Pyrazole Derivatives Research Articles

Synthesis of polysubstituted pyrazoles and their biological applications

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.

Primary amine-catalyzed enantioselective 1,4-Michael addition reaction of pyrazolin-5-ones to α,β-unsaturated ketones.

The enantioselective 1,4-addition reaction of pyrazolin-5-ones to α,β-unsaturated ketones catalyzed by a cinchona alkaloid-derived primary amine-Brønsted acid composite is reported. Both enantiomers of the anticipated pyrazole derivatives were obtained in good to excellent yields (up to 97%) and high enantioselectivities (up to 98.5% ee) under mild reaction conditions. In addition, this protocol was further expanded to synthesize highly enantioenriched hybrid molecules bearing biologically relevant heterocycles.

3 + 2] Cycloaddition Reaction of Vinylsulfonium Salts with Hydrazonoyl Halides: Synthesis of Pyrazoles.

An efficient [3 + 2] cycloaddition reaction between in situ generated nitrile imines from hydrazonoyl halides and vinylsulfonium salts is developed. The nitrile imines are demonstrated to be a new class of reaction partner for vinylsulfonium salts to conduct the [3 + 2] cycloaddition reaction. The process provides a concise and efficient method for the construction of pyrazole derivatives under mild reaction conditions with broad substrate scope, good product yields, and high regioselectivity.

Microwave assisted facile one pot synthesis of novel pyrazole derivative for multi-analyte detection (Fe3+ and Zn2+) and its solvatochromic studies

A novel heterocyclic pyrazole-based probe Ph-DB was synthesised by microwave assisted concatenation of phenyl hydrazine and 2,5-dibromo-3-thiophenecarboxylaldehyde. The veracity of synthesized pyrazole derivative was established using 1H NMR,13C NMR, HRMS and FT-IR. ICT studies were conducted in different organic solvents of varying polarity to comprehend the solvatochromic nature of compound. DFT studies were performed to elucidate the intricacies of the Ph-DB’s electronic structure. The electrochemical band gap and optical band gap were calculated using cyclic voltammetry and Tauc's plot respectively. SEM analysis was carried out to explore the surface morphology of Ph-DB which was found to show small microwires like structures which supports optoelectrical properties of Ph-DB. The photophysical studies were carried out to check the chromogenic and fluorogenic response of Ph-DB towards different metal ions. It was observed that Ph-DB shows noticeable fluorescence enhancement with Zn2+ ions with the detection limit of 6.1 µM and chromogenic change with Fe3+ with a detection limit of 6.6 µM. Additionally quantum yield, binding constant and recovery experiment of Ph-DB probe were performed. Ph-DB probe was utilised for precise monitoring of Zn2+ and Fe3+ ions in water samples.

Recent Advances in Xanthine Oxidase Inhibitors.

Uric acid is a product of purine nucleotide metabolism, and high concentrations of uric acid can lead to hyperuricemia, gout and other related diseases. Xanthine oxidase, the only enzyme that catalyzes xanthine and hypoxanthine into uric acid, has become a target for drug development against hyperuricemia and gout. Inhibition of xanthine oxidase can reduce the production of uric acid, so xanthine oxidase inhibitors are used to treat hyperuricemia and related diseases, including gout. In recent years, researchers have obtained new xanthine oxidase inhibitors through drug design, synthesis, or separation of natural products. This paper summarizes the research on xanthine oxidase inhibitors since 2015, mainly including natural products, pyrimidine derivatives, triazole derivatives, isonicotinamide derivatives, chalcone derivatives, furan derivatives, coumarin derivatives, pyrazole derivatives, and imidazole derivatives, hoping to provide valuable information for the research and development of novel xanthine oxidase inhibitors.

Synthesis of Novel Acetamide, Acrylamide, Pyrazole, and Pyridine Derivatives Comprising Benzothiazole Moiety as Antioxidant Agents

Synthesis of Novel Acetamide, Acrylamide, Pyrazole, and Pyridine Derivatives Comprising Benzothiazole Moiety as Antioxidant Agents

Synthesis and Multifaceted Exploration of 4-Phenylpiperidin-4-ol Substituted Pyrazole: Photophysical Insights with Biological Activity

Abstract 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.

Comprehensive investigation of a new pyrazole derivative Schiff base complex: Revealing its potent protection against carbon steel corrosion

A new pyrazole derivative from 4-Aminoantipyrine Schiff base complex, which has the potential for corrosion inhibition, have been successfully synthesized (HL). The objective of this research is to enhance the corrosion inhibition activities of the synthesized HL by coordinating it with Cobalt to form complex compound (Co-L) on mild steel. HL and Co-L molecules will be immobilized on the surface of mild steel, creating a protective layer against corrosion-causing species. The synthesized compounds underwent characterization using various techniques, including UV-Visible Spectrophotometer, Fourier Transform Infrared, Nuclear Magnetic Resonance, X-Ray Diffraction, Magnetic Susceptibility Balance, and Elemental Analysis, confirming the success of the synthesis. Corrosion tests were conducted using the Weight Loss method and Potentiodynamic Polarization (PDP). The results indicate that the complex forms of compounds exhibit higher corrosion inhibition efficiency compared to their ligands. In the Weight-Loss method test (in 1.0 M HCl solution), Co-L compounds demonstrated superior performance efficiency at a concentration of 1 ×10−4 M, reaching 92.96 %, while HL showed an efficiency of only 86.89 %. The PDP test revealed that the HL and Co-L exhibited inhibition efficiencies of 87.13 % and 93.97 %, respectively, at a specific concentration. Monte Carlo simulation further supported these findings, indicating that inhibitor molecules are adsorbed on the metal surface, with the energy of adsorption for the Co-L inhibitor surpassing that of HL. This simulation result correlates linearly with experimental observations.

Design and synthesis of Novel 3,5-Diamino-4-(2′,3′,4′-Substituted Phenylazo)-1–2,5-dichlorphenylpyrazoles: Unveiling dual proficiency against inflammation and bacteria

This study introduces a novel series of 3,5-diamino-4-(2′,3′,4′-substitued phenylazo)-1–2,5-dicholorphenylpyrazole (4a-i) derivatives, synthesized through nucleophilic substitution reactions between 2-[(substituted phenyl) hydrazono] malononitrile (3) and 2,5-dichlorophenyl hydrazine under reflux conditions in an ethanolic medium. These compounds exhibit potent antibacterial and anti-inflammatory properties, demonstrated through in vitro assays and molecular docking studies. The structural uniqueness of the synthesized pyrazoles contributes to their dual proficiency, marking a significant advancement in the field of organic chemistry. The structural characterization of the synthesized derivatives was accomplished using IR, 1H, 13C NMR, and mass spectrometry analyses. The antibacterial (in vitro) and anti-inflammatory (in vivo) potential of the newly synthesized substituted pyrazoles was systematically evaluated. Carrageenan-induced inflammation inhibition was notably prominent in compound 4 h, demonstrating remarkable anti-inflammatory activity. In vitro antibacterial assays were conducted against four bacterial strains, including Bacillus subtilis (MTCC 121), Staphylococcus aureus (MTCC 96), Escherichia coli (MTCC 1652), and Pseudomonas fluorescens (MTCC 741). The synthesized pyrazole derivatives exhibited moderate to excellent antibacterial activity against both Gram-positive and Gram-negative bacterial strains. Compound 4 g displayed the highest inhibitory zone with a Minimum Inhibitory Concentration (MIC) of 250 μg/mL against E.coli. Molecular docking analysis against COX-2 (PDB-ID: 4COX) was performed, employing celecoxib as a reference molecule. Compound 4e exhibited a remarkable docking score of -8.55, surpassing the reference compound celecoxib (Docking score = -10.38). Quantum chemical calculations utilizing the B3LYP methodology were also employed to determine the relative energies of compounds 4a–i. This comprehensive study unveils the successful synthesis of a novel series of pyrazole derivatives and their potent antibacterial and anti-inflammatory properties. The results offer valuable insights for the potential development of these derivatives as promising candidates for addressing bacterial infections and inflammatory disorders.

A polymeric copper complex based on a pyrazole derivative: Synthesis, spectroscopic, X‐ray, and biological activity studies

A novel 1D coordination polymeric copper complex based on 4‐(4′‐nitrophenylhydrazono)‐5‐trifluoromethyl‐2,4‐dihydropyrazol‐3‐one was prepared and characterized spectroscopically and thermally and via X‐ray crystallographic investigation. The prepared copper‐based structure was proved to have a 1D coordination polymer. X‐ray studies showed that the polymeric copper complex was of octahedral geometry, the ligand acted as a bidentate ligand, and the nitro group attached to the ligand acted as a bridging group. The cytotoxic activities of the copper polymer were evaluated including against MCF‐7 cells (breast cancer cell line), HepG‐2 cells (hepatocellular carcinoma), and HCT‐116 cells (colon cancer cell line). The morphological alterations of the complex treated cells were investigated using an inverted microscope. The cell cycle and apoptosis were evaluated and reported. The copper polymer exhibited the best antitumor activity against HepG‐2 cells (35.22 ± 4.80 μM) while also causing a decline in the G2/M phase and a remarkable enhancement in the early apoptosis.

Insights of newly synthesized novel pyrazole compounds for mild steel corrosion inhibition in an acidic environment by experimental and computational calculations

Pyrazole derivative Ethyl (E)-2-cyano-3-(1,3-diphenyl-1H-pyrazol-4-yl)acrylate (Pz-a) and its novel nitro derivative Ethyl (E)-2-cyano-3-(3-(3-nitrophenyl)-1-phenyl-1H-pyrazol-4-yl)acrylate (Pz-b) were synthesized and characterised using Mass spectra, IR, 1H NMR, 13C NMR and utilized to safeguard mild steel from degradation in 1 M Hydrochloric acid environment. The inhibition effectiveness and mechanism were examined through both experimental and theoretical calculations. Electrochemical analysis illustrate that the protective property of pyrazoles rises proportionally with concentration. Potentiodynamic polarization reveals, both pyrazoles exhibit characteristics of mixed type inhibitors, inhibiting both oxidation and reduction processes. Pz-a and Pz-b adhesion on mild steel surface resembles the Langmuir isotherm. Gibbs free energy of adsorption (ΔGads) indicates Pz-a and Pz-b adsorbs physically and chemically over metal surface. The inhibition efficiency was found to be 89.85 % for Pz-b and 84.47 % for Pz-a at 10−2 M concentration. AFM scanning further confirms that the inhibitors are confined over mild steel. Better understanding of the corrosion inhibition mechanism has been facilitated by theoretical investigations through DFT parameters.

Studies on Photophysical and Biological Activity of Newly Synthesized of 4-Methylpiperidin-4-ol Substituted Pyrazole Derivatives

Studies on Photophysical and Biological Activity of Newly Synthesized of 4-Methylpiperidin-4-ol Substituted Pyrazole Derivatives

CuO−La2O3 Nanocomposite as a Recyclable and Eco‐Friendly, Heterogeneous Catalyst for the One‐Pot Synthesis of Pyrano [2, 3‐c] Pyrazoles

AbstractIn this work, the unique performance of binary acid‐base CuO/La2O3 nanocomposite as a highly efficient heterogeneous catalyst was successfully examined for the one‐pot multicomponent synthesis of pyrano [2, 3‐c] pyrazole derivatives. The strong interactions between La and Cu had a profound effect on the catalytic activity of nanocatalysts. In addition, high selectivity, easy recovery, reusability, a very reasonable price, simple preparation and eco‐friendliness are other important advantages of this nanocatalyst. The characterized nanocomposite demonstrated excellent structural and morphological properties, leading to high catalytic efficiency. Characterization using Fourier Transform Infrared Spectroscopy (FT‐IR), X‐ray Powder Diffraction (XRD) confirmed crystallographic structure, and Field Emission Scanning Electron Microscopy (FE‐SEM) showed a spherical particle size of approximately 43 nm. Energy‐Dispersive X‐ray (EDX) analysis confirmed the composition of La, O, and Cu elements in the nanocomposite as 86.4 %, 13.5 %, and 0.2 %, respectively. The optimal condition for the synthesis resulted in a 98 % yield of pyrano [2, 3‐c] pyrazole derivatives under reflux with 0.02 g of CuO/La2O3 catalyst in a 10‐minute reaction time.

Structure optimization of Cmpd-15 as negative allosteric modulators for the β2-adrenergic receptor

19 derivatives of 1-benzyl-3-arylpyrazole-5-carboxamides (H1-H19) and 5 derivatives of 1-benzyl-5-arylpyrazole-3-carboxamides (J1-J5) have been designed and synthesized as potential negative allosteric modulators (NAMs) for the β2-adrenergic receptor (β2AR). The new pyrazole derivatives were screened on the classic G-protein dependent signaling pathway at β2AR. The majority of 1-benzyl-3-aryl-pyrazole-5-carboxamide derivatives show more potent allosteric antagonistic activity against β2AR than Cmpd-15, the first reported β2AR NAM. However, the 1-benzyl-5-arylpyrazole-3-carboxamide derivatives exhibit very poor or even no allosteric antagonistic activity for β2AR. Furthermore, the active pyrazole derivatives have relative better drug-like profiles than Cmpd-15. Taken together, we discovered a series of derivatives of 1-benzyl-3-arylpyrazole-5-carboxamides as a novel scaffold of β2AR NAM.

Path of Pyrazoles from Synthetic Factors to Anti-inflammatory Potential: A Review

Pyrazoles, a class of heterocyclic compounds, have garnered considerable attention in drug development due to their intriguing properties, particularly those containing a pyrazole moiety. Pyrazole, a pivotal chemical in the creation of potent bioactive agents, encompasses five heterocyclic members. The discovery of certain pyrazole compounds exhibiting robust biological activities has spurred interest in this field of inquiry. Heterocyclic compounds incorporating nitrogen and its derivatives have historically served as crucial sources of medicinal compounds. Given that the heterocyclic group constitutes a vast reservoir of organic molecules, its significance in both theoretical and applied chemistry has grown significantly. Extensive literature indicates that researchers have employed diverse synthetic strategies in recent years to produce substituted pyrazole derivatives with promising biological potential as anti-HIV, anti-inflammatory, antitumor and antimicrobial agents. Inflammation, a multifaceted biological response essential for the body’s defense mechanisms, can also contribute to various pathological conditions when dysregulated. Understanding the underlying molecular mechanisms offers a foundation for targeted interventions against inflammatory disorders. These insights fuel ongoing endeavors to discover effective and innovative anti-inflammatory agents with potential therapeutic applications. This review delves into the synthesis and characterization of various pyrazole derivatives, emphasizing structural modifications influencing their anti-inflammatory efficacy. The insights provided herein are invaluable for the rational design and synthesis of novel anti-inflammatory agents. Furthermore, the review concludes with a discussion on future perspectives, underscoring the imperative for further research to optimize the therapeutic potential of pyrazole derivatives as anti-inflammatory agents.

Synthesis and evaluation of biological activity of novel curcumin-pyrazole derivatives using KSF@Ni and [γ-Fe2O3@HAp-SO3H] nanocatalysts

Curcumin is a β-diketone constituent of the turmeric obtained from the powdered root of Curcuma longa Linn. This natural product has many biological and pharmacological properties such as antiviral, anti-inflammatory, antimicrobial, and antioxidant.In this research and in the first part of the work, pyrazole derivatives were made from the combination of curcumin and hydrazine. Also, pyrazole - oxsazole and pyrazole–thiazole derivatives were prepared from the reaction of semi and thiosemicarbazide with curcumin and phenacyl bromide or Dicarboxylate.In conclusion, the antioxidant activity of synthesized products was investigated, and some showed promising activities. The research results and experimental data were obtained from FT-IR, 1HNMR, and 13CNMR spectroscopies.

Design, synthesis, and structure–activity relationship of 2-chloro-3-formylquinoline containing hybrids as powerful antibacterial agents

This work aims to evaluate the antimicrobial activity of some new quinoline derivatives linked to pyrazole derivatives. The target compounds pyrazolylvinylquinoline 11a-g and 12a-g were achieved by the reaction of 2-chloro-6-nitro-3-quinolinecarboxaldehyde (4) with bromotriphenylphosphonylmethylpyrazole derivatives 9a,b to give the new quinoline derivatives 10a,b which in turn reacted with different aryl amines to afford 11a-g and 12a-g. Pyrazole derivatives 9a,b were obtained by the reaction of hydroxymethylpyrazole derivatives 8a,b with triphenylphosphine hydrobromide. Antimicrobial evaluation of the newly synthesized compounds showed that most of the new compounds appeared active toward Gram-positive bacteria more than Gram-negative bacteria. The biological evaluation of compounds 12d-g displayed the highest antimicrobial activity against the tested microorganism strains. Additionally, compounds 12d and 12f showed excellent activity against P. aeruginosa (MIC50 0.019 mg/mL), while compounds 11d, 11f, 12e, and 12g displayed good activity against the same microorganism (MIC50 0.07 mg/mL). On the other hand, most of the new compounds have moderate activity against E. coli. Compounds 12d and 12f showed excellent activity versus C. albicans in vitro antifungal activity (MIC50 0.15 mg/mL) comparing to or slightly lower than that of Fluconazole. Using molecular docking simulations, we evaluated the binding affinities and interactions of four chosen derivatives 12d-g with a target PDB code 3WT0 protein.

Pyrazoles have a multifaceted anti-inflammatory effect targeting prostaglandin E2, cyclooxygenases and leukocytes’ oxidative burst

Elevated levels of prostaglandin E2 have been implicated in the pathophysiology of various diseases. Anti-inflammatory drugs that act through the inhibition of cyclooxygenase enzymatic activity, thereby leading to the suppression of prostaglandin E2, are often associated with several side effects due to their non-specific inhibition of cyclooxygenase enzymes. Consequently, the targeted suppression of prostaglandin E2 production with innovative molecules and/or mechanisms emerges as a compelling therapeutic strategy for the treatment of inflammatory-related diseases. Therefore, in this study, a systematic analysis of 28 pyrazole derivatives was conducted to explore their potential mechanisms for reducing prostaglandin E2 levels. In this context, the evaluation of these derivatives extended to examining their capacity to reduce prostaglandin E2in vitro in human whole blood, inhibit cyclooxygenase-1 and cyclooxygenase-2 enzymes, modulate cyclooxygenase-2 expression, and suppress oxidative burst in human leukocytes. The results enabled the establishment of significant structure-activity relationships, elucidating key determinants for their activities. In particular, the 4-styryl group on the pyrazole moiety and the presence of chloro substitutions were identified as key determinants. Pyrazole 8 demonstrated the capacity to reduce prostaglandin E2 levels by downregulating cyclooxygenase-2 expression, and pyrazole-1,2,3-triazole 18 emerged as a dual-acting agent, inhibiting human leukocytes' oxidative burst and cyclooxygenase-2 activity. Furthermore, pyrazole 26 demonstrated effective reduction of prostaglandin E2 levels through selective cyclooxygenase-1 inhibition. These results underscore the multifaceted anti-inflammatory potential of pyrazoles, providing new insights into the substitutions and structural frameworks that are beneficial for the studied activity.

In Vivo and In Silico Molecular Modeling Studies of Newly Synthesized Pyrazoles for Their Anti-Inflammatory and Analgesic Properties

Background: Pyrazole derivatives have gained attention as potential leads for developing anti-inflammatory and analgesic drugs. Chemical modifications of pyrazole structures offer a strategy to enhance their therapeutic properties, while minimizing undesirable effects. Objective: This study aimed to synthesize novel pyrazole derivatives through chemical modifications and assess their anti-inflammatory and analgesic activities. Methods: A series of pyrazole variants were synthesized by reacting various acetophenone derivatives and diethyl oxalate in basic conditions, followed by treatment with glacial acetic acid and hydrazine hydrate. The resulting compounds were further methylated and acetylated. The synthesized compounds were characterized using elemental analysis, 1H NMR, IR, and MASS spectroscopy. The anti-inflammatory activity was evaluated using the rat paw edema technique induced by carrageenan, while the analgesic activity was assessed using the writhing reflux method. Results: Among the newly synthesized pyrazole derivatives, compounds 3b, 3e and 3g′ demonstrated significant anti- inflammatory activity with reduced ulcerogenic potential. Compounds 3d, 3b′ and 3d′ exhibited notable analgesic activity compared to the standard drug. The chemical modifications introduced in these derivatives were confirmed through spectroscopic analyses. Conclusion: The findings of this study highlight the potential of pyrazole derivatives as promising candidates for anti- inflammatory and analgesic drug development. The structural modifications performed in this research improved the therapeutic activities of the compounds, while addressing safety concerns. Further investigations are warranted to elucidate the underlying mechanisms of action and optimize the pharmacological profiles of these novel pyrazole derivatives.

Synthesis, characterization, and antimicrobial activity of novel ferrocene-containing 1-(thio)acetyl pyrazolines

The pyrazoline pharmacophore is the source of numerous biological activities. The synthesis and biological evaluation of new pyrazoline heterocycles is the first step in the development of new potential drugs. Therefore, ferrocene-containing 1-(thio)acetyl pyrazolines were synthesized to test their in vitro antimicrobial activity. All new heterocycles were characterized by standard spectroscopy methods due to confirmation of the structures. In addition, single-crystal X-ray analyses were performed for three representative pyrazole derivatives. Their electrochemical properties were investigated by cyclic voltammetry indicating a reversible one-electron redox couple originating from the ferrocene/ferrocenium pair. All obtained products were evaluated for their antibacterial and antifungal activity. It has been shown that pyrazolines have slightly better antifungal activity compared with their antibacterial activity.