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Chemical reactivity and applications of 4-alkynylated pyrazol-3-ones are described. A facile access to the synthesis of novel pyrazol-4-yl furan- and/or thiophene-2-carboxylates through the ring transformation and subsequent acylation of 4-alkynylated pyrazol-3-ones as the key intermediates, which were prepared from pyrazole-4,5-dione and terminal alkynes, in moderate to good yields is achieved. All the synthesized compounds were characterized by spectroscopic analysis. [ABSTRACT FROM AUTHOR]

Novel library of pyrazole derivatives (6a–k) from substituted 4-dioxaborolanyl-1H-pyrazole and halo benzaldehyde through simultaneous Suzuki reaction, nucleophilic addition, and hydrolysis under moderate reaction conditions. The desired compounds 6a–k have been formed in good to high yield. All the compound structures were characterized by analytical and spectral (1H NMR,13C NMR and MS) studies. Furthermore, the evaluation of biological activity of synthesized molecules. [ABSTRACT FROM AUTHOR]

A series of 4-hydroxy-6-methyl-3-(1-(4-(aryl/methyl)thiazol-2-yl)-1H-pyrazol-3-yl)-2H-pyran-2-ones 3a–h have been synthesized from aryl/methyl halomethylketones and a key pyrazole intermediate 1 using a convenient one-pot synthesis method. All compounds were characterized by NMR and MS, and the structure of three of them (3a, 3b and 3f) was resolved by X-ray diffraction. These heteroatom-rich thiazole compounds were then evaluated as inhibitors of Mycobacterium tuberculosis InhA, a key enzyme involved in the type II fatty acid biosynthesis pathway of the mycobacterium. Although inhibitory activities were found to be rather weak, molecular docking studies were also been carried out to understand a possible mode of interaction with key residues in the enzyme's active site. [ABSTRACT FROM AUTHOR]

In search of novel antimicrobial agents, new series of N-(arylsulfonyl)-l-proline-derived hybrids tethered with pharmacologically attractive cores as 1-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)piperazine and 5-(Piperazin-1-yl)benzofuran-2-carboxamide were synthesized and evaluated for in vitro antimicrobial potential against six different representative human pathogenic strains. Among all, N-acetyl derivative 5e containing phenylpyrazolyl moiety displayed an appreciable inhibitory value (MIC: 107 µg/mL) with noteworthy binding energy (–6.65 kcal/mol) against S. aureus as compared to standard ampicillin (MIC: 250 µg/mL). The N-phenyl-pyrazolyl containing analogue 5b elicited comparable activity against E. coli and P. aeruginosa with MIC values of 104 µg/mL and 121 µg/mL, respectively. Moreover, 5b, 5d, and 6c showed appreciable antioxidant activity (IC50:19.25–20.69 µg/mL) as compared to butylated hydroxytoluene (BHT, IC50:16.47 μg/mL). Molecular docking studies against target tyrosyl-tRNA synthetase (TyrRS) of S. aureus (PDB: 1JIJ) revealed the potential binding mode of the ligands to the appropriate site of targets and their plausible mechanism of in vitro antibacterial activity. [ABSTRACT FROM AUTHOR]

This article explores the use of melamine as a catalyst for synthesizing dihydropyrano[2,3-c]pyrazole derivatives. The authors compare melamine to other catalysts and emphasize its benefits of being reusable, readily available, and cost-effective. The article provides a detailed procedure for the synthesis and notes that the melamine catalyst can be recycled multiple times without significant decreases in product yields. The authors also suggest that melamine may have potential applications in the synthesis of other heterocycles. [Extracted from the article]

N-phenyl benzohydrazonoyl halide derivatives are important building blocks in the synthesis of a large number of heterocyclic compounds that include pyrazoles, pyridazine, etc. The main factor in the importance of hydrazonyl halide is the easy release of the nitrile imine when treated in an alkaline medium through the preparation process. Owing to the wide range of applications of these precursors, we will introduce a general overview for the synthesis and reactions of these types of compounds. [ABSTRACT FROM AUTHOR]

Both pyrazole and coumarin moiety are important scaffolds for their natural occurrences as well as a broad spectrum of pharmaceutical properties. When coumarin fuses with pyrazole containing a diverse functionality, synergic effect may be observed in the field of medicinal and material chemistry. Owing to their various functionality on the pyrazole as well as coumarin moiety of the title compounds, they possess fantastic biological properties including antimicrobial, antiproliferative, CpIMPDH inhibition, α-glucosidase inhibition, selective hCA IX inhibition as well as anticancer activities. Some architectural pyrazolo[c]coumarin derivatives were reported to be used in bipolar host materials and blue TADF-OLEDs. For these reasons, a special attention has been paid to researchers for the searching of new, greener and efficient protocols for the design and synthesis of pyrazolo[c]coumarins to evaluate their biological activities. This paper reviews the research data in the literature on the synthetic strategies for structurally designed pyrazolo[c]coumarin derivatives. Furthermore, the biological properties of these synthesized compounds are described by highlighting their mode of interactions with different cells and enzymes. [ABSTRACT FROM AUTHOR]

This review mainly focused on the synthesis of 3(5)-trifluoromethylpyrazoles via condensation of trifluoromethyl-β-diketones with hydrazines. Also, a special emphasis is led on the biological potential of fluorine containing compounds and pyrazoles in introduction section. We have covered all the literature reported condensation reactions of trifluoromethyl-β-diketones with hydrazines. [ABSTRACT FROM AUTHOR]

AbstractThe novel N-naphthylcyanoacrylamide thioglycosides 4 were readily prepared by the reaction of N-napthylcyanoacetamide 1 with aryl isothiocyanates in the presence of potassium hydroxide, followed by coupling of the produced salts 2 with 2,3,4,6-tetra-O-acetyl-α-d-gluco- and galacto-pyranosyl bromides 3. The N-naphthyl acrylamide thioglycoside 12 was prepared by the reaction of N-napthylcyanoacetamide 1 with glucose isothiocyante 10 in the presence of potassium hydroxide, followed by alkylation of the produced salt 11 with methyl iodide. The reaction of thioglycoside compounds 4 with hydrazines afforded the corresponding naphthyl-pyrazole hybrids. [ABSTRACT FROM AUTHOR]

Herein, an effective and facile synthesis of 3-(pyrazol-1-yl) succinimides is first presented through silver-catalyzed aza-Michael addition of pyrazoles to maleimides. In the presence of 5 mol% of Ag2CO3, various pyrazoles smoothly reacted with maleimides in dichloroethane at 100 °C, to generate 3-(pyrazol-1-yl) succinimides in excellent yields. Notably, 3-substituted asymmetric pyrazoles exclusively give 3-pyrazolyl succinimides in excellent yields possibly due to the steric bulk of the 3-substituent excluding the formation of addition products of N². The method can also extend to gram scale. [ABSTRACT FROM AUTHOR]

Design and synthesis of three novel series of aryl enaminones (3a–f and 5a–c) and pyrazole (4a-c) linked compounds with sulphonamides, sulfaguanidine, or carboxylic acid functionalities were reported as carbonic anhydrase inhibitors (CAIs) using the "tail approach" strategy in their design to achieve the most variable amino acids in the middle/outer rims of the hCAs active site. The synthesised compounds were assessed in vitro for their inhibitory activity against the following human (h) isoforms, hCA I, II, IX, and XII using stopped-flow CO2 hydrase assay. Enaminone sulphonamide derivatives (3a–c) potently inhibited the target tumour-associated isoforms hCA IX and hCA XII (KIs 26.2–63.7 nM) and hence compounds 3a and 3c were further screened for their in vitro cytotoxic activity against MCF-7 and MDA-MB-231 cancer cell lines under normoxic and hypoxic conditions. Derivative 3c showed comparable potency against both MCF-7 and MDA-MB-231 cancer cell lines under both normoxic ((IC50 = 4.918 and 12.27 µM, respectively) and hypoxic (IC50 = 1.689 and 5.898 µM, respectively) conditions compared to the reference drug doxorubicin under normoxic (IC50 = 3.386 and 4.269 µM, respectively) and hypoxic conditions (IC50 = 1.368 and 2.62 µM, respectively). Cell cycle analysis and Annexin V-FITC and propidium iodide double staining methods were performed to reinforce the assumption that 3c may act as a cytotoxic agent through the induction of apoptosis in MCF-7 cancer cells. [ABSTRACT FROM AUTHOR]

A series of novel isoniazid pyrazole derivatives were synthesized by an efficient, multicomponent reaction of various substituted aromatic aldehydes, isoniazid, and malononitrile in aqueous ethanol. The catalyst-free, green, three-component reaction took place well with good to excellent yields of the desired derivatives. The synthesized novel derivatives were screened for antimicrobial, antioxidant, and anti-TB properties along with the molecular docking study. Some of the synthesized compounds exhibit moderate antibacterial and comparable antifungal properties, while all of them display strong antioxidant activity. The compound 4l demonstrates the most significant activity against M. tuberculosis with MIC = 0.125 µg/mL. The various analytical techniques including FT-IR, 1H NMR, 13C NMR, and HRMS were utilized to confirm the structures of the newly synthesized compounds. [ABSTRACT FROM AUTHOR]

A new set of pyrazolo[1,5-a]pyrimidines 5–8 and imidazo[1,2-b]pyrazoles 9–11 incorporating isoxazole as pharmacologically attractive cores were synthesized starting with aminopyrazole derivative 4. Moreover, the treatment of arylidine derivative 3 with hydroxylamine hydrochloride as nucleophilic reagent afforded the isoxazole derivative 12. All the new target derivatives were assessed in vitro antimicrobial candidates against six strains (three Gram + ve Bacteria and three Gram -ve Bacteria) and two fungi. Target compounds 4, 5, 6, 9 and 10 illustrated potent activity against some of the pathogens compared to the reference drug Ampicillin with minimum inhibitory concentration (MIC) values in some cases less than the reference the other derivatives represented moderate to week and in some cases inactive as a compound 8. Compounds 4, 5, 6 and 10 showed moderate activity against fungi. Finally, antioxidant activities were performed for the most promising targets (except 3a,b and 8) which displayed moderate to very strong antioxidant activities. [ABSTRACT FROM AUTHOR]

Metal organic frameworks are frameworks of 1–3 D formed by the interaction between metal ions/clusters and organic molecules. The high specific surface area and large pore volume of these molecules render them as ideal candidates for catalysis applications. A metal-organic framework (MOF-199) has been synthesized by facile chemical method and characterized by infrared (IR) spectroscopy, proton nuclear magnetic resonance (1H NMR), transmission electron microscopy (TEM) and energy dispersive X-ray (EDS) technique. In this study an efficient eco-friendly procedure for the synthesis of spiro[indoline-3,4′-pyrano[2,3-c]pyrazole] derivatives has been developed through a four-component condensation of isatin and its derivatives, hydrazine hydrate, ethyl acetoacetate, and malononitrile/ethyl cyanoacetate, in the presence of catalytic amount of MOF-199 in H2O at room temperature. The advantages of this protocol include mild reaction condition, green, and nontoxic solvent, high yield, easy separation, reusability of the catalyst and operational simplicity. [ABSTRACT FROM AUTHOR]

Cancer is the second leading cause of death worldwide. There is always a huge demand for novel anticancer. New series of pyrazole, pyridine, thiazole derivatives containing sulfonamide moiety were prepared and screened for their antitumor activity against breast cancer cell line (MCF-7). The results of this investigation revealed that compounds 3 and 8 had a significant anticancer activity against MCF-7 cancer cell line with IC50 values 19.2 and 14.2 µM, respectively, in relation to the standard drug, doxorubicin. [ABSTRACT FROM AUTHOR]

Stability studies are essential to ensure that a drug maintains its qualities after leaving the production line until the end of the validity date. This study aimed to identify the alterations related to shelf time in commercial formulations containing dipyrone (metamizole) and to model the shelf time by Raman spectroscopy (830 nm, 350 mW). Spectra of nine commercial medicines containing dipyrone sodium were obtained during the validity period (valid samples) and after the expiration date (overdue samples) with shelf times ranging from 46 to 62 months. The spectra were compared to identify changes due to the dipyrone degradation and develop a model to estimate the shelf time. The Raman analysis of valid and overdue samples showed peaks due to the hydrolysis-oxidation of dipyrone: a blue-shift (N feature in the difference spectrum) of the bands assigned to aromatic and pyrazole rings due to the presence of the metabolite N-methylaminoantipyrine, a decrease in peaks related to the dissociation of − SO3Na due to the hydrolysis/oxidation, and an increase in peaks associated with sodium sulfate/disulfate. A regression model based upon principal component analysis (PCA) showed a strong correlation between shelf time and the PCA variable PC2 (Pearson's correlation coefficient r = 0.804). The study showed the feasibility of Raman spectroscopy in identifying the degradation of dipyrone sodium to characterize the shelf time and use in the quality control of commercial medicines. [ABSTRACT FROM AUTHOR]

Owing to its broad spectrum biological activity, pyrimidines have been extensively employed as building blocks for synthesizing various drug mimic molecules. In the present work, a novel 2-hydrazineyl-5-(2-phenylhydrazineylidene)pyrimidine-4,6(1H,5H)-dione 3 was prepared and was subsequently reacted with a variety of substituted benzaldehyde derivatives 4a–c, 6, and heteroaryl ketones namely, 2-acetylthiophene 8, acetophenone 10a, 2-acetylpyridine 10b, or 3-acetylindole 12 to give the respective hydrazones 5a–c, 7, 9, 11a,b, or 13. Moreover, the reaction of hydrazine 3 with commercially available active methylene compounds, namely, ethyl benzoylacetate 14, acetylacetone 16, and diethyl malonate 18, afford the respective pyrazole derivatives 15, 17, and 19. All reactions were preceded in good yields and the structures of the synthesized compounds were confirmed by elemental analysis, IR, 1H-NMR, 13C-NMR and mass spectral data. The anti-viral activity of the synthesized derivatives was investigated against SARS-CoV-2 main protease (Mpro) using molecular docking combined with molecular dynamics simulation (MD). The docking scores against (PDB: 6LU7), were calculated via Standard Precision (SP) method of the Glide docking module of Meastro. The docking score of the novel compounds ranged between −7.29 and −6.02 with good affinity toward Mpro. Pyrazolinone 19 demonstrated the lowest docking score (-7.293 kcal/mol) and glide emodel −72.978, showed three hydrogen bond interactions with GLU166, GLY143 and the catalytic dyad CYS145. Thus, compound 19 was chosen for further molecular dynamics simulation study for 20 ns. The results indicated that the protein was almost stabilized with average four to five hydrogen bonds with compound 19 during the simulation period. This means the potential inhibitory activity of the promising pyrazolinone 19 against SARS-CoV-2 Mpro. [ABSTRACT FROM AUTHOR]

The photochemical behavior of terarylenes containing benzofuran and aminopyrazole fragments was studied. It was found that the presence of an amino group in the structure of the studied terarylenes blocks photocyclization. At the same time, the transformation of the amino group into a pyrrole fragment allows one to remove the aforementioned blocking effect. As a result, UV-irradiation of pyrrole-containing compounds leads to 6π-electrocyclization of the 1,3,5-hexatriene system with the formation of polycyclic molecules. For the first time an efficient method for the photogeneration of pyrrole molecule using the phototransformation of substituted 2-arylbenzofurans was proposed. The structure of one of the target products was established by X-ray diffraction. [ABSTRACT FROM AUTHOR]

A series of novel 6-amino-4-thioxo-pyrano[2,3-c]pyrazole-5-carbonitriles, 7-amino-5-thioxo-pyrano[2,3-d]pyrimidine-6-carbonitriles and 4,7-diamino-5-thioxo-pyrido[2,3-d] pyrimidine-6-carbonitriles were achieved by facile green one-pot and three-component synthesis. The method depended on one-pot three-component reaction of readily available starting materials carbon disulfide, malononitrile and heterocyclic active methylene compounds catalyzed by triethylamine in water as solvent under ultra-sonication technique. The remarkable advantages of this method are the simple procedure; high yields, short rection time and environmentally benign method are the advantages of this protocol. There is no need for any additional chromatographic separation with this procedure. Analytical and spectroscopic methods were used to comprehensively characterize the structures of all newly products. [ABSTRACT FROM AUTHOR]

Pyrazole category with all derivatives have well-known with biological and industrial applications. Pyrazole combined with other cycle (aliphatic or heterocycles) through one carbon atoms afforded spiropyrazoles. This spiropyrazoles characterized with biological importance as antitumor, analgesic, anti-inflammatory, vasodilation, aldosterone antagonistic, antimicrobial, phosphodiesterase, anabolic, androgenic, progestational, and salt-retaining activities. We interested in this review to collect and sort the spiropyrazoles according to their combined rings and illustrated the different methods of synthesis until the middle of 2021. [ABSTRACT FROM AUTHOR]

In this article, an efficient and practicable synthesis of 1,3,4-trisubstituted pyrazoles with an acyl functionality attached on the 4-position of the pyrazole scaffolds is reported. The precursor 4-cyanopyrazoles used for the fabrication of target compounds were synthesized from 4-formylpyrazoles via oxime formation followed by reaction with Vilsmeier–Haack reagent. The reaction of 4-cyanopyrazoles with various Grignard reagents afforded the corresponding 1,3,4-trisubstituted pyrazoles in 71–88% yield. The operational simplicity, economical starting materials, and high efficiency compared to reported methods are the advantages of this approach. All the pyrazole derivatives have been screened for antimicrobial activity and some of the derivatives exhibit significant activity against bacterial and fungal isolates. Further, time resolved photoluminescence studies for 5d, 5h, & 5o were carried out using pulsed nitrogen laser as the source with a pulse width of few nanoseconds and wavelength of 337 nm. The spectrum was observed in microsecond time domain in all the cases, however, fluorescent lifetime is found to higher in 5d & 5h. [ABSTRACT FROM AUTHOR]

A series of new pyrimidine derivatives were synthesized, including sulfapyrimidines and pyrazolo[1,5-a]pyrimidines. In basic medium, pyrimidine compounds were produced by reacting sulfa guanidine with either 2-cyano-3-(dimethylamino)-N-acrylamides or N-(4-chlorophenyl)-2-cyano-3-(4-aryl)-acrylamides. The reaction of 5-amino-1H-pyrazole-4-carboxamides with either 2-cyano-3-(dimethylamino)-N-acrylamides or N-(4-chlorophenyl)-2-cyano-3-(4-aryl)acrylamides resulted in the synthesis of pyrazolo[1,5-a]pyrimidine compounds. [ABSTRACT FROM AUTHOR]

The extraction of Am3+ and Eu3+ with 6,6'-bis(5-alkyl-1H-pyrazol-3-yl)-2,2'-bipyridine (BPzBPy, alkyl = i-Bu, n-Bu, n-Oct) from HNO3 medium and the complexation of BPzBPy with Eu3+ were investigated. By using meta-nitrobenzotrifluoride (F-3) as a diluent, iBu-BPzBPy ligand in combination with 2-bromohexanoic acid was able to extract Am3+ over Eu3+ with the nature of significantly high efficiency, relatively fast extraction kinetics, and easy stripping. Slope analysis showed the formation of a 1:2 metal/ligand extraction species. The analyses of electrospray ionization mass spectrometry (ESI-MS), Fourier transform infrared (FT-IR) and time-resolved laser fluorescence spectrum (TRLFS) revealed that the composition of the extracted complex was [Eu(H2O)L2]A3 (L = ligand; HA = 2-bromohexanoic acid). The complexation of iBu-BPzBPy ligand with Eu3+ was an enthalpy-driven spontaneous, exothermic, and entropy-decreasing process. Besides, the complex stability constants were also obtained via UV–vis spectrophotometric titration. Combining the results of solvent extraction and complexation studies, a cation exchange extraction model was also proposed. [ABSTRACT FROM AUTHOR]

A series of thiazolyl pyrazoles (4a–f, 6a–f, and 8a–b) were synthesized by a conventional method using thiosemicarbazide, substituted phenacyl bromides, or substituted 3-(2-bromoacetyl) coumarins, 1-Boc-3-cyano-4-pyrrolidone, or 1-Boc-3-cyano-4-piperidone. All synthesized compounds' structures were confirmed by spectral (1H- and 13C-NMR, FTIR, Mass) and analytical data. The target compounds were screened for their in vitro anticancer activity. The results found that the compound 8a and 8b has shown significant antiproliferative activity against HeLa, A549, and MDA-MB-231 cancer lines. Furthermore, in silico ADME profiles were also predicted to set effective lead candidates for future anticancer drug discovery initiatives. The synthesized thiazolyl pyrazoles derivatives were further subjected to docking simulations, and the results were in agreement with the in vitro results. [ABSTRACT FROM AUTHOR]

Nano-Zn[4-nitrophenyl-salicylaldimine-pyranopyrimidinedione]Cl2 {Nano-[Zn-4NSP]Cl2}, as a new Schiff base complex and heterogeneous catalyst, was prepared and fully characterized by different analyses. Nano-[Zn-4NSP]Cl2 was applied as an efficient catalyst for the synthesis of some 5-amino-1H-pyrazole-4-carbonitrile derivatives. [ABSTRACT FROM AUTHOR]

A mild and efficient protocol was developed for the synthesis of pyrazole and 2°-amine hybrid conjugates through an InCl3 Ugi four-component reaction followed by a base mediated secondary amine coupling reaction. MCRs have been used extensively in the field of combinatorial chemistry, which offers the synthesis of libraries of similar molecules in a parallel fashion. A small library of novel N-allyl-N-(1-(4-(aminomethyl) phenyl)-2-(tert-butylamino)-2-oxoethyl)-1,3-diphenyl-1H-pyrazole-4-carboxamide scaffold was designed and synthesized through a one-pot four-component Ugi reaction, the resulting Ugi product pyrazole derivative coupled with various secondary amines to prepare target pyrazole – amine conjugate molecules. The structures of synthesized conjugates confirmed by spectroscopic techniques (NMR, C, H, N analysis, and MS). The in vitro antimicrobial survey of these pyrazole-secondary amine conjugates was supported by DFT studies; thereby notifies the conjugates are promising antimicrobial agents and are comparable to the standard antimicrobial molecules such as ampicilin, griseofulvin, isoniazide and rifampicin. [ABSTRACT FROM AUTHOR]

Interaction with components of the extracellular matrix, particularly various forms of collagen, is essential for the design of successful scaffolds for tissue engineering applications. Both Type II and Type III collagen are found in various connective tissues in the body, providing stability, wound healing, and in some cases assisting in fibrillogenesis. In this study, we designed short peptide conjugates with phenyl pyrazole moieties and examined their interactions with Type II and III triple helical collagen models. The number of hydrophobic groups was varied by varying the phenyl pyrazole moieties that were conjugated with three separate peptides (SYED; SLKD and SLYD). Molecular dynamics (MD) and docking studies revealed that in most cases conjugating with phenyl pyrazole improved binding affinity and stability compared to neat peptides. Computational studies were also carried out to examine the formation of stable scaffold assemblies using MD simulations by integrating the peptide conjugates with either Type II or III collagen and chondroitin sulfate, in order to mimic the formation of a scaffold. As a proof of concept, we examined the binding interactions of the short peptides with Type II and III collagen using SPR and CD spectroscopy, and then synthesized two of the peptide conjugates and integrated them with either Type II or Type III collagen and chondroitin sulfate by layer-by-layer assembly to develop scaffolds to validate computational results. AFM imaging showed the formation of fibrillary structures. The cytocompatibility of the scaffolds was then examined in the presence of mesenchymal stem cells, that showed the formation of cell-scaffold matrices particularly with SLYD conjugates. Our results indicate that such peptide-pyrazole conjugates, may be developed for designing scaffolds for tissue engineering applications. [ABSTRACT FROM AUTHOR]

As pyrazoles are familiar for showing various biological properties, a series of novel isocoumarin tethered carbothioamide linked pyrazole derivatives were prepared successfully in the presence of environmental favor conditions and evaluated for their pathogenic resistance against four bacteria and two fungi, showing significant activity against different microbial except compound 5d. Among the active compounds, 5f displayed highest antimicrobial property. In fact, 5b and 5l motifs showing good inhibitory activity. Further, a detailed structure activity relationship also discussed, which revealed that the presence of electron withdrawing -NO2 group in 5f compound may delivered highest biological property, while the amino group attached in compound 5d delivered inactive antibacterial property. Moreover, computer aided studies of biologically effective compounds to determine the interactions and docking score with the crystal structure of Escherichia coli 24 kDa DNA gyrase subunit B in complex with clorobiocin. It was observed that the amino acid residues present in the active binding site of the protein1KZN can frequently interact with targets. [ABSTRACT FROM AUTHOR]

Novel scaffolds are expected to treat Alzheimer's disease, pyrazole-5-fluorosulfates were found as selective BuChE inhibitors. Compounds K1-K26 were assayed for ChE inhibitory activity, amongst them, compound K3 showed potent BuChE and hBuChE inhibition (IC50 = 0.79 µM and 6.59 µM). SAR analysis showed that 1-, 3-, 4-subtituent and 5-fluorosulfate of pyrazole ring affected BuChE inhibitory activity. Molecular dock- ing showed that the fluorosulfate increased the binding affinity of hBuChE through π-sulphur interaction. Compound K3 was a reversible, mixed and non-competitive BuChE inhibitor (Ki = 0.77 µM) and showed remarkable neuroprotection, safe toxicological profile and BBB penetration. In vivo behavioural study showed that K3 treatment improved the Aβ1-42-induced cognitive impairment, and significantly pre- vented the effects of Aβ1-42 toxicity. Therefore, selective BuChE inhibitor K3 has potential to be further developed as AD therapeutics. [ABSTRACT FROM AUTHOR]

A series of N-(4-chlorophenyl) substituted pyrano[2,3-c]pyrazoles was synthesised and screened for their potential to inhibit kinases and exhibit anticancer activity against primary patient-derived glioblastoma 2D cells and 3D neurospheres. A collection of 10 compounds was evaluated against glioma cell lines, with compound 4j exhibiting promising glioma growth inhibitory properties. Compound 4j was screened against 139 purified kinases and exhibited low micromolar activity against kinase AKT2/PKBβ. AKT signalling is one of the main oncogenic pathways in glioma and is often targeted for novel therapeutics. Indeed, AKT2 levels correlated with glioma malignancy and poorer patient survival. Compound 4j inhibited the 3D neurosphere formation in primary patient-derived glioma stem cells and exhibited potent EC50 against glioblastoma cell lines. Although exhibiting potency against glioma cells, 4j exhibited significantly less cytotoxicity against non-cancerous cells even at fourfold–fivefold the concentration. Herein we establish a novel biochemical kinase inhibitory function for N-(4-chlorophenyl) substituted pyrano[2,3-c]pyrazoles and further report their anti-glioma activity in vitro for the first time. Anti-glioma pyrano[2,3-c]pyrazole 4j inhibited the 3D neurosphere formation in primary patient-derived glioma stem cells. 4j also displayed PKBβ/AKT2 inhibitory activity. 4j is nontoxic towards non-cancerous cells. [ABSTRACT FROM AUTHOR]

The synthesis of dihydropyrano[2,3 I c i ]pyrazoles continues to be an object of attention among organic chemists, due to their diverse bioactivity profiles, which include action as therapeutic agents.[1] The compounds are potential inhibitors of human Chk1 kinase,[2] and they have anticancer,[3] molluscicidal[4] and antimicrobial[5] properties. The reaction was achieved via the tandem Knoevenagel-Michael cyclocondensation of ethyl acetoacetate, hydrazine hydrate, aryl aldehydes and malononitrile using CMC as catalyst. In this vein, our own work has been aimed at developing green synthetic processes.[22],[23] We here report a solvent-free environmentally friendly synthesis of the title compounds through the use of carboxymethyl cellulose (CMC) (Figure 1) as a green, recyclable, and biodegradable catalyst (Scheme 1).[24],[25] The reaction is envisioned as taking place through the tandem Knoevenagel-Michael cyclocondensation of ethyl acetoacetate, hydrazine hydrate, aryl aldehydes and malononitrile using CMC as catalyst. [Extracted from the article]

The synthesis and characterization of a variety of novel heterocyclic compounds bearing the pharmacophore N-carbamimidoylsulfamoyl moiety that are relevant to antibacterial and antifungal activities are described. All the newly synthesized compounds have been characterized on the basis of IR, 1H MR and 13C NMR spectral data as well as physical data. The synthesized compounds, except thiophene 10, were tested against six standard microbial pathogens, and the antimicrobial activity of these compounds was evaluated according to the microdilution method. Most of the newly tested derivatives showed good to excellent antimicrobial activity when applied to MIC/MBC and MIC/MFC values. [ABSTRACT FROM AUTHOR]

A rapid and green procedure has been introduced for the preparation of pyrano[2,3-c]pyrazole and xanthene-1,8-dione derivatives in the presence of a natural catalyst in aqueous medium. Sodium tetraborate pentahydrate was found as a nontoxic or minimally toxic, readily available, cheap, and ecologically favorable agent catalyst for the synthesis of these important heterocyclic compounds. The introduced method offers some advantages such as high efficiency, an inexpensive and easy-to-handle catalyst, avoidance of organic solvents, and simple work-up that they are consistent with green chemistry. [ABSTRACT FROM AUTHOR]

Two series of nicotinonitrile-linked chromenes attached to pyrazole units were synthesized in the current study. A [3 + 2] cycloaddition protocol was used to produce the target hybrids in high yields by reacting the respective nitrilimines, which were generated in situ by the action of triethylamine on hydrazonoyl chlorides, with chromene-based enaminone. Generally, the acetylcholinesterase and DPPH free radical inhibitory activity are related to the electronic properties of the para-substituent that is attached to the arene unit at pyrazole-C1. Furthermore, 3-acylpyrazole unit has a significant effect on the new hybrids' efficacy. At 25 and 50 µM concentrations, the 3-acetylpyrazole attached to p-OMe unit demonstrated the best acetylcholinesterase inhibitory activity, with inhibition percentages of 75.8 and 88.3, respectively. Furthermore, the previous hybrid demonstrated the most effective antioxidant activity, with an inhibition percentage of 82.6 at a tested concentration of 25 µg/mL. According to SwissADME, the majority of the pyrazoles tested are drug-like. [ABSTRACT FROM AUTHOR]

A new series of organic tellurium compounds containing pyrazole derivatives were prepared. Initially, penta-2,4-dione-3-tellurocyanate (1) was prepared by the refluxing equimolar amounts of potassium tellurocyanate with 3-chloro-2,4-pentadione. Compound 1 was oxidized by excess bromine to obtain the corresponding tribromide (2). The cycloaddition reaction of compound 1 with phenylhydrazine formed 3,5-dimethyl-1-phenyl-4-tellurocyanatopyrazole (3 (in good yield. Treatment of compound 3 with excess bromine gave 3,5-dimethyl-1-phenylpyrazole-4-yltellurium tribromide (4) in an excellent yield. Reduction of compound 3 with a solution of 10% NaOH gave the corresponding ditelluride (5) in excellent yield. Compounds with a general formula of ArTeX3; X = Cl (6) or I (7) were synthesized in excellent yields by reacting compound 3 with excess thionyl chloride or iodine, respectively. Refluxing ditelluride 5 with activated copper powder gave the corresponding telluride (8) in very good yield. Finally, tellurated pyrazole dihalides compounds 9–11 were prepared by reacting 8 with equimoles of the thionyl chloride, bromine and iodine, respectively. The structures of compounds 1–11 were elucidated according to their CHN elemental analyses and FTIR, 1H- and 13C-NMR spectroscopies and mass spectrometry. The antibacterial activity for both Gram-positive and Gram-negative bacteria were evaluated. The tested compounds showed a good degree against the growth of fungi and bacteria. Most the antimicrobial activity of the prepared compounds was better than fluconazole. [ABSTRACT FROM AUTHOR]

A series of new 6,8-dichloro-imidazo[1,2-a]pyridine derivatives incorporating pyridine, thiazole, and pyrazole ring systems was synthesized. The synthetic strategy of imidazopyridinyl-pyridine hybrids 2 and 3 involves one pot reaction of the precursor 3-acetyl-6,8-dichloro-2-methylimidazo[1,2-a] pyridine (1) with aldehydes, malononitrile, and/or ethyl cyanoacetate. Treatment of 1 with thiosemicarbazide and/or bromine followed by subsequent cyclization with ethyl bromoacetate, chloroacetone, phenacyl chloride, and/or thiourea was applied as synthetic routes for accessing the imidazopyridinyl-thiazole hybrids 5, 6, and 8–10. The reaction of 1 with dimethylformamide-dimethylacetal followed by subsequent treatment with hydrazine was employed to prepare the imidazopyridinyl-pyrazole motif 12. The antibacterial potency of these imidazopyridine hybrids has been evaluated against some model bacteria. The results indicated that the imidazopyridine-thiazole hybrids revealed remarkable antibacterial activities. [ABSTRACT FROM AUTHOR]

New series of 4-methyl-2-(4-substituted phenyl)-5-(4-((4-(4-substituted phenyl)-1H-1,2,3-triazol-1-yl)methyl)-1-phenyl-1H-pyrazol-3-yl)thiazole, 6a-t and 4-(1,3-diphenyl-1H-pyrazol-4-yl)-1-((1,3-diphenyl-1H-pyrazol-4-yl)methyl)-1H-1,2,3-triazole, 11a-o derivatives have been synthesized by applying copper-catalyzed [3 + 2] cycloaddition reaction. The newly synthesized 1,3-thiazolyl-pyrazolyl-1,2,3-triazole (6a-t) and bis-pyrazolyl-1,2,3-triazole (11a-o) derivatives were screened for in vitro antimycobacterial activity against M. Tuberculosis H37Ra dormant and active and antibacterial activity against four pathogenic bacteria, E. coli (NCIM 2576), P. flurescence (NCIM 2059), S. aureus (NCIM 2602) and B. subtilis (NCIM 2162). Compounds 6a, 6f, 6j, 11e and 11m showed good activity against M tuberculosis H37Ra Active strain, also compounds 6g, 6h, 11f, 11n and 11o showed good activity against M tuberculosis H37Ra Dormant strain. Compounds 6b, 6i, 6l, 6o, 6r, 11k, 11l and 11m showed good activity against B. subtilis with IC50 1.99-2.96 µg/mL. The antibacterial activity of thiazolyl-pyrazolyl-1,2,3-triazole and bis-pyrazolyl-1,2,3-triazole derivatives suggested that, these derivatives could lead to new compounds for treatment against bacterial infection. [ABSTRACT FROM AUTHOR]

In this work, nano-AlPO4/Ti(IV) (NAPT) as a new nanocomposite was prepared and then characterized by FT-IR, XRD, FESEM, TEM, BET and TGA. This nano-catalyst was used for synthesis of dihydropyrano[2,3-c]pyrazole (DHPP) derivatives by one-pot four component reaction of aldehyde, ethyl acetoacetate, malononitrile and hydrazine hydrate. An uncomplicated work-up, high yields of product, short reaction times and use of low-cost catalyst are considerable properties of present procedure. [ABSTRACT FROM AUTHOR]

Osmium(IV) pyrazole carbothioamide complexes with different substituted pyrazole carbothioamide heterocyclic ligands have been synthesized and characterized. The ligands have been characterized using 1H-NMR, 13C-APT, LC-MS, elemental analysis, and IR spectroscopy. Whereas, osmium(IV) compounds have been characterized using ESI-MS, ICP-OES, IR spectroscopy, magnetic, and conductance measurements. The compounds have been evaluated for various biological activities. The binding constant of ligands and complexes have been found in the range of 1.2–3.6 × 104 and 1.2–6.8 × 104 M−1, respectively. The docking energy values of complexes have been found in the range of −286.28 to −326.49 kJ/mol. The Ksv and Kf values of Os(IV) compounds evaluated using fluorescence quenching activity have been found in the range of 4.7–9.2 × 103 and 1.3–7.6 × 103 M−1, respectively. The minimum inhibitory concentration of osmium(IV) compounds and ligands have been found in the range of 50–75 µM and 120–135 µM, respectively. The LC50 values evaluated using brine shrimp lethality assay of osmium(IV) compounds and ligands have been found in a range of 7.52–16.12 µg/mL and 15.80–20.03 µg/mL, respectively. [ABSTRACT FROM AUTHOR]

An unexpected efficient basic catalyzed heterocyclization reactions were carried out to build blocks of potentially bioactive 2-{pyrano[2,3-c]pyrazoles-4-ylidene}malononitrile skeleton fused with pyrazole, pyridine, pyrimidine, diazepine, chromone, pyrano[2,3-c]pyrazole, and pyrano[2,3-d]pyrimidine systems in novel molecular frames. The method depended on treatment of 6-amino-4-(4-oxo-4H-chromen-3-yl)-3-phenyl-1,4-dihydro-pyrano[2,3-c]pyrazole-5-carbonitrile (1) with different nitrogen and carbon nucleophiles in ethanolic sodium ethoxide. Possible mechanisms for the reactions were suggested. Elemental analyses and spectral techniques confirmed the structures of the isolated products. The compounds were evaluated for cytotoxic activities. Among the synthesized compounds, both 4 and 11 exhibited the most potent cytotoxicity against all used cancer cell lines. [ABSTRACT FROM AUTHOR]

The synthesis, spectral characteristics, thermal properties and single crystal structures of [Co(N-meim)2(4-nba)2] (N-meim = N-methylimidazole; 4-nba = 4-nitrobenzoate) (1), [Co(2-meim)2(4-nba)2] (2-meim = 2-methylimidazole) (2), [Co(pyr)3(4-nba)2] (pyr = pyrazole) (3), [Co(H2O)2(form)2(4-nba)2]·form (form = formamide) (4), [Co(H2O) (aceta)2(4-nba)2] (aceta = acetamide) (5) and [Co(H2O)3(N-mepyr)(4-nba)](4-nba) (N-mepyr = N-methylpyrazole) (6) are reported. The central Co(II) exhibits tetrahedral geometry in 1 and 2, trigonal bipyramidal geometry in 3 and octahedral geometry in 4–6. In the anhydrous compounds 1–3 as well as the diaqua compound 4, the monoaqua compound 5 and the triaqua compound 6, the neutral N-donor co-ligands or the O-donor amides function as terminal ligands. The aromatic 4-nba ligand exhibits monodentate binding mode in 1–4 and monodentate and bidentate binding in 5, while 6 contains an uncoordinated 4-nba in addition to a bidentate 4-nba ligand. A single C-H···O interaction links molecules of 1 into an infinite chain while the N-H···O bonds in 2 result in a two-dimensional network. Compounds 4 and 5 exhibit three varieties of H-bonding. Thermal decomposition of 1–6 results in the formation of a spinel oxide. A comparative study of thirty-one structurally characterized cobalt-4-nitrobenzoates is described. [ABSTRACT FROM AUTHOR]

In recent years, there has been a lot of interest in the modern organic synthesis using enzymes as biocatalysts. A multicomponent reaction of 4-formylphenyl benzoates, malononitrile, and pyrazolones utilizing pepsin as a biocatalyst was investigated in different reaction conditions. The best yields of pyrano[2,3-c]pyrazoles were obtained by grinding the respective reactants in a mortar in the presence of pepsin for 1.5–2 h at room temperature. Instead of pyrazolones, 1,3-cyclic diketones and 4-arylazo-5-aminopyrazoles were used to prepare new series of 4H-chromenes, and pyrazolo[1,5-a]pyrimidines in good to excellent yields after grinding the respective reactants for 0.5–3 h. The new target molecules showed a wide range of antibacterial activity against four different ATCC bacterial strains. The pyrazolo[1,5-a]pyrimidines 14a and 14f displayed moderate antibacterial activity against the K. pneumoniae and S. aureus strains with inhabitation zones of 29.6–30.3 mm and MIC values of 125–250 μg/mL. [ABSTRACT FROM AUTHOR]

In the present study, we have designed a novel series of pyrazolyl-1,3,4-thiadiazole analogues by accommodating 1,3,4-thiadiazole ring at C – 4 of pyrazole ring with and without an amide linkage; 5-methyl-1,3-diphenyl-N-(5-phenyl-1,3,4-thiadiazol-2-yl)-1H-pyrazole-4-carboxamide and 2-(5-methyl-1,3-diphenyl-1H-pyrazol-4-yl)-5-phenyl-1,3,4-thiadiazole respectively. We have designed this class of heterocycles by keeping a wide audience in mind, which augment their scientific knowledge. Newly synthesized compounds were characterized by 1H NMR, 13C NMR, mass, IR spectral studies. Single crystal X-ray analysis of some compounds also gave insight into the structural information. [ABSTRACT FROM AUTHOR]

Historically, heterocyclic compounds including N-heterocycles and their derivatives are valuable source for the identification of therapeutically active agents. Studies in the recent two decades have been reported escalating data utilizing drug optimization parameters on various pyrazole clubbed pyrimidine derivatives with numerous pharmacological activities. The present review article deals to emphasize the diverse synthetic approaches reported by researchers on pyrazole clubbed/fused pyrimidines for their antimicrobial potency. Ring variation, ring fusion, substitution variant and spacer addition strategies allied with electron withdrawing groups at active sites on pyrazole and pyrimidine are the best combination to achieve potent antimicrobial motifs. N-substituted aromatic or hetero-aromatic groups along with EWG are also good structural modifications to improve the pharmacokinetic properties in pre-clinical drug species. A new age antimicrobials can be synthesized with the next level of potency by this prospective. [ABSTRACT FROM AUTHOR]

.5Trace ht 1 SP a sp Reaction conditions: B 1 b (1 mmol), B 2 b (1 mmol), B 3a b (1 mmol), B 4 b (1 mmol), catalyst (15 mol%), in solvent (10 mL). 3 ht 3 SP a sp Reaction conditions: B 1 b (1 mmol), B 2 b (1 mmol), B 3a b (1 mmol), B 4 b (1 mmol) and (DL)-mandelic acid in water (10 mL) for 1.5 h. 4 SP b sp Isolated yields. The success of green chemistry in the drug discovery process is considerably dependent on new advances in methodology for heterocyclic multi-component reactions (MCRs) and on new developments in environmentally benign MCR procedures.[[1], [3]] Pyrazoles are a vital class of compounds in drug development, as they comprise the core structures of numerous blockbuster drugs such as celecoxib, viagra, and pyrazofurine, among others.[[4], [6]] Compounds with the dihydropyrano[2,3-C]pyrazole moiety[7] have anticancer,[8] analgesic,[9] anti-inflammatory,[10] antimicrobial[11] and molluscicidal activities.[12] These molecules are also used as potential inhibitors of human Chk1 kinase.[13] Thus, the formation of dihydropyrano[2, 3-C]pyrazoles is an important and useful task in preparative organic chemistry. [Extracted from the article]

Full chemical-kinetics of the green one-pot four-component condensation among ethyl acetoacetate 1, hydrazine hydrate 2, malononitrile 3 and various substituents of benzaldehyde 4 has been spectrally investigated for the generation of pyranopyrazoles 5. The extremely large negative ΔS‡ values were obtained for all the reactions, particularly in four-component reaction among 1, 2, 3 and para electron-withdrawing substituted benzaldehyde 4. The high unfavorable ΔS‡ value (-188.2 J mol−1 K−1) is compensated by the favorable Δ H electron − withdrawing ‡ value (lower, 13.47 k J mol−1) in comparison with ΔH‡ values of unsubstituted benzaldehyde 4 (19.1 k J mol−1) and electron-donating substituted benzaldehyde 4 (37.4 k J mol−1), herein, the reaction rate with lesser value of Δ G electron − withdrawing ‡ = 69.58 k J mol−1 is faster than other reactions, compared to Δ G unsubstituted ‡ = 72.74 and Δ G electron − donating ‡ = 76.63 k J mol−1. A reliable correlation of log k and σ R + with an excellent DPF (r = 0.990) and positive value of reaction constant ( ρ = + 1.1003) demonstrated that both resonance and inductive effects "altogether" contributed on the reaction center with a strong electron-withdrawing group, accompanied by high positive charges, which can be stabilized by electron-donating compound. The substituent effects on the reaction kinetics generally obey the same kinetics role for the series of compounds used in this work (Hammett, Exner and isokinetic relationship studies). Among ten steps inside the reaction mechanism, only step8 with the substituent group near the reaction center could be resonated directly with this center. So, step8was identified as RDS. [ABSTRACT FROM AUTHOR]

The highly versatile 6-cyano-5-oxo-3,5-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine (6) has been synthesized and utilized as a building block for the design of new tricyclic and tetracyclic ring systems incorporating the triazolo[1,5-a]pyrimidine skeleton. The synthetic strategy for the construction of novel tricyclic classes, pyrazolo[4,3-e]triazolo[1,5-a]pyrimidines 7–8, pyrido[3,4-e]triazolo[1,5-a]pyrimidines 9–10, and pyrano[3,4-e]triazolo[1,5-a]pyrimidines 12–14, based on reactions of the precursor 6 with hydrazines, activated nitriles, β-diketones, β-ketonitriles, and pyrazolones. The tetra-heterocyclic systems in which the pyrimido-[1,2,4]triazolo[1,5-a]pyrimidine fused with different rings such as tetrazole, triazole, imidazole, and/or pyrazole were synthesized through the heterocyclization of the precursor 6 with various α-aminoazoles (namely; 5-amino-1H-tetrazole, 3-amino-4H-1,2,4-triazole, 2-aminobenzimidazole, 5-amino-3-methyl-1H-pyrazole, and/or 5-amino-4-arylazo-pyrazoles). The newly synthesized polyheterocyclic ring systems were characterized by spectroscopic evidence, using IR, 1H and 13C NMR, and mass analyses. The triazolo[1,5-a]pyrimidine-based compounds were assayed for antioxidant properties by the ABTS technique to identify the tricyclic pyrano[3,4-e]triazolo[1,5-a]pyrimidine compounds 12a and 12b that exhibit the best antioxidant activity with percent inhibition (86.07% and 85.29%). [ABSTRACT FROM AUTHOR]

3-Chloro-3-(4,9-dimethoxy-5-oxo-5H-furo[3,2-g]chromen-6-yl)prop-2-enal (2) was utilized as a synthetic intermediate for construction of a variety of heterocyclic system linked furo[3,2-g]chromene (khellin) moiety. Reaction of compound 2 with some heterocyclic amines produced the Schiff bases 5 and 6. Treatment of compound 2 with a diversity of 1,2-, 1,3- and 1,4-binucleophilic reagents afforded a diversity of furo[3,2-g]chromenes bearing pyrazoles, pyridines, pyrimidine, pyrazolopyridine, triazolo[4,3-a]pyrimidine, pyrimido[1,2-a]benzimidazole, pyrido[1,2-a] benzimidazole, pyrido[2,3-d]pyrimidine, pyrazolo[3,4-b]pyridine, benzodiazepine, benzoxazepine and benzothiazepine. The prepared compounds were screened for their antimicrobial and anticancer activities demonstrating variable inhibitory effect. Analytical and spectral data were used to verify the structures of the newly prepared compounds. [ABSTRACT FROM AUTHOR]

A catalyst-free and convenient synthetic route to the green one-pot preparation of dihydropyrano[2,3-c]pyrazole scaffolds via four-condensation domino reaction of tandem Knoevenagel-Michael cyclocondensation reaction of ethyl acetoacetate, hydrazine hydrate, aryl aldehyde derivatives and malononitrile in glycerol as a reusable and biodegradable promoting media has been described. All reactions are completed in short period of times and the products are obtained in excellent yields. The salient features of this green and expedient approach are catalyst-free conditions, a green and biodegradable reaction medium, excellent yields, straightforward work-up with no column chromatographic separation, avoidance of toxic organic solvents and reagents, one-pot procedure, simplicity of operation and high atom-economy. Also, the glycerol was highly stable and could be reused in four successive runs with no significant structural change and loss of activity which makes it highly beneficial to address the industrial needs and environmental concerns. [ABSTRACT FROM AUTHOR]

Herein, BiFeO3 nanoparticles are successfully established as promising catalyst of heterogeneous nature for one pot production of pyrano[2,3-c] pyrazoles. The desired BiFeO3 nanoparticles were synthesized using a facile auto combustion route in the presence of urea as a fuel. Further, the production was carried out at diverse range of temperatures of calcination (150 °C–650 °C), in order to determine the optimal temperature required for development of pure, BiFeO3 nanoparticles. Each of the prepared, BiFeO3 nanoparticles were fully characterized using XRD, FT-IR, VSM, TEM and BET. The catalytic performance of as BiFeO3 nanoparticles was then investigated for the creation of pyrano[2,3-c] pyrazoles. [ABSTRACT FROM AUTHOR]