birch reduction conditions. [ABSTRACT FROM AUTHOR]

Starting with 4-aminoantipyrine compound (4-amino-1,5-dimethyl-2-phenyl-1,2-dihydro-3Hpyrazol- 3-one), two N-alkyl derivatives were synthesized (5) or (6) by reaction with chloroacetyl chloride or 3-chloropropionyl chloride, respectively. On the other hand, hydrazide compounds (thiophene- 2-carbohydrazide and benzocarbazide) were used to synthesize 1,3,4-oxadiazole and 1,2,4-triazole thiol derivatives (2a), (2b), (4a), and (4b), by cyclization reaction. Finally, six derivatives were synthesized (7a-10a) and (11b-12b) by nucleophilic substitution reaction of thiol moiety in (2a, 2b, 4a or 4b) compounds with (5) or (6). The synthesized compounds were characterized using elemental microanalysis, IR, and 1H-NMR spectroscopy. The analgesic activity of the compounds was evaluated using the hot plate method and compared with paracetamol as a standard drug. Compounds (9a and 11b) gave potent activity (81 and 66%, respectively) greater than other synthesized compounds, and compound (11b) has potent activity compared with paracetamol (73%) as a standard drug. Whereas, other compounds (6, 8a, and 10a) showed moderate activity compared with the standard drug. [ABSTRACT FROM AUTHOR]

Background & aimsReactive oxidative species (ROS) are believed to be involved in the progression of nonalcoholic steatohepatitis (NASH). However, little is known about the sources of ROS in hepatocytes or their role in disease progression. We studied the effects of nicotinamide adenine dinucleotide phosphate reduced oxidase 4 (NOX4) in liver tissues from patients with NASH and mice with steatohepatitis.MethodsLiver biopsy samples were obtained from 5 patients with NASH, as well as 4 patients with simple steatosis and 5 patients without steatosis (controls) from the University of California, Davis Cancer Center Biorepository. Mice with hepatocyte-specific deletion of NOX4 (NOX4(hepKO)) and NOX4(floxp+/+) C57BL/6 mice (controls) were given fast-food diets (supplemented with high-fructose corn syrup) or choline-deficient l-amino acid defined diets to induce steatohepatitis, or control diets, for 20 weeks. A separate group of mice were given the NOX4 inhibitor (GKT137831). Liver tissues were collected and immunoblot analyses were performed determine levels of NOX4, markers of inflammation and fibrosis, double-stranded RNA-activated protein kinase, and phospho-eIF-2α kinase-mediated stress signaling pathways. We performed hyperinsulinemic-euglycemic clamp studies and immunoprecipitation analyses to determine the oxidation and phosphatase activity of PP1C.ResultsLevels of NOX4 were increased in patients with NASH compared with controls. Hepatocyte-specific deletion of NOX4 reduced oxidative stress, lipid peroxidation, and liver fibrosis in mice with diet-induced steatohepatitis. A small molecule inhibitor of NOX4 reduced liver inflammation and fibrosis and increased insulin sensitivity in mice with diet-induced steatohepatitis. In primary hepatocytes, NOX4 reduced the activity of the phosphatase PP1C, prolonging activation of double-stranded RNA-activated protein kinase and phosphorylation of extracellular signal-regulated kinase-mediated stress signaling. Mice with hepatocyte-specific deletion of NOX4 and mice given GKT137831 had increased insulin sensitivity.ConclusionsNOX4 regulates oxidative stress in the liver and its levels are increased in patients with NASH and mice with diet-induced steatohepatitis. Inhibitors of NOX4 reduce liver inflammation and fibrosis and increase insulin sensitivity, and might be developed for treatment of NASH.

Reactive oxygen species (ROS) produced by nicotinamide adenine dinucleotide phosphate oxidase (NOX) play a key role in liver injury and fibrosis. Previous studies demonstrated that GKT137831, a dual NOX1/4 inhibitor, attenuated liver fibrosis in mice as well as pro-fibrotic genes in hepatic stellate cells (HSCs) as well as hepatocyte apoptosis. The effect of NOX1 and NOX4 deficiency in liver fibrosis is unclear, and has never been directly compared. HSCs are the primary myofibroblasts in the pathogenesis of liver fibrosis. Therefore, we aimed to determine the role of NOX1 and NOX4 in liver fibrosis, and investigated whether NOX1 and NOX4 signaling mediates liver fibrosis by regulating HSC activation. Mice were treated with carbon tetrachloride (CCl4) to induce liver fibrosis. Deficiency of either NOX1 or NOX4 attenuates liver injury, inflammation, and fibrosis after CCl4 compared to wild-type mice. NOX1 or NOX4 deficiency reduced lipid peroxidation and ROS production in mice with liver fibrosis. NOX1 and NOX4 deficiency are approximately equally effective in preventing liver injury in the mice. The NOX1/4 dual inhibitor GKT137831 suppressed ROS production as well as inflammatory and proliferative genes induced by lipopolysaccharide (LPS), platelet-derived growth factor (PDGF), or sonic hedgehog (Shh) in primary mouse HSCs. Furthermore, the mRNAs of proliferative and pro-fibrotic genes were downregulated in NOX1 and NOX4 knock-out activated HSCs (cultured on plastic for 5 days). Finally, NOX1 and NOX4 protein levels were increased in human livers with cirrhosis compared with normal controls. Thus, NOX1 and NOX4 signaling mediates the pathogenesis of liver fibrosis, including the direct activation of HSC.

Abstract Pyrazoles, thiazoles and fused thiazoles have been reported to possess many biological activities. 3-Methyl-5-oxo-4-(2-arylhydrazono)-4,5-dihydro-1H-pyrazole-1-carbothioamides 3a,b (obtained from the reaction of ethyl 3-oxo-2-(2-arylhydrazono)butanoates 1a,b with thiosemicarbazide) could be transformed into a variety of thiazolyl-pyrazole derivatives 6a–h, 10a–c, 15a–c, 17, 19 and 21 via their reaction with a diversity hydrazonoyl chlorides as well as bromoacetyl derivatives. Moreover, the computational studies were carried out for all new compounds. The results indicated that five compounds showed promising binding affinities (10a: − 3.4 kcal/mol, 6d: − 3.0 kcal/mol, 15a: − 2.2 kcal/mol, 3a: − 1.6 kcal/mol, and 21: − 1.3 kcal/mol) against the active site of the epidermal growth factor receptor kinase (EGFR). The cytotoxicity of the potent products 3a, 6d, 10a, 15a, and 21 was examined against human liver carcinoma cell line (HepG-2) and revealed activities close to Doxorubicin standard drug. There was an understanding between the benefits of restricting affinities and the data obtained from the practical anticancer screening of the tested compounds.

Nadia Hanafy Metwally,1 Gamal Riad Saad,1 Esraa Azmy Abd El-Wahab21Chemistry Department, Faculty of Science, Cairo University, Giza, Egypt; 2Department of Engineering Mathematics and Physics, Faculty of Engineering Shoubra, Benha UniversityCorrespondence: Nadia Hanafy MetwallyChemistry Department, Faculty of Science, Cairo University, Giza 12613, EgyptEmail nhmmohamed@yahoo.comIntroduction: It 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 methods: Pyrazole 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).Results: The 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).Conclusion: The 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.Keywords: carbon nanotubes, pyrazoles, pyrazolones, grafting, antimicrobial activity, zeta-potential, molecular docking study

In silico evaluation of various regioisomeric 5- and 3-hydroxy-substituted alkyl 1-aryl-1H-pyrazole-4-carboxylates and their acyclic precursors yielded promising results with respect to their binding in the active site of dihydroorotate dehydrogenase of Plasmodium falciparum (PfDHODH). Consequently, four ethyl 1-aryl-5-hydroxy-1H-pyrazole-4-carboxylates and their 3-hydroxy regioisomers were prepared by two-step syntheses via enaminone-type reagents or key intermediates. The synthesis of 5-hydroxy-1H-pyrazoles was carried out using the literature protocol comprising acid-catalyzed transamination of diethyl [(dimethylamino)methylene]malonate with arylhydrazines followed by base-catalyzed cyclization of the intermediate hydrazones. For the synthesis of isomeric methyl 1-aryl-3-hydroxy-1H-pyrazole-4-carboxylates, a novel two-step synthesis was developed. It comprises acylation of hydrazines with methyl malonyl chloride followed by cyclization of the hydrazines with tert-butoxy-bis(dimethylamino)methane. Testing the pyrazole derivatives for the inhibition of PfDHODH showed that 1-(naphthalene-2-yl)-5-hydroxy-1H-pyrazole-4-carboxylate and 1-(naphthalene-2-yl)-, 1-(2,4,6-trichlorophenyl)-, and 1-[4-(trifluoromethyl)phenyl]-3-hydroxy-1H-pyrazole-4-carboxylates (~30% inhibition) were slightly more potent than a known inhibitor, diethyl α-{[(1H-indazol-5-yl)amino]methylidene}malonate (19% inhibition).

Pyrazolones are a vital class of heterocycles possessing various biological properties and much attention is paid to the diversified synthesis of enantiopure pyrazolone derivatives. We describe here the development of diphenylphosphinoalkanoic acid based chiral bisphosphine ligands, which are successfully applied to the palladium-catalyzed asymmetric allenylation of racemic pyrazol-5-ones. The reaction affords C-allenylation products, optically active pyrazol-5-ones bearing an allene unit, in high chemo- and enantioselectivity, with DACH-ZYC-Phos-C1 as the best ligand. The synthetic potential of the C-allenylation products is demonstrated. Furthermore, the enantioselectivity observed with DACH-ZYC-Phos-C1 is rationalized by density functional theory studies. Chiral pyrazolone derivatives show promising biological activity in commercial drugs. Here, the authors report an enantioselective allenylation of pyrazolones by fine tuning of Trost's ligands, which leads to a chiral pocket featuring high efficiency and asymmetric induction in the catalytic process. [ABSTRACT FROM AUTHOR]

Pyrazolone is a five-membered lactam ring containing two Nitrogens and one ketonic group in its structure. Numerous pyrazolone derivatives were exhibited with diverse biological, pharmacological, and chemical applications. When pyrazolones were discovered, they were only known as NSAIDs but in recent times they play a versatile role in several complications like cerebral ischemia, cardiovascular diseases, antibacterial, antioxidant, anticancer and several other pharmacological activities. Over the last few decades, pyrazolone derivatives have been used for various biochemical applications. Some of these derivatives such as metamizole, phenazone, aminopyrine, and propyphenazone, are widely used as anti-inflammatory and analgesics. The chemistry of pyrazolone has gained increasing attention due to its diverse pharmacological properties such as anticancer, analgesic, anti-inflammatory, antimicrobial, antioxidant, antifungal, antiviral, antidiabetic, and several other biological activities. Thus, keeping because of their importance, synthetic strategies for existing as well as novel pyrazolone derivatives have been developed and explored their biochemical utility. This review deals with the various pharmacological properties of different pyrazolone derivatives and puts chemical synthetic schemes. [ABSTRACT FROM AUTHOR]

In addition to the basic pyrazolone skeleton, the title compound contains a I i -diketone moiety, and a 4-(4-bromophenyl)thiazol-2-yl group. Dehydroacetic acid has also been employed as the starting material to obtain pyrazolone derivatives containing a -diketone moiety [[7]]. Table 1 contains crystallographic data and Table 2 contains the list of the atoms including atomic coordinates and displacement parameters. [Extracted from the article]

Pyrazolone is an important class of heterocyclic compounds with numerous applications in the fields of organic/material/pharmaceutical chemistry, food/textile industry and cosmetics. Because of these importances, the synthesis of biologically active complex molecules by employing pyrazolone has emerged. Dihydropyrano[2,3-c]pyrazoles and spiro-pyrano[2,3-c]pyrazoles are synthesized from pyrazolone and hold huge potential in the field of medicinal chemistry because of their wide-ranging biological activities. This review article will summarize the up to date advances on the application of pyrazolone in multicomponent reactions for the synthesis of dihydro- and spiro-pyrano[2,3-c]pyrazoles in aqueous medium. [ABSTRACT FROM AUTHOR]

Epithelial-to-mesenchymal transition (EMT) is one of the main causes of peritoneal fibrosis. However, the pathophysiological mechanisms of EMT, specifically its relationship with autophagy, are still unknown. This study aimed to evaluate the role of autophagy in transforming growth factor-beta 1 (TGF-β1)-induced EMT in human peritoneal mesothelial cells (HPMCs). Primary cultured HPMCs were treated with TGF-β1 (2 and 5 ng/mL) and changes in autophagy markers and the relationship between autophagy and EMT were evaluated. We also identified changes in EMT- and autophagy-related signaling pathways after autophagy and NADPH oxidase 4 (NOX4) inhibition. TGF-β1 increased the generation of NOX4 and reactive oxygen species (ROS) in HPMCs, resulting in mitochondrial damage. Treatment with GKT137831 (20 μM), a NOX1/4 inhibitor, reduced ROS in the mitochondria of HPMC cells and reduced TGF-β1-induced mitochondrial damage. Additionally, the indirect inhibition of autophagy by GKT137831 (20 μM) downregulated TGF-β1-induced EMT, whereas direct inhibition of autophagy using 3-methyladenine (3-MA) (2 mM) or autophagy-related gene 5 (ATG5) gene silencing decreased the TGF-β1-induced EMT in HPMCs. The suppressor of mothers against decapentaplegic 2/3 (Smad2/3), autophagy-related phosphoinositide 3-kinase (PI3K) class III, and protein kinase B (Akt) pathways, and mitogen-activated protein kinase (MAPK) signaling pathways, such as extracellular signal-regulated kinase (ERK) and P38, were involved in TGF-β1-induced EMT. Autophagy and NOX4 inhibition suppressed the activation of these signaling pathways. Direct inhibition of autophagy and its indirect inhibition through the reduction of mitochondrial damage by upstream NOX4 inhibition reduced EMT in HPMCs. These results suggest that autophagy could serve as a therapeutic target for the prevention of peritoneal fibrosis in patients undergoing peritoneal dialysis., (© 2024. The Author(s).)

Background: Synthesize new complexes of Ag(I) to enhance efficacy or stability and also, pharmacological activities on the operation of pyrazolone's biological properties. Results: Efficient and high yielding pathways starting from the versatile and readily available 3-methyl-1-phenyl-5-pyrazolone by Knoevenagel condensation of a sequence of 4-arylidene-3-methyl-1-phenyl-5-pyrazolone derivatives (2a-c) have been formed by the reaction of various substituted aromatic aldehydes Used as ligands to synthesize Ag(I) chelates. Synthesized compounds and their complexes have been characterized by elemental analysis, magnetic and spectroscopic methods (IR, 13C, 1HNMR, mass) and thermal analysis. The spectrophotometric determinations suggest distorted octaedral geometry for all complexes. Both ligands and their metal complexes have also been tested for their antibacterial and antifungal efficacy. Conclusions: Newly synthesized compounds have shown potent antimicrobial activity. The results showed that the complex 's high activity was higher than its free ligands, and that Ag(I)-L3 had the highest activity. [ABSTRACT FROM AUTHOR]

Dialkyl 5,5'-dioxo-4,4'-bipyrazole-4,4'-dicarboxylates are readily obtained by the reaction of 5-hydroxypyrazole-4-carboxylates in refluxing thionyl chloride. The obtained diesters can be transformed into the corresponding 4,4'-bipyrazoles via alkaline hydrolysis and subsequent decarboxylation. Detailed NMR spectroscopic investigations (1H, 13C, 15N) were undertaken with all products prepared. Moreover, the structure of a representative 5,5'-dioxo-4,4'-bipyrazole-4,4'-dicarboxylate was confirmed by X-ray crystal structure analysis.

Small-molecule agonism of peroxisome proliferator-activated receptor α (PPARα), a ligand-activated transcriptional factor involved in regulating fatty acid metabolism, is an important approach for treating dyslipidemia. Here, we determined the structures of the ligand-binding domain (LBD) of PPARα in complex with 1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid derivatives, which were recently identified as PPARα-selective activators with markedly different structures from those of the well-known PPARα agonists fibrates. The crystal structures of the complexes showed that they form a canonical hydrogen-bond network involving helix 12 in the LBD, which is thought to be essential for PPARα activation, as also observed for fibrates. However, the phenyl side chain of the compounds occupies a small cavity between Ile272 and Ile354, which is rarely accessed by fibrates. This unique feature may be essential for subtype selectivity and combine with the well-characterized binding mode of fibrates to improve activity. These findings demonstrate the advantage of using 1H-pyrazolo-[3,4-b]pyridine as a skeleton of PPARα agonists and provide insight into the design of molecules for treating dyslipidemia. [ABSTRACT FROM AUTHOR]

Here we report the synthesis of interesting 3-alkyl-4-hydroxy-1-aryl-4-(propa-1,2-dienyl)1H-pyrazol-5(4H)-ones and 9-alkyl-7-aryl-1-oxa-7,8-diazaspiro[4.4]nona-3,8-dien-6-ones, starting from 1,2-diaza-1,3-dienes (DDs) and propargyl alcohol. The reaction proceeds through a sequence Michael-type nucleophilic attack/cyclization/[2,3]-Wittig rearrangement. In the same way, the reaction between the aforementioned DDs and allyl alcohol furnished 4-allyl-4-hydroxy-3-alkyl-1-aryl-1H-pyrazol-5(4H)-ones. A DFT study was also carried out, in order to have decisive clarifications about the mechanism.

Graphical abstract Highlights • Pyrazolo pyrimidine derivatives have synthesized. • Pyrazolo pyrimidine compounds showed significant inhibition of Eg5. • Molecular docking studies used for Insilico of pyrazolo pyrimidine derivatives. Abstract Human kinesin Eg5 is a potential inhibiting site for cancer chemotherapy. Blocking metaphase by binding foreign inhibitors with Eg5 eventually leads to apoptotic cell death. Here, we report the pyrazolopyrimidine derivates as potent inhibitors of Eg5 that prevents mitotic kinesin progression. IC 50 values were evaluated against the motor domain of Eg5 using steady-state ATPase assay. To better understanding, we have performed molecular docking simulation. It reveals that the interactions of the proposed inhibitors with both the allosteric sites (helices α2, α3 and loopL5, and helices α4 & α6). Out of fifteen pyrazolopyrimidine derivates, three compounds (12, 25, and 27) have shown significant inhibition of Eg5. The synthesized compounds (12, 25, and 27) were tested for their in-vitro anticancer activity against cervical cancer cell line (HeLa). [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • 16 new Schiff base derivatives were synthesized. • Synthesized compounds were evaluated for their acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and monoamine oxidases A and B (MAO-A and MAO-B) enzymes inhibitory activities. • Compounds 3g and 3h were found as the most potent derivatives against AChE and MAO-B enzymes, respectively. • A good ADME (Absorption, Distribution, Metabolism, and Excretion) and BBB (Blood, Brain, Barier) profile was predicted for all synthesized compounds. • Molecular docking studies were performed to define and evaluate the interaction mechanism between compounds 3g and 3h and related enzymes. Abstract In the current work, Schiff base derivatives of antipyrine were synthesized. The chemical characterization of the compounds was confirmed using IR, 1H NMR, 13C NMR and mass spectroscopies. The inhibitory potency of synthesized compounds was investigated towards acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and monoamine oxidases A and B (MAO-A and MAO-B) enzymes. Some of the compounds displayed significant inhibitory activity against AChE and MAO-B enzymes, respectively. According to AChE enzyme inhibition assay, compounds 3e and 3g were found as the most potent derivatives with IC 50 values of 0.285 µM and 0.057 µM, respectively. Also, compounds 3a (IC 50 = 0.114 µM), 3h (IC 50 = 0.049 µM), and 3i (IC 50 = 0.054 µM) were the most active derivatives against MAO-B enzyme activity. So as to understand inhibition type, enzyme kinetics studies were carried out. Furthermore, molecular docking studies were performed to define and evaluate the interaction mechanism between compounds 3g and 3h and related enzymes. ADME (Absorption, Distribution, Metabolism, and Excretion) and BBB (Blood, Brain, Barier) permeability predictions were applied to estimate pharmacokinetic profiles of synthesized compounds. [ABSTRACT FROM AUTHOR]

A novel, alternative and efficient organic-inorganic hybrid was synthesized by immobilizing 1-(1,3-diphenyl-5-hydroxy-1H-pyrazol-4-yl)ethanone on silica gel, previously modified with 3-aminopropyltrimethoxysilane. This novel material was well characterized by fourier transform infrared spectroscopy, 29Si and 13C cross-polarization magic-angle-spinning solid-state nuclear magnetic resonance, scanning electron microscopy, Brunauer–Emmett–Teller surface area, X-ray diffraction and elemental analysis. Thermal stability of the material was determined by thermogravimetry curves (TGA). This new chelating agent effectively removed Lead ions Pb(II) from the aqueous solution and showed very high adsorption capacity (qe (mg/g) up to 120.83 mg/g for hyper toxic Pb(II) ions. [ABSTRACT FROM AUTHOR]