Series Of Pyrazole Derivatives Research Articles

Discovery of novel pyrazole based Urea/Thiourea derivatives as multiple targeting VEGFR-2, EGFRWT, EGFRT790M tyrosine kinases and COX-2 Inhibitors, with anti-cancer and anti-inflammatory activities

A novel series of pyrazole derivatives with urea/thiourea scaffolds 16a-l as hybrid sorafenib/erlotinib/celecoxib analogs was designed, synthesized and tested for its VEGFR-2, EGFRWT, EGFRT790M tyrosine kinases and COX-2, pro-inflammatory cytokines TNF-α and IL-6 inhibitory activities. All the tested compounds showed excellent COX-2 selectivity index in range of 18.04–47.87 compared to celecoxib (S.I. = 26.17) and TNF-α and IL-6 inhibitory activities (IC50 = 5.0–7.50, 6.23–8.93 respectively, compared to celecoxib IC50 = 8.40 and 8.50, respectively). Screening was carried out against 60 human cancer cell lines by National Cancer Institute (NCI), compounds 16a, 16c, 16d and 16 g were the most potent inhibitors with GI% ranges of 100 %, 99.63–87.02 %, 98.98–43.10 % and 98.68–23.62 % respectively, and with GI50 values of 1.76–15.50 µM, 1.60–5.38 µM, 1.68–7.39 µM and 1.81–11.0 µM respectively, in addition, of showing good safety profile against normal cell line (F180). Moreover, compounds 16a, 16c, 16d and 16 g had cell cycle arrest at G2/M phase with induced necrotic percentage compared to sorafenib of 2.06 %, 2.47 %, 1.57 %, 0.88 % and 1.83 % respectively. Amusingly, compounds 16a, 16c, 16d and 16 g inhibited VEGFR-2 with IC50 of 25 nM, 52 nM, 324 nM and 110 nM respectively, compared to sorafenib (IC50 = 85 nM), and had excellent EGFRWT and EGFRT790M kinase inhibitory activities (IC50 = 94 nM, 128 nM, 160 nM, 297 nM), (10 nM, 25 nM, 36 nM and 48 nM) respectively, compared to both erlotinib and osimertinib (IC50 = 114 nM, 56 nM) and (70 nM, 37 nM) respectively and showed (EGFRwt/EGFRT790M S.I.) of (range: 4.44–9.40) compared to erlotinib (2.03) and osmertinib (1.89).

Novel pyrazole derivatives: rationale design, synthesis, sar study and biological potential based on In Vitro Study

A new series of pyrazole derivatives was synthesized and its chemical structure was confirmed by physicochemical and spectral means. The synthesized compounds were evaluated for their in vitro antimicrobial, antioxidant, antidiabetic and anti-inflammatory activities. The antimicrobial results showed that, compounds Intermediate 1 (MICbs= 14.74µM), P10 (MICkp=12.95 µM), P14 (MICsa=16.26 µM), P19 (MICec=17.34 µM), and P20 (MICst=12.41 µM) shown significant antibacterial activity, but compound P7 (MICca= 13.19 µM) and Intermediate 5 (MICan= 17.29 µM) shown significant antifungal activitywhen compared to standard medications. Compound P4 had the highest level of antioxidant potential (IC50 = 52.21 µM), whereas Compound P12 demonstrated the highest level of antidiabetic potential (IC50 = 38.00 µM). Compound P2 has excellent potency against inflammation, with IC50 values 29.55 µM. Further, the molecular docking study has been carried to find out the interaction between active pyrazole compounds with 4FFW, 2CDU and IFJ4 (PDB id) indicated that compound P12, P4 and P10 showed good docking score with better potency within the ATP binding pocket respectively and may be used as a lead for rational drug designing of the novel molecules.To get more light on the regioselective synthesis of new hybrid compounds, mechanistic studies were performed using DFT calculations with B3LYP/6–31G(d,p) basis set.

Pyrazoles as Anti-inflammatory and Analgesic Agents: In-vivo and In-silico Studies

Background:: Pyrazole is a well-known nucleus in the pharmacy field with a wide range of other activities in addition to anti-inflammatory and analgesic, i.e., anticonvulsant, antiviral, and anticancer activities. There are well-known marketed drugs having pyrazole moi-ety as celecoxib, and lonazolac as COX-II inhibitors. Aims:: We aim to synthesize better anti-inflammatory than existing ones. Thiophene is also known for its analgesic and anti-inflammatory action. Thus, the fusion of both gives better anti-inflammatory agents. In the present studies, derivatives from two series of pyrazole were prepared by reacting substituted chalcone (3a-3f) derivatives prepared from 2-acetyl thiophene. They substituted aromatic aldehydes with phenyl hydrazine to form (5a-5f) and with 2, 4-dinitro phenyl hydrazine giving compounds (6a-6f) separately. Methods:: Purified and characterized pyrazoles have been analyzed for in-vivo analgesic and anti-inflammatory activities by using standard methods. Compounds 5e, 5f, and 6d were proved to be potent analgesics and series (5a-5f) was found to have anti-inflammatory action, which was further validated using docking and ADME studies. Results:: The ADME profile of synthesized compounds was found to be satisfactory. Conclusion:: The synthesized compounds can serve as lead for further drug designing.

Novel pyrazoline and pyrazole "turn on" fluorescent sensors selective for Zn2+/Cd2+ at λem 480 nm and Fe3+/Fe2+ at λem 465 nm in MeCN.

A small series of simple pyrazoline and pyrazole based sensors, all derived from the same chalcone precursors, were synthesised, characterised and screened for their fluorescence "turn on" properties in the presence of multiple metals. Pyrazole 8 displayed an excellent fluorescence profile with approx. 20× fold increase in λem 480 nm with Zn2+ compared to a 2.5× fold increase with Cd2+. Pyrazole 9 displayed a 30× fold increase at λem 465 nm for Fe3+ compared to Fe2+ with a Fe3+ limit of detection of 0.025 μM. The corresponding pyrazolines displayed contrasting properties with important implications for future pyrazoline and pyrazole sensor design.

Synthesis and theoretical study of a new family of pyrazole derivative

Pyrazole-containing molecules are key in the development of new pharmaceuticals or pesticides. Thus, we synthesize a new series of pyrazole derivates using the cycloaddition methods. The synthesized compounds present a (E)-4-((4-iodophenyl)diazenyl)-3,5-dimethyl-1-(R-phenyl)-1H-pyrazole structure. The compounds were characterized by UV-vis, FTIR, 1H-NMR, and 13C-NMR. Also, DFT and Hammet correlation calculations were performed over the whole family of derivatives. Our results demonstrate that the synthesized compound was obtained with a overall yield of 50 %. UV/Vis spectroscopic characterization shows that all compounds present three absorption bands related to the pyrazole ring, the -N=N- bond and benzene rings. Additionally, theoretical calculation shows that the dihedral angle decreases when the electron-attractive nature of the substituent of the pyrazole ring increases. Finally, Hammett correlation studied shows a good fit in some of the measured properties.

Synthesis, Characterization and In-Vitroanti-Tumor Activity of Some Novel Pyrazole Derivatives

Pyrazole and its derivatives are considered a pharmacologically important active scaffold that possesses almost all types of pharmacological activities. The presence of this nucleus in pharmacological agents of diverse therapeutic categories such as a potent anti-inflammatory, antipsychotic , anti-obesity drug, an analgesic, and anti-depressant agents have proved the pharmacological potential of the pyrazole moiety. Owing to this diversity in the biological field, this nucleus has attracted the attention of many researchers to study its skeleton chemically and biologically. This heterocyclic can be traced in a number of well-established drugs belonging to different categories with diverse therapeutic activities. Aim of the present study is to synthesize and characterize various 4-[1-(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-en-1-yl)3,4-(phenyl]-5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one derivatives using an efficient Scheme. The synthesized compounds (1-10) were evaluated for their in vitro anti-cancer activity.In order to develop potent anti-cancer agents, a novel series of pyrazole derivatives were synthesized and the structures of all compounds were confirmed by spectral studies. MTT assay has been employed to study anti-proliferative activity of these compounds with four human cancer cell lineDLD1 (Human Colorectal Adenocarcinoma) at various concentration (6.25-100µg/mL). The results revealed that compounds VEPD and 4MEPD shows goodanti-tumoractivity and the other compounds shows moderate activity against theDLD1cell line.

Synthesis and in-Silico Studies of Some New Thiazole Carboxamide Derivatives with Theoretical Investigation

Based on the tremendous pharmacological activities of compounds containing thiazole and carboxamide moieties, the current study aims to prepare new series of thiazole, pyrazole, pyridine, and thiophene derivatives incorporating thiazole carboxamide moiety. Construction of the target compounds was achieved via different chemical transformations and using easily accessible starting materials. The structures of the synthesized compounds were confirmed by all possible spectral and elemental analyses. Results from the in-silico studies showed different Lipophilicity (log p) and Number of Lipinsk’s violations due to the presence of NH2, C≡N, OH, and C=O groups which make more electrostatic hydrogen bond interactions in compounds 17 and 20 which increase their TPSA (Å2). These results were confirmed through docking simulation with PDBID: 5I9I which showed the least binding affinity with different proteins, and optimization of these heterocyclic compounds with computational calculations and identification of their physical descriptors which showed more stabilities and directed us for biological evaluation for further studies.

Synthesis and Antibacterial Evaluation of Pyrazole Integrated Oxadiazole Derivatives

Pyrazole, Pyridine, and oxadiazole are important scaffolds because of having medicinal applications like anticonvulsant, hypoglycemia, molluscicidal, stimulant, and anticancer, etc. At present, to achieve a highly potent molecule we have synthesized a novel series of pyrazole bearing 1,3,4-oxadiazole heterocycles 4a–o (1-(3,5-substituted-diphenyl-4,5-dihydro-1H-pyrazol-1-yl)-2-((5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl)thio)ethan-1-one) were and characterized by mass spectroscopy, 1H and 13C NMR spectroscopy, and Infrared spectroscopy. All synthesized compounds were evaluated against gram-positive and gram-negative bacterial strains.

Anti-Breast Cancer Activity of Some Synthesized Pyrazole Derivatives Bearing Imidazo[1,2a]pyridine Moiety

A novel series of pyrazole derivatives containing imidazo[1,2-a]pyridine D1-D8 moiety has been synthesized. The reaction of 2-aminopyridine with 4-phenylphenacyl bromide and 4-bromophenacyl bromide gave the products A and A1, respectively. These products then reacted with DMF and POCl3 to obtain new aldehyde derivatives B and B1. These two aldehydes were condensed with various acetophenone substitutes to yield the corresponding chalcone derivatives C1-C10. Following this, the cycloaddition reaction with hydrazine hydrate provided new pyrazole derivatives D1-D8. The prepared compounds were verified by FT-IR, 1H NMR, and 13C NMR spectroscopy. Two of these derivatives (C5 and D1) were chosen to investigate their cytotoxic efficacy against breast cancer using the MTT assay.

Synthesis and antimicrobial activity of new series of thiazoles, pyridines and pyrazoles based on coumarin moiety

Microbial infections are currently a widespread disease in hospitals and community health centres and are a major cause of death worldwide. In pursuit of searching new antimicrobial agents, coumarin linked to thiazoles, pyridines and pyrazoles have been developed and evaluated for their antimicrobial properties against two Gram + bacteria, two Gram − bacteria as well as two fungi. Some of the prepared coumarins displayed high to moderate activity against the tested microorganisms with respect to the reference drugs. However, compound 3 exhibited antimicrobial effect equal to the reference drug Ciprofloxacin for Gram − baceria Enterobacter cloacae. Compound 12 was found to be the most potent compound against Bacillus pumilis with MIC of 7.69 (µmol/ml). Compounds 3, 4 and 12 showed remarkable activity against Streptococcus faecalis with MIC of 14.34, 3.67 and 15.36 (µmol/ml), respectively. Regarding Escherichia coli, most compounds recorded high to moderate MIC values (4.73–45.46 µmol/ml). Moreover, in case of E. cloacae compound 9 was the most potent compound with MIC value of 22.76 (µmol/ml).

Design, synthesis and anticancer activities evaluation of novel pyrazole modified catalpol derivatives

Catalpol, a natural product mainly existed in plenty of Chinese traditional medicines, is an iridoid compound with the comprehensive effects on neuroprotective, anti-inflammatory, choleretic, hypoglycemic and anticancer. However, there are some disadvantages for catalpol such as a short half-life in vivo, low druggability, stingy binding efficiency to target proteins and so on. It is necessary to make structural modification and optimization which enhance its performance on disease treatments and clinic applications. Pyrazole compounds have been reported to have excellent anticancer activities. Based on the previous research foundation of our research group on iridoids and the anticancer activities of catalpol and pyrazole, a series of pyrazole modified catalpol compounds were synthesized by principle of drug combination for serving as potential cancer inhibitors. These derivatives are characterized by 1H NMR, 13C NMR and HRMS. The efficacy of anti-esophageal cancer and anti-pancreatic cancer activities were evaluated by the MTT assay on two esophageal cancer cells Eca-109 and EC-9706, and two pancreatic cancer cells PANC-1, BxPC-3 and normal pancreatic cell line HPDE6-C7, which showed that the compound 3e had strong inhibitory activity against esophageal cancer cells, this providing a theoretical basis for the discovery of catalpol-containing drugs.

Effect of hydrophobic extension of aryl enaminones and pyrazole-linked compounds combined with sulphonamide, sulfaguanidine, or carboxylic acid functionalities on carbonic anhydrase inhibitory potency and selectivity

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.

Ag2CO3 catalyzed aza-michael addition of pyrazoles to α, β-unsaturated carbonyl compounds: A new access to N-alkylated pyrazole derivatives

An efficient Ag2CO3 catalyzed aza-Michael addition of pyrazoles to α, β-unsaturated carbonyl compounds is developed. In the present of 5 mol% of Ag2CO3, the reaction smoothly occurs in DCE at 120 °C to afford a series of N-alkylated pyrazoles in good to excellent yields. It is noteworthy that N1-alkylated pyrazoles are obtained with high regioselectivity (N1/N2 up to above 25:1) when asymmetrically substituted pyrazoles reacted with α, β-unsaturated carbonyl compounds. The method can also extend to gram scale.

Development of novel pyrazole, imidazo[1,2-b]pyrazole, and pyrazolo[1,5-a]pyrimidine derivatives as a new class of COX-2 inhibitors with immunomodulatory potential

Searching for new compounds with anti-inflammatory properties is a significant target since inflammation is a major cause of pain. A series of pyrazole, imidazopyrazolone, and pyrazolopyrimidine derivatives were designed and synthesized by reaction of 3,5-diamino-1H-pyrazole derivative with cyclic and acyclic carbonyl reagents. The structure of the newly synthesized derivatives were fully characterized using different spectroscopic data and elemental analysis, and therefore, evaluated as COX-2 inhibitors. The in vitro COX-2 activity of the tested derivatives 2–13 displayed moderate to good potency with two derivatives 8 and 13 that exhibiting high potency to COX-2 with IC50 values of 5.68 ± 0.08 and 3.37 ± 0.07 μM compared with celecoxib (IC50 = 3.60 ± 0.07 μM) and meloxicam (IC50 = 7.58 ± 0.13 μM). Furthermore, the most active pyrazolo[1,5-a]pyrimidine derivatives 8 and 13 were evaluated to measure the levels of pro-inflammatory proteins such as TNF-α and IL-6 using qRT-PCR in RAW264.7 cells, and the results showed down-regulation of two immunomodulatory proteins. Surprisingly, these derivatives 8 and 13 revealed a decrease in IL-6 level with inhibition percentages of 65.8 and 70.3%, respectively, compared with celecoxib (% = 76.8). Further, compounds 8 and 13 can regulate and suppress the TNF-α with percentage inhibition of 63.1 and 59.2% to controls, while celecoxib displayed an inhibition percentage of 72.7. The Quantum chemical calculation was conducted, and data explained the structural features crucial to the activity. The molecular docking simulation and ADMET predictions revealed that the most active derivatives have good binding affinity, possess appropriate drug-likeness properties and low toxicity profiles. Finally, compounds 8 and 13 demonstrated COX-2 inhibitors with α-TNF and IL-6 suppression capabilities as a dual-action strategy to get more effective treatment.

Synthesis of pyrazoles from sulfonyl hydrazone and benzyl acrylate under transition-metal-free conditions.

Pyrazoles as an important class of heterocyclic compounds, are widely found in pharmaceuticals and bioactive natural products. Herein we report a [3 + 2] cycloaddition reaction for the synthesis of a series of pyrazoles, with the yield up to 77%. This approach exhibits many notable features, such as convenient operating conditions, excellent functional group compatibility and readily accessible raw materials, providing an alternative route for the construction of pyrazole derivatives.

Synthesis, Molecular Docking, and Antitumor Evaluation of Some New Pyrazole, Pyridine, and Thiazole Derivatives Incorporating Sulfonamide Residue

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.

SYNTHESIS AND MOLECULAR DOCKING STUDIES ON BIOLOGICALLY ACTIVE PYRAZOLE TERMINATED IMINO NAPHTHYL DERIVATIVES

In this present study, a series of pyrazole terminated imino naphthyl derivatives were synthesized by the condensation reaction between 1,3 - diphenyl pyrazol-4-carboxaldehyde with substituted aromatic amines. The compounds were analyzed for their in vitro antimicrobial activities against some bacterial and fungal species and compared with the standard drugs. The molecular docking studies with protein and DNA were also carried out and revealed that all the synthesized compounds showed moderate to good biological activities, both experimentally and theoretically.

Synthesis and Antiproliferative Screening of Some Heterocycles Derived from 4-((5-Chloro-3-Methyl-1-Phenyl-1H-Pyrazol-4-yl)Methylene)-2-Phenyloxazol-5(4H)-One

A new series of pyrazole derivatives was synthesized starting from the pyrazole-based oxazolone derivative 3. The activity of compound 3 toward some mono- and bidentate nucleophiles was investigated. Some of the synthesized compounds were screened for their antiproliferative activity against colon and breast cancer cell lines. The results of the biological assay revealed that the triazinone derivative 13 was the most potent against the two HCT116 and MCF7 cell lines since it showed IC50 = 8.37 ± 0.5 µM and 3.81 ± 0.2 µM, respectively, as compared to the reference drug doxorubicin (IC50 = 5.23 ± 0.3 and 4.17 ± 0.2 µM, respectively).

Synthesis, Characterization, In vitro Antimicrobial Evaluation and Molecular Docking Studies of Pyrazole Based Pyrimidine and Pyrazolone Motifs

Background: In the past few decades, mankind is suffering from tormented life-threatening infectious diseases caused by multidrug-resistant bacteria. As a result, new antimicrobial classes with distinct modes of action are required to combat multidrug-resistant infections. Objective: The pyrazole-based pyrimidine and pyrazolone motifs were synthesized, characterized, and screened for their antimicrobial activity. Molecular docking was carried out for the development of antimicrobial agents based on the results of biological activity obtained. Methods: We have synthesized a new series of pyrazole containing pyrimidine-pyrazolone hybrids by using multi-step reactions in the search of antimicrobial agents (7a-o). The structures were determined by 1H NMR, 13C NMR, IR, and mass spectroscopy techniques. Moreover, synthesized compounds were evaluated for their antimicrobial activity by using serial Broth dilution method. Results: Antimicrobial activity of synthesized compounds has been tested against bacterial and fungal strains. Compound 7o was most effective against S. aureus with MIC = 0.096 M/mL. A molecular docking study against microbial DNA gyrase revealed important information about the mechanisms underlying antimicrobial efficacy. Through significant interactions with active site residues, all of the compounds were able to dock well into the enzyme's active site. Furthermore, Compounds 7a (0.531 M/mL), 7b (0.456 M/mL), and 7m (0.485 M/mL) showed excellent antifungal activity against C. albicans compared to the positive control griseofulvin. Conclusion: It has been concluded that compounds containing electron-donating groups are found to be most active against bacterial strains while compounds having both electron-donating as well as electron-withdrawing groups are most favorable for antifungal activity.

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.