Pyrazole Nucleus Research Articles

Synthesis of Novel Pyrazole Derivatives as Promising DNA-Binding Agents and Evaluation of Antitumor and Antitopoisomerases I/II Activities.

Molecules bearing pyrazole nucleus present diverse biological properties such as antitumor and anti-inflammatory activities that can be associated with DNA interactions. This study aimed to the synthesis of new pyrazol derivatives and evaluated their ability to interact with the DNA and antitumor and topoisomerase inhibition activities. All derivatives were successfully synthesized, and their structures were elucidated by 1H-NMR and high resolution (HR)-MS (electrospray ionization positive mode (ESI+)). Antiproliferative inhibition assays, UV titration assays, fluorescence titration assays, circular dichroism (CD) assays, KI quenching studies, topoisomerase inhibitory activity assays and molecular docking were evaluated for these compounds. Especially, compounds 5e and 5q showed higher antitumor activity with IC50 values <13 µM for the tested cell lines. However, compounds 5e and 5q did not inhibit the topoisomerase activity evaluated by relaxation assay. These results show that the pyrazole nucleus contributes to the incorporation of molecules into the DNA. Moreover, it was highlighted that positive charges are relevant for the design of promising antitumor and DNA binding compounds.

The Synthetic and Biological Attributes of Pyrazole Derivatives: A Review.

Pyrazole nucleus is a unique structural scaffold which acts as an interesting template for combinatorial as well as medicinal chemistry. This review presents a detailed overview on the synthesis, QSAR and pharmacological applications of pyrazole. In addition, it covers most recent reports on structural modifications on pyrazole illustrating vital structural activity relationship.

STRUCTURAL EXPLORATION AND PHARMACOPHORIC INVESTIGATION OF PYRAZOLE BASED ANALOGS AS NOVEL HISTONE DEACETYLASE 1 INHIBITOR USING COMBINATORIAL STUDIES

Objective: Histone deacetylase inhibitors (HDACi) have four essential pharmacophores as cap group, connecting unit, a linker moiety and zinc binding group for their anticancer and histone deacetylase (HDAC) inhibition activity. On the basis of this fact, the objective of this research was to evaluate the exact role of pyrazole nucleus as connecting unit and its role in the development of newer HDACi.Methods: Ligand and structure-based computer-aided drug design strategies such as pharmacophore and atom based 3D QSAR modelling, molecular docking and energetic based pharmacophore mapping have been frequently applied to design newer analogs in a precise manner. Herein, we have applied these combinatorial approaches to develop the structure-activity correlation among novel pyrazole-based derivatives.Results: the Pharmacophore-based 3D-QSAR model was developed employing Phase module and e-pharmacophore on compound 1. This 3D-QSAR model provides fruitful information regarding favourable and unfavourable substitution on pyrazole-based analogs for HDAC1 inhibition activity. Molecular docking studies indicated that all the pyrazole derivatives bind with HDAC1 proteins and showed critical hydrophobic interaction with 5ICN and 4BKX HDAC1 proteins.Conclusion: The outcome of the present research work clearly indicated that pyrazole nucleus added an essential hydrophobic feature in cap group and could be employed to design the ligand molecules more accurately.

Pyrazole nucleus fused tri-substituted imidazole derivatives as antioxidant and antibacterial agents

A novel series of tri-substituted imidazole derivatives were synthesized according to the well-known Radziszewski reaction. The desired molecules were obtained by a reaction of benzil, ammonium acetate and different derivatives of 1H-pyrazole-4-carbaldehyde. Structures of the synthesized entities were confirmed with the support of modern techniques like elemental analysis (CHN) and spectral analysis (FTIR, 1H and 13C NMR and LC–MS). All compounds were screened for their biological potency: antibacterial activity using a serial broth dilution method and antioxidant activity using the DPPH method. Antimicrobial activity was performed against Gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis) and Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa). The title compounds showed moderate to excellent antimicrobial and antioxidant potency against different bacterial strains and the DPPH radical.

Synthesis of new quinoxaline, pyrimidine, and pyrazole furochromone derivatives as cytotoxic agents

A series of novel quinoxaline, pyrimidine, and pyrazole furochromone derivatives were synthesized for the first time. These derivatives were prepared under mild conditions using a stepwise efficient methodology. The developed protocol led to the synthesis of furochromone derivatives in moderate to good yields (60–75%). The structures of the prepared derivatives were identified using several spectroscopic techniques including IR, NMR, and mass spectrometry. The cytotoxic activity of the synthesized derivatives was evaluated using in vitro Ehrlich ascites assay. Pyrazolobenzofurans exhibited the most potent effect suggesting the importance of pyrazole nucleus for the cytotoxic activity.

Synthesis of tetrasubstituted pyrazoles containing pyridinyl substituents.

A synthesis of tetrasubstituted pyrazoles containing two, three or four pyridinyl substituents is described. Hence, the reaction of 1,3-dipyridinyl-1,3-propanediones with 2-hydrazinopyridine or phenylhydrazine, respectively, affords the corresponding 1,3,5-trisubstituted pyrazoles. Iodination at the 4-position of the pyrazole nucleus by treatment with I2/HIO3 gives the appropriate 4-iodopyrazoles which served as starting materials for different cross-coupling reactions. Finally, Negishi cross-coupling employing organozinc halides and Pd catalysts turned out to be the method of choice to obtain the desired tetrasubstituted pyrazoles. The formation of different unexpected reaction products is described. Detailed NMR spectroscopic investigations (1H, 13C, 15N) were undertaken with all products prepared. Moreover, the structure of a condensation product was confirmed by crystal structure analysis.

Design, synthesis and biological evaluation of new pyrazolyl-ureas and imidazopyrazolecarboxamides able to interfere with MAPK and PI3K upstream signaling involved in the angiogenesis

Taking into account the structure activity relationship information given by our previous studies, we designed and synthesized a small library of pyrazolylureas and imidazopyrazolecarboxamides fluorinated on urea moiety and differently decorated on pyrazole nucleus. All compounds were preliminary screened by Western blotting technique to evaluate their activity on MAPK and PI3K pathways by monitoring ERK1/2, p38MAPK and Akt phosphorylation, and also screened with a wound healing assay to assess their capacity in inhibiting endothelial cell migration, using human umbilical vein endothelial cells stimulated with VEGF. Pyrazoles and imidazopyrazoles did not show the same activity profile. SAR consideration showed that specific substituents and their position in pyrazole nucleus, as well as the type of substituent on the phenylurea moiety play a pivotal role in determining increase or decrease of kinases phosphorylation. On the other hand the loss of flexibility in imidazopyrazole derivatives is responsible for activity potentiation. Screening of the compound library for inhibition of endothelial cell migration, a function required for angiogenesis, showed significant activity for compound 3. This compound might interfere with cell migration by modulating the activity of different upstream target kinases. Therefore, compound 3 represents a potential inhibitor of angiogenesis. Furthermore, it may be used as a tool to identify unknown mediators of endothelial migration and thereby unveiling new therapeutic targets for controlling pathological angiogenesis in diseases such as cancers.

Synthesis of fused pyrazoles via intramolecular cyclization of appropriately ortho-substituted nitroarenes and nitroheteroarenes

Among numerous approaches for the synthesis of condensed heterocycles bearing a pyrazole nucleus, the intramolecular cyclization of a suitable ortho -substituted nitroaromatic and nitroheteroaromatic precursors is one of the most convenient routes. This review summarizes recent developments in the application of this approach for the synthesis of fused pyrazoles, their 1-oxides, and 1-hydroxy derivatives.

Design, synthesis, and in vitro antiproliferative and kinase inhibitory effects of pyrimidinylpyrazole derivatives terminating with arylsulfonamido or cyclic sulfamide substituents

A novel series of substituted pyrimidine compounds bearing N-phenylpyrazole and terminating with aryl and cyclic sulfonamido moiety were designed, synthesized, and evaluated in vitro as antiproliferative agents against a panel of 53 cell lines of different tissues at the NCI. Among them, compound 1d with p-chlorobenzenesulfonamido terminal moiety, ethylene spacer, and 4-chloro-3-methoxyphenyl ring at position 3 of the pyrazole nucleus showed the highest mean percentage inhibition value over the whole cancer cell line panel at 10 μM concentration. It showed broad-spectrum antiproliferative activity over many cell lines of different cancer types. For instance, compound 1d inhibited the growth of HL-60 (TB), SR leukemia, and T-47D and MCF-7 breast cancer cell line by 135.92%, 119.44%, 95.32%, and 82.03% at 10 μM, respectively. And it inhibited the growth of COLO 205 colon, HT29 colon, BT-549 breast, and ACHN renal cancer cell lines by more than 80% at the same test concentration. However, testing compound 1d upon determining its IC50 against the most sensitive cell lines showed to good extent selectivity against HT29 colon cancer cell line than HL-60 leukemia and MRC-5 lung fibroblasts (normal cells). Compound 1d was further tested against 12 kinases of different kinase families, and the highest inhibitory effect was exerted against RAF1, V600E-B-RAF, and V600K-B-RAF kinases.

Current status of pyrazole and its biological activities.

Pyrazole are potent medicinal scaffolds and exhibit a full spectrum of biological activities. This review throws light on the detailed synthetic approaches which have been applied for the synthesis of pyrazole. This has been followed by an in depth analysis of the pyrazole with respect to their medical significance. This follow-up may help the medicinal chemists to generate new leads possessing pyrazole nucleus with high efficacy.

Design, synthesis, and characterization of a fluoro substituted novel pyrazole nucleus clubbed with 1,3,4-oxadiazole scaffolds and their biological applications

A novel series of compounds incorporating a fluoro substituted pyrazole nucleus clubbed with 1,3,4-oxadiazole scaffolds (7a–p) was synthesized in good yields (79–89%).

Sorption-desorption of fipronil in some soils, as influenced by ionic strength, pH and temperature.

The sorption-desorpion of fipronil insecticide is influenced by soil properties and variables such as pH, ionic strength, temperature, etc. A better understanding of soil properties and these variables in sorption-desorption processes by quantification of fipronil using liquid chromatography may help to optimise suitable soil management to reduce contamination of surface and groundwaters. In the present investigation, the sorption-desorption of fipronil was studied in some soils at varying concentrations, ionic strengths, temperatures and pH values, and IR specta of fipronil sorbed onto soils were studied. The sorption of fipronil onto soils conformed to the Freundlich isotherm model. The sorption-desorption of fipronil varied with ionic strength in each of the soils. Sorption decreased but desorption increased with temperature. Sorption did not change with increasing pH, but for desorption there was no correlation. The cumulative desorption of fipronil from soil was significantly and inversely related to soil organic carbon content. IR spectra of sorbed fipronil showed the involvement of amino, nitrile, sulfone, chloro and fluoro groups and the pyrazole nucleus of the fipronil molecule. The sorption of fipronil onto soils appeared to be a physical process with the involvement of hydrogen bonding. An increase in soil organic carbon may help to reduce desorption of fipronil. High-temperature regimes are more conducive to the desorption. © 2015 Society of Chemical Industry.

Trifluoromethylpyrazoles as anti-inflammatory and antibacterial agents: A review

In the recent past trifluoromethylpyrazoles have gained much attention, particularly as anti-inflammatory and antibacterial agents, in the field of medicinal chemistry. The location of trifluoromethyl group, specially on 3- or 5-position of pyrazole nucleus, is greatly associated with variation in activity profile of the compounds. Therefore, the main objective of this article is to highlight the importance of trifluoromethylpyrazoles as anti-inflammatory and antibacterial agents on a single front. The present review covers the literature from 2000 to 2015 and would certainly be proven as a great help to the medicinal chemists to explore some novel anti-inflammatory and antibacterial agents with better action profiles with minimal side effects.

ChemInform Abstract: A Study of Negishi Cross‐Coupling Reactions with Benzylzinc Halides to Prepare Original 3‐Ethoxypyrazoles.

The Negishi palladium-catalyzed cross-coupling reaction between 3-ethoxy-4-iodo-1H-pyrazole and various benzylzinc halides was extensively studied. Using simplified, robust, and optimized reaction conditions, a series of electron-poor benzylzinc halides were prepared and used to synthesize 4-benzyl-3-ethoxy-1H-pyrazoles derivatives. From these, iodination on C5 of the pyrazole nucleus led to the corresponding 4-benzyl-3-ethoxy-5-iodo-1H-pyrazoles, these are original building blocks for the preparation of libraries of new chemical entities.

Design, synthesis, and antibacterial evaluation of new Schiff’s base derivatives bearing nitroimidazole and pyrazole nuclei as potent E. coli FabH inhibitors

New Schiff’s base derivatives 5a–j have been synthesized by reaction between 5-aryloxypyrazole-4-carbaldehydes 3a–j and 2-(2-methyl-5-nitro-1H-imidazol-1-yl)acetohydrazide 4 in the presence of nickel (II) nitrate as a catalyst in ethanol at room temperature with good yield (75–88 %). All compounds were tested for antibacterial properties and inhibition of E. coli FabH. Of the compounds studied, the majority of the compounds showed effective antibacterial properties and inhibition of E. coli FabH activity. Compound 5i showed the most effective inhibition (IC50 = 4.6 ± 0.2 µM) by binding into the active site of the E. coli FabH receptor with minimum binding energy (ΔGb = −54.2961 kcal/mol). The binding was stabilized by two hydrogen bonds, two π–π, and three π–cation interactions.

A Study of Negishi Cross-Coupling Reactions with Benzylzinc Halides­ To Prepare Original 3-Ethoxypyrazoles

The Negishi palladium-catalyzed cross-coupling reaction between 3-ethoxy-4-iodo-1<i>H</i>-pyrazole and various benzylzinc halides was extensively studied. Using simplified, robust, and optimized reaction conditions, a series of electron-poor benzylzinc halides were prepared and used to synthesize 4-benzyl-3-ethoxy-1<i>H</i>-pyrazoles derivatives. From these, iodination on C5 of the pyrazole nucleus led to the corresponding 4-benzyl-3-ethoxy-5-iodo-1<i>H</i>-pyrazoles, these are original building blocks for the preparation of libraries of new chemical entities.

Heteroring Annulated Benzimidazolinone Condensed Azepinone Derivatives: A New Class of Highly Potent Antioxidants

A new class of benzimidazolinone condensed azepinone derivatives annulated on its face “d” with pyrazole, isoxazole, pyrimidine, benzodiazepine, and benzothiazepine nucleus in 3–8, respectively, have been evaluated for their antioxidant activity by DPPH method. Results indicate these to belong to a novel class of highly potent antioxidant agents.

ChemInform Abstract: Pyrazole Scaffold: A Remarkable Tool in the Development of Anticancer Agents

AbstractReview: 97 refs.

Pyrazole scaffold: A remarkable tool in the development of anticancer agents

Pyrazole has been the topic of interest for thousands of researchers across the world because of its wide spectrum pharmacological activities. Various structural modifications of the pyrazole nucleus have been made to explore its characteristics and biological potential. The present work aims to review the use of molecular modeling in the designing of novel pyrazole analogs that may target various receptors such as protein kinase inhibitor, tyrosine kinase, Aurora-A kinase, tumor growth factor (TGF), cyclin dependent kinase (CDK) and fibroblast growth factor (FGF), which are significant for the management of cancer. An insight has been given in this article for the importance of pyrazoles in the treatment of cancer and the perspectives that they hold for future research.

Synthesis, hypoglycemic activity and molecular modeling studies of pyrazole-3-carbohydrazides designed by a CoMFA model

Diabetes and obesity are two universal health problems that constitute a research objective of several groups due to the lack of efficient and safe drug treatment. In this sense, cannabinoid receptor 1 (CB1) has attracted interest because of its role in food intake and metabolic balance, two targets in the control of metabolic syndrome. In this work, novel 1,5-diaryl pyrazole derivatives were synthesized in accordance with the pKi prediction of a previously reported CoMFA model by our group. To further investigate the biological activity of these compounds in metabolic disorders, their hypoglycemic activity in an in vivo model was tested. Interestingly, a high degree of correlation was observed between the predicted pKi and hypoglycemic effect 7 h after administration. Compounds 4, 9 and 13 showed the most significant plasma glucose reduction with decreases of 60%, 64% and 60% respectively. This result not only surpasses the activity of the lead rimonabant, but also that of the reference drug glibenclamide. Moreover, PASS prediction and molecular docking in an excellent validated homology model of CB1 suggest that these compounds would probably act as CB1 antagonists/inverse agonists and therefore, anti-obesity agents. The ligand–receptor complexes demonstrate that 1,5-diaryl pyrazole derivatives bind to the proposed binding site where a hydrophobic moiety interacts with the phenyl rings in the pyrazole nucleus and Lys192 forms a hydrogen bond with the oxygen of the carbonyl group. Dynamics simulations were also carried out to study the stability of the ligand–receptor complexes where the most active compounds showed smaller ΔG values and more hydrogen bonds throughout the simulation. These compounds are considered useful leads for further optimization in the treatment of such metabolic illnesses.