Synthesis Of Pyrazoles Research Articles

A New Insight into the Synthesis and Biological Activities of Pyrazole based Derivatives

Abstract: The aim of this review is to collate literature work reported by researchers (from 1994 to 2021) to provide an overview of the available methodologies for the synthesis and diverse pharmacological activities exhibited by pyrazole based molecules. This review highlights recent reports on various routes of synthesis and potential biological evaluation studies viz. anticancer, AT (II) inhibitory, anti-inflammatory activities, HIV-1-RT inhibitory, antihypertensive, herbicidal, antitubercular, insecticidal, antiviral, antimicrobial and COX-2 inhibitory activity, etc. of pyrazole derivatives and also presents recent efforts made on this heterocyclic moiety.

Design, molecular modeling, synthesis and biological evaluation of novel pyrazole based schiff Bases as fungal biofilm inhibitors

We designed series of pyrazole based Schiff bases on the basis of Bioisosteric replacement principle and validated for drug likeness using Absorption, Distribution, Metabolism, and Excretion (ADMET) criteria. The designed Schiff bases who have excellent pharmacokinetics properties, Low toxicity when In-silico analyzed for inhibition potential using molecular docking study. The top hit of molecular docking having free energy of binding in between -6.95to -4.28 kcal/mol was synthesized and biologically evaluated for fungal biofilm inhibition and minimum inhibitory concentration. The invitro biological assay of synthesized Schiff bases suggesting antibiofilm activity of Schiff base MPY10 inhibitory concentration (IC50=41.7μM) and MPY1 (IC50=44.7μM) very much equivalent to standard drug Fluconazole. The inhibition potential of MPY10 (MIC=42.6μg), MPY1 (MIC=54.4μg), MPY2 (MIC=58.1μg), MPY6 (MIC=61.8μg) and MPY4 (MIC=64.2μg) reproduces the molecular docking results shown against c. albicans biofilm drug target secreted aspartic proteinases (Sap5) signifying antifungal activity as that of standard.

Recent Advances in Synthesis and Properties of Pyrazoles

Pyrazole-containing compounds represent one of the most influential families of N-heterocycles due to their proven applicability and versatility as synthetic intermediates in preparing relevant chemicals in biological, physical-chemical, material science, and industrial fields. Therefore, synthesizing structurally diverse pyrazole derivatives is highly desirable, and various researchers continue to focus on preparing this functional scaffold and finding new and improved applications; this review highlights some of the most recent and strategic examples regarding the synthesis and properties of different pyrazole derivatives, mainly reported from 2017–present. The discussion involves strategically functionalized rings (i.e., amines, carbaldehydes, halides, etc.) and their use in forming various fused systems, predominantly bicyclic cores with 5:6 fusion taking advantage of our experience in this field and the more recent investigations of our research group.

Rh(III)-Catalyzed (4 + 1) Annulation of Pyrazol-3-ones with Alkynoates via Ortho-Alkenylation/Cyclization Cascade: Synthesis of Indazole-Fused Pyrazoles.

A facile synthesis of novel indazole-fused pyrazoles from pyrazol-3-ones and alkynoate esters/amides via Rh(III)-catalyzed sequential C-H activation/ortho-alkenylation/intramolecular cyclization cascade is reported. The important characteristic of this method is that the resulting scaffold bearing quaternary carbon has been obtained through unusual [4 + 1] rather than expected [4 + 2] addition where alkynoate acts as a one-carbon unit.

Pyridinium-based dual acidic ionic liquid supported on the pectin for efficient synthesis of pyrazoles

In this work, we developed for the first time a pectin-supported dual acidic pyridinium ionic liquid with rich sulfonic acid groups as an efficient catalyst for the synthesis of pyrazole derivatives. Pectin (Pec) as a biopolymer is initially modified with 2,6-diamino pyridine (DAP) to obtain the Pec-DAP nanoparticles. The produced Pec-DAP reacts with 1,4-butane sultone (BS), and followed by treatment with a H2SO4 solution to afford the Pec-DAP-BS catalyst. The structure of the catalyst is characterized by different techniques. This catalyst presented a remarkable activity as a metal-free catalytic system for the three-component synthesis of pyrazoles from aldehydes, phenylhydrazines, and malononitrile due to the cooperative effect of dual acidic sites. Under optimized conditions, pyrazole derivatives are obtained with high turnover frequencies (TOF) up to 184.7 h−1 and excellent yields (92–96%) in short reaction times (15–50 min) in aqueous ethanol as a green solvent. Moreover, the catalyst is used in at least five cycles without significant loss of activity, and its heterogeneous nature is confirmed by the hot-filtration test.

Synthesis of Pyrazoles by 1,3‐Dipolar Cycloaddition under Aqueous Micellar Catalysis

AbstractEthyl diazoacetate (EDA), which is easily prepared from ethyl glycinate and NaNO2, reacts in situ with alkynes in a water micelle environment without organic solvent to form pyrazoles. The reaction is pH dependent, as in the presence of protic catalysis (H2SO4 4 %, pH 3.5) a mixture of 3,5‐ and 4,5‐disubstituted pyrazoles was obtained, while, at pH 5.5, only the 3,5‐disubstituted isomer was obtained. The presence of the surfactant TPGS‐750‐M was crucial to secure clean crude reaction mixtures and high yields of the products. The same protocol was successfully applied to the synthesis of substituted pyrazolines.

Synthesis, characterization and thermal degradation kinetics of a new pyrazole derived methacrylate polymer, poly(1,3-diphenyl-1H-pyrazol-5-yl methacrylate).

A new pyrazole derived methacrylate monomer, 1,3-diphenyl-1H-pyrazol-5-yl methacrylate, was synthesized from the reaction of 1,3-diphenyl-5-pyrazolone with methacryloyl chloride in the presence of triethylamine. After that, its homopolymerization was carried out by free radical polymerization method at 60 °C initiated with benzoyl peroxide. Spectral characterizations were achieved by 1H-NMR andFTIR spectroscopies. The kinetics of thermal degradation of the new polymer, poly(1,3-diphenyl-1H-pyrazol-5-yl methacrylate), poly(DFPMA), were investigated by thermogravimetric analysis (TGA) at different heating rates. The initial decomposition temperature of the polymer changed from 216.3 °C to 243.5 °C depending on the increasing heating rate. The thermal decomposition activation energies in a conversion range of 7-19% were 79.45 kJ/mol and 81.56 kJ/mol by the Flynn-Wall-Ozawa and Kissinger methods, respectively. Thermodegradation mechanism of the poly(DFPMA) were investigated in detail by using different kinetic methods available in the literature such as Coats-Redfern, Tang, Madhusudanan and Van Krevelen. Among all these methods, the best result was obtained for Coats-Redfern method (E =90.93 kJ/mol) at the optimum heating rate of 15 °C/min for D1 mechanism. That means the thermodegradation mechanism of poly(DFPMA) proceeds over a one-dimensional diffusion type deceleration mechanism.

Anomaly of Pyrano[2,3‐c]pyrazole Synthesis towards Pyrazolyl‐aryl‐methyl‐malononitrile Derivatives and Their Antimicrobial Activity

AbstractOur attempt to prepare pyrano[2,3‐c]pyrazole derivatives from 2‐methyl‐5‐propyl‐1,2‐dihydro‐pyrazolone, malononitrile and benzaldehyde rather lead to the formation of pyrazolyl‐aryl‐methyl‐malononitrile derivatives. Fascinating by this opportunity to branch out the synthesis of substituted pyrazolone derivatives using an efficient multicomponent synthetic approach for pyrazolyl‐aryl‐methyl‐malononitrile derivatives. The synthesis was accelerated using guanidine carbonate as a catalyst in the water reaction medium. The rection has blossomed with the green aspects of synthesis such as organocatalyst, water as reaction medium and ambient temperature providing clean product in higher yield. The synthesized derivatives have been screened for anti‐microbial activity. Compounds 4 c and 4 n showed excellent activity. Six compounds were found to be much effective against the Staphylococcus aureus bacterial strain. The molecular docking study of 4 n showed a high binding affinity with the receptor. Collectively, our study provides eco‐friendly synthesis towards pyrazolyl‐aryl‐methyl‐malononitrile derivatives and we evaluated them as a new class of anti‐microbial compounds.

Synthesis of pyrazole tethered oxadiazole and their analogs as potent antioxidant agents

AbstractPreparation of organic compounds in environmental favor media always a fresh tool in the synthetic research. If those prepared compounds may possess therapeutically potentiality, then it called as efficient research. Herein, we report the 12 new oxadiazole linked carboxamide pyrazole substances have been synthesized and screened for their free radical scavenging activity by using hydrogen peroxide (H2O2), nitric oxide (N2O), and diphenyl picryl hydrazide (DPPH) methods. All the compounds displayed reliable biological properties. Among them, compound 8f hold high antioxidant activity may be due to the presence of methoxy group at para position of benzene ring. From the synthetic point of view, this is the novel environment favor method for the synthesis of pyrazole linked oxadiazoles, and the biological results of these compounds may stand as a referee for further development of biologically active pyrazole tethered oxadiazoles.

(3+2) Cycloadditions of Vinyl Sulfonyl Fluorides with Ethyl Diazoacetate or Azides: Metal-Free Synthesis of Pyrazole and Triazole Scaffolds via SO2 Elimination

AbstractA (3+2) cycloaddition reaction between substituted vinyl sulfonyl fluorides and ethyl diazoacetate or azides for the rapid construction of pyrazole or triazole cores via Michael addition and SO2 gas elimination is developed. Trimethylsilyl azide or organic azide selectively attacks at the β-carbon of vinyl sulfonyl fluoride rather than at the S(VI) center and generates C-substituted or C,N-disubstituted triazole. In contrast, vinyl sulfonyl fluorides react with ethyl diazoacetate to generate pyrazoles in good to high yields.

Ruthenium-Catalyzed Divergent Acceptorless Dehydrogenative Coupling of 1,3-Diols with Arylhydrazines: Synthesis of Pyrazoles and 2-Pyrazolines.

Herein, the divergent transformations of 1,3-diols with arylhydrazines via acceptorless dehydrogenative coupling reactions to selectively synthesize pyrazoles and 2-pyrazolines were reported, which were based on Ru3(CO)12/NHC-phosphine-phosphine catalytic systems. The reactions featured low catalyst loading, high selectivity, wide substrate scope, and good yields, with only water and hydrogen gas (H2) as the byproducts.

Nickel chloride catalyzed synthesis of pyrazoles and phthalazin-1(2H)-ones from hydrazines at room temperature

Herein an efficient and simple protocol was developed for the synthesis of pyrazoles and phthalazin-1(2H)-ones from a common precursor hydrazines catalyzed by nickel chloride. The reactions proceeded in water at room temperature. The advantages of the protocol are that both the medicinally important scaffolds could be synthesized with low-cost catalyst, green solvent, relatively lower reaction time and superior yield of the product making the protocol synthetically very useful. Electronically diversed pyrazoles and phthalazinones could be achieved in good to excellent yields in relatively shorter reaction time.

Synthesis and Antibacterial Activity of Novel Chalcone-derived Pyrazoles

Synthesis and Antibacterial Activity of Novel Chalcone-derived Pyrazoles

Synthesis of Novel Pyrazole Tagged Pyridine Derivatives; Their Antimicrobial Activity

: Novel pyrazole tagged pyridine derivatives 5a-n synthesized starting from 3-cyano-4-trifluoromethyl-6- thiophenyl 2(1H) pyridone 1. Compound 1 on hydrolysis followed by decarboxylation resulted in 4-trifluoro-methyl-6- thiophenyl 2(1H)pyridone 2. Compound 2 treated with POCl3 to get 2- chloro-4-trifluoromethyl-6- thiophenyl pyridine 3 further reaction with hydrazine hydrate, which resulted in the formation of compound 4. Compound 4 on reaction with different substituted 1,3-diketones in ethanol reflux condition to afford pyrazole substituted pyridine derivatives 5a-n. All derivatives were tested against Gram-positive and Gram-negative bacterial strains and different Candida strains by well diffusion method, compounds 5k and 5l showed significant activity. The binding mode of 5k and 5l also studied by molecular docking studies.

Synthesis, bioassay and molecular docking of novel pyrazole and pyrazolone derivatives as acetylcholinesterase inhibitors

- Synthesis of pyrazole and pyrazolone derivatives ( 1 ), ( 3 ) and ( 4 ). - In silico study of pyrazole and pyrazolone derivatives as (AChE) inhibitors. - In vitro (AChE) inhibition study of pyrazole and pyrazolone ( 1 ), ( 3 ) and ( 4 ). - pyrazolone derivative ( 1) exhibited good inhibitory activity against AchE. - pyrazolone derivative ( 1) has potential for in vivo anti-Alzheimer evaluations. Pyrazole and pyrazolone derivatives have attracted growing interest over the years because of their versatile applications in various fields. In this work, we describe the condensation of thiosemicarbazide and tosylhydrazine with ethyl acetoacetate using different catalysis. Docking study was performed for the reference compound rivastigmine and the prepared pyrazole and pyrazolones against human acetylcholinesterase (AChE). Based on the binding pose, compound ( 1 ) and ( 3 ) were occupying the site located in the deep cavity of AChE and rivastigmine was occupied the central active site cavity of AChE. While, the compound ( 4 ) was occupied the exterior active site cavity of the enzyme. The detailed interactions between the rivastigmine and the synthesized compounds and human acetylcholinesterase were determined and showed that the AChE- compound ( 1 ) complex was established several interactions with catalytic residues (His 447 and Ser 203) and the critical residue for the inhibition of the human enzyme (Tyr 337). Thus, this compound was predicted to be the most potent compound. The in vitro Acetylcholinesterase (AChE) inhibition studies showed that compound ( 1 ) has a good inhibitory activity against AChE and this activity is similar to that of rivastagmine with an IC 50 value of 0.38 ± 0.019 mg/mL (p < 0.05) and 0.36 ± 0.018 mg/mL (p < 0.05), respectively. These findings confirmed the in silico results and suggest the possibility of using compound ( 1 ) as anti-Alzheimer drug.

Ketone Derivatives of Propargylamines as Synthetic Equivalents of Conjugated 2,4,1-Enynones in the Synthesis of Acetylenic 2-Pyrazolines and Pyrazoles.

An interaction of 1,5-diaryl-3-X-pent-4-yn-1-ones (where X stands for piperidin-1-yl, morpholin-4-yl, 4-methylpiperazin-1-yl) with arylhydrazines proceeds at room temperature and results in 3-aryl-5-arylethynyl-1-phenyl-4,5-dihydro-1H-pyrazoles with up to 57-73% yields. Under similar conditions, the cyclocondensation of conjugated 2,4,1-enynones with arylhydrazine proceeds only in the presence of cyclic amines. 1,5-Diaryl-3-X-pent-4-yn-1-ones are reported as synthetic equivalents of conjugated 2,4,1-enynones in reactions with arylhydrazines. On the basis of obtained data, there are highly efficient methods developed for the synthesis of 5-arylethynyl-substituted 4,5-dihydro-1H-pyrazoles, as well as for similarly structured 1H-pyrazoles prepared by oxidation in AcOH. Presented products possess quite marked fluorescent abilities. Emission maximum wavelengths are located at 453-465 and 363-400 nm, respectively; certain compounds show extremely large Stokes shifts that may reach 91,000 cm-1.

Design, synthesis, and SAR studies of novel 4-methoxyphenyl pyrazole and pyrimidine derivatives as potential dual tyrosine kinase inhibitors targeting both EGFR and VEGFR-2

Guided by the pharmacophoric features of both EGFR and VEGFR-2 antagonists, two novel series of 4-methoxyphenyl pyrazole and pyrimidine derivatives [(4a-c) and (5a-c, 6, 7a-c, 8, 9, 10, 11a,c, 12, 13a-c, 14a-c, and 15a,b)], respectively, were designed and synthesized as dual EGFR/VEGFR-2 inhibitors. Interestingly, compound 12 showed very strong antiproliferative effects towards all the five studied cell lines (HepG-2, MCF-7, MDA-231, HCT-116, and Caco-2) with IC50 values of 3.74, 7.81, 4.85, 2.96, and 9.27 µM, respectively. Also, it achieved the highest inhibitory activities against both EGFR and VEGFR-2 as well (IC50 = 0.071 and 0.098 µM) compared to the two reference drugs, erlotinib (IC50 = 0.063 µM) and sorafenib (IC50 = 0.041 µM), respectively. Moreover, four compounds (4a, 7a, 7c, and 12) were selected for further evaluation through cell cycle analysis and Annexin V-based flow cytometry assay in the HepG-2 cell line. In addition, deep computational studies including molecular docking, physicochemical properties, profiling pharmacokinetics, ADMET studies, and toxicity predictions were performed for the designed compounds to evaluate the prospective drug candidates. Finally, analyzing the structure–activity relationship (SAR) of the new derivatives gives us a lot of interesting promising results which could help medicinal chemists to design more potent drug candidates soon as well.

Synthesis of Pyrazole–Oxothiazolidine Hybrids as Potential Anticancer Agents in [Bmim]OH Ionic Liquid Medium

Synthesis of Pyrazole–Oxothiazolidine Hybrids as Potential Anticancer Agents in [Bmim]OH Ionic Liquid Medium

Pyridine coupled pyrazole analogues as lethal weapon against MRSA: An in-vitro and in-silico approach

The treatment of Methicillin-resistant staphylococcus aureus (MRSA) infections has become challenging due to the growth of multidrug resistance in the bacteria. Here we report the synthesis of pyridine-coupled pyrazoles as an antimicrobial agent against MRSA. A series of pyridine coupled pyrazoles were synthesized and synthesized compounds were characterized using FT-IR, 1H NMR, and Mass spectroscopy. The ADMET results of all the 14 active compounds are interpreted. To identify the potent compound the synthesized compounds screened for minimum inhibitory concentrations against MRSA and compared with standard drug vancomycin. Among the synthesized compounds 6d exhibited good antibacterial activity with MIC value 21 μg/mL, bacterial cell membrane damage study was studied potassium efflux, and cellular content leakage assay. Anticoagulant study for the potent compound also studied and validated by molecular docking and molecular dynamics simulation studies. The docking study of the synthesized compound was carried out and the study depicted that the pyridine ring of all the analogues binds with the various amino acids in the binding pocket of the active site of the Staphylocoagulase and PBP2a protein of MRSA.

Synthesis, analgesic and anti-inflammatory activities of some pyrazolo[3,4-c]pyrazole derivatives

Historically, heterocyclic compounds containing Nitrogen, and their derivatives have been invaluable as a source of therapeutic agents. Pyrazole, with two nitrogen atoms and aromatic character, provides diverse functionality and stereochemical complexity in a five-membered ring structure. In Knorr pyrazole synthesis, diimine compound gets deprotonated to regenerate the acid catalyst and provide the final pyrazole product. Formation of pyrazole derivatives from hydrazines, hydrazides, semicarbazides, thiosemicarbazide and aminoguanidines by condensation with 1,3-dicarbonyl compounds is possible. As fused pyrazoles are reported to be well known pharmacophores, this has motivated to synthesize some of the pyrazolopyrazole derivatives by using hydrazine hydrate, thiosemicarbazide and semicarbazide. A series of 3-(aryl)-4-methyl-3a,6-dihydropyrazolo[3,4-c]pyrazole-2(3H)-carboxamides (IVa3-e3), 3-(aryl)-4-methyl-3a,6-dihydropyrazolo[3,4-c]pyrazole-2(3H)-carbothioamide (IVa2-e2) and 4-(aryl)-3-methyl-1,3a,4,5-tetrahydropyrazolo[3,4-c]pyrazoles (IVa1-e1) were synthesized by conventional method where fused pyrazopyrazoles were prepared. All the compounds were synthesized with good yield (56-81 %) and characterized by IR, 1H NMR spectral data and C, H, N elemental analysis. All the synthesized compounds exhibited analgesic and anti-inflammatory activities.