Pyrazole Derivatives Research Articles

Synthesis of Pyrazole Derivative Incorporating Fluorine in the Aromatic Substitution for Physiological and Pharmacological Studies

Over the past decade, drug resistance has become a growing problem in the treatment of infectious diseases caused by bacteria, fungi and viruses. In particular, resistance of bacterial pathogens to current antibiotics has emerged as a measure of health problems. This is especially true in the case of infectious diseases such as pneumonia, meningitis and tuberculosis, which would once have been easily treated with antibiotics, is no longer so readily treated. At present, all widely used antibiotic, including some of the agent such as streptogramins and new generation fluoroquinolones are subjected to bacterial resistance. The search for new antimicrobial agent is one of the most challenging tasks to the medicinal chemist. A search for new antimicrobial compounds with potent and minor toxicity continues to be a region of exploration in medicinal chemistry. It has been well recognized that nitrogen containing heterocyclic molecule is a seat of diverse medicinal activities. Heterocyclic nucleus Pyrazole constitutes an important class of compounds for new drug development. The synthesis of these derivatives and investigation of their chemical and biological behavior have gained more importance in recent decades. Owing to the pharmacological importance of Pyrazole, and its derivatives, in the present work, it has been contemplated to combine various biologically active moieties with these heterocycles through active functional systems to form new molecular framework. Prompted by the therapeutic importance of these heterocyclic derivatives, in the present research work we have synthesized Pyrazole with fluorinated aromatic rings, and its derivatives through multistep reaction. Appropriate synthetic methodologies have been developed for the synthesis of new molecules. Their purification techniques have been established. All the newly synthesized compounds have been characterized by 1H NMR, 13C NMR, mass spectral, IR and elemental analyses. Also structures of a few molecules have been confirmed by X-ray crystallographic analysis. Further, the target molecules have been evaluated for their in vitro antibacterial and antifungal activity. From the pharmacological evaluation, it has been observed that some of Pyrazole, derivatives showed good antimicrobial activity

Synthesis and antimicrobial activity evaluation of pyrazole derivatives containing the imidazo[2,1-b][1,3,4]thiadiazole moiety.

Four series of novel pyrazole derivatives (compounds 17a-m, 18a-m, 19a-g, and 20a-g) were synthesized, and their antibacterial and antifungal activities were evaluated. Most of the target compounds (17a-m, 18k-m, and 19b-g) showed strong antifungal activity and high selectivity relative to both Gram-positive and Gram-negative bacteria. Among them, compounds 17l (minimum inhibitory concentration [MIC] = 0.25 µg/mL) and 17m (MIC = 0.25 µg/mL) showed the strongest antifungal activity, being 2- and 4-fold more active than the positive controls gatifloxacin and fluconazole, respectively. In particular, compound 17l showed little cytotoxicity against human LO2 cells and did not exhibit hemolysis at ultrahigh concentrations, as did the positive control compounds gatifloxacin and fluconazole. These results indicate that these compounds are valuable for further development as antifungal agents.

Synthesis of novel Fe3O4 nanostructures surrounded by Ti-MOF nanostructures as bioactive and efficient catalysts in three-component synthesis of new pyrazole derivatives

Synthesis and reporting of new nanoparticles with diverse properties is important in chemistry. A one-step, rapid and controllable synthesis of the new Fe3O4 surrounded in Ti-MOF nanostructures was carried out with microwave technology. After identifying and confirming the structure, Fe3O4 surrounded in Ti-MOF nanostructures was used as a suitable catalyst with high thermal resistance and recyclable in a three-component reaction of phenylhydrazine, malononitrile and aldehyde to synthesis novel pyrazole derivatives. Continuing investigations on Fe3O4 surrounded in Ti-MOF nanostructures, its antimicrobial properties were tested on Gram-positive bacterial species, Gram-negative bacterial species and fungi bacterial. Identification of Fe3O4 surrounded in Ti-MOF nanostructures with morphology and size distribution technique (SEM), surface area technique (BET), Infrared spectroscopy (FT-IR), Energy-Dispersive X-ray spectroscopy (EDX/EDX mapping), and Vibrating Sample Magnetometer (VSM) were performed. Synthesized pyrazole derivatives with Fe3O4 surrounded in Ti-MOF nanostructures than previously reported methods have less synthesis time and high efficiency. In antimicrobial properties high effects were observed based on MIC, MBC, and MFC values.

Synthesis, characterization, and biological evaluation of new chitosan derivative bearing diphenyl pyrazole moiety

This work reports the synthesis of a new pyrazole derivative by reacting 5-amino-1,3-diphenyl pyrazole with succinic anhydride and bearing the product chemically on the chitosan chains via amide linkage to achieve a new chitosan derivative (DPPS-CH). The prepared chitosan derivative was analyzed by IR, NMR, elemental analysis, XRD, TGA-DTG, and SEM. As compared with chitosan, DPPS-CH showed an amorphous and porous structure. Coats-Redfern results showed that the thermal activation energy for the first decomposition of DPPS-CH is 43.72 KJ mol−1 lower than that required for chitosan (88.32 KJ mol−1), indicating the accelerating effect of DPPS on the thermal decomposition of DPPS-CH. The DPPS-CH manifested a powerful wide spectrum antimicrobial potential against pathogenic gram-positive and gram-negative bacteria and Candida albicans at minute concentrations (MIC = 50 μg mL−1) compared to chitosan (MIC = 100 μg mL−1). The MTT assay proved the toxic properties of DPPS-CH against a cancer cell line (MCF-7) at a minute concentration (IC50 = 15.14 μg mL−1) while affecting normal cells (WI-38) at seven times this concentration (IC50 = 107.8 μg mL−1). According to the current findings, the chitosan derivative developed in this work appears to be a promising material for use in biological domains.

Preparation of novel pyrazole substituted triazole libraries and estimation of their biological activity

AbstractWe have constructed a new library of 1,2,3‐triazole tethered pyrazole derivatives (6 a–h & 7 a–h) from propargyl alcohol through simultaneous click process, oxidation, condensation, and rearrangement under mild reaction conditions. The final products were obtained in moderate to good yields. All the compound structures were characterized by analytical and spectral (1H NMR, 13C NMR & HRMS) studies. Furthermore, the evaluation of biological activity of newly synthesized molecules was done against three human cancer cell lines, such as HeLa (Human cervical cancer), A549 (Human alveolar adenocarcinoma), MCF‐7 (Human breast adenocarcinoma). Compound 7 e has showed good anti‐proliferation activity with HeLa (IC50 0.13±0.02 μM), MCF‐7 (IC50 2.7±0.3 μM), while compounds 6 a and 6 g gave favourable anti‐proliferation against above three human cancer cell lines, compared with the standard drug Doxorubicin.

Synthesis and docking studies of pyrazole-benzamide-benzothiazole conjugates as xanthine oxidase inhibitor candidates

A series of benzothiazole bearing pyrazole derivatives (6a-j) were synthesized via mechanochemical synthesis through hand grinding using pestle and mortar, and their xanthine oxidase inhibition efficiency and antioxidant properties were evaluated. The 1H NMR, 13C NMR, FT-IR, and mass spectroscopy techniques were employed for the characterization of the synthesized molecules. Initially, the xanthine oxidase (XO) enzyme inhibitory activity for all the compounds (6a-j) was performed using standard reference. Further, for the potent compound (6h) with methyl sulphonyl substitution in the benzothiazole ring the kinetic analysis of XO was carried out. Later, anti-oxidant assays like DPPH, ABTS, and superoxide radical scavenging assays for title compounds were conducted. Also in these assays, the compound (6h) was found to exhibit good antioxidant activity, and the inhibitory constant of XO was found to be 1.78 µg. Furthermore, the docking and dynamic studies were carried out, and the compound (6h) was found to show the lowest binding energy. Also, the analysis of RMSD, RMSF, Rg, SASA, and the number of hydrogen bonds of the compound (6h) was conducted and the binding free energy of the compound (6h) was calculated.

New Niflumic Acid Derivatives as EGFR Inhibitors: Design, Synthesis, In silico Studies, and Anti-proliferative Assessment.

1,3,4-oxadizole and pyrazole derivatives are very important scaffolds for medicinal chemistry. A literature survey revealed that they possess a wide spectrum of biological activities including anti-inflammatory and antitumor effects. To describe the synthesis and evaluation of two classes of new niflumic acid (NF) derivatives, the 1,3,4-oxadizole derivatives (compounds 3 and (4A-E) and pyrazole derivatives (compounds 5 and 6), as EGFR tyrosine kinase inhibitors in silico and in vitro. The designed compounds were synthesized using conventional organic synthesis methods. The antitumor activities of the new NF derivatives against HepG2 hepatocellular carcinoma and A549 non-small cell lung cancer cell lines were assessed in vitro via MTT assay, flow cytometry, RT-PCR, as well as via molecular docking studies. The cytotoxicity results indicated that the newly synthesized NF derivatives were cytotoxic against the two cancer cell lines, with compound 6 being the most cytotoxic, achieving the lowest IC50 concentration. Furthermore, compound 6 targeted EGFR tyrosine kinase leading to cell cycle arrest at the G2/M cell cycle phase and induction of apoptosis. The in vitro biological investigation results matched those of the molecular docking analysis. In conclusion, the new NF derivatives, specifically compound 6, exhibited favorable pharmacokinetic features and are promising EGFR tyrosine kinase inhibitors. A series of niflumic acid derivatives (3, 4A-E, 5, and 6) were successfully created, and FT-IR, <sup>1</sub>H, ₁₃CNMR, and HRMS were used to confirm their chemical structures. According to molecular docking studies, compounds 3, 5, and 6 have the highest docking scores (ΔG), and most tested compounds have a good pharmacokinetic profile. Results of compound 6 in vitro antitumor activities showed that it is a promising EGFR tyrosine kinase inhibitor.

Synthesis by microwave irradiation of new pyrazole-imidazoline-pyrimidine analogs: Physicochemical and photophysical properties and their biological activity against Trypanosoma cruzi

Pyrazole derivatives are pharmacologically important agents that possess a wide spectrum of biological activities. Thus, the optimization of their synthetic approaches is of great interest for medicinal and pharmaceutical chemistry. In this work, eleven new 7-aryl-2,3-dihydro-7H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidines 1(a-k) were synthesized employing microwave irradiation conditions (150 W, 15–45 min). All compounds were completely characterized through Fourier Transform Infrared Spectroscopy (FT-IR), Nuclear Magnetic Resonance (NMR), and High-resolution Mass Spectrometry (HRMS) analyses. The in silico prediction of physicochemical properties showed that all analogs do not violate Lipinki's rule with prediction of good oral bioavailability. Analogs showed low activity against T. cruzi. Correlated experimental methods have been applied to investigate the photophysical properties of 1(a-k), describing their absorption properties in function of substituents. The molecular set exhibits a cyan emission, enabling it to investigate the basic fluorescence spectroscopy in solution.

Design, Synthesis, and Anticancer Evaluation of New Coumarin and Pyrazole Derivatives Bearing Benzenesulfonamide Moiety

Design, Synthesis, and Anticancer Evaluation of New Coumarin and Pyrazole Derivatives Bearing Benzenesulfonamide Moiety

Synthesis and SARs study of novel spiro-oxindoles as potent antiproliferative agents with CDK-2 inhibitory activities.

A series of 16 novel spirooxindole analogs 8a-p were designed and constructed via cost-effective single-step multicomponent [3+2] cycloaddition reaction of azomethine ylide (AY) generated in situ from substituted isatin (6a-d) with suitable amino acids (7a-c) and ethylene-engrafted pyrazole derivatives (5a,b). The potency of all compounds was assayed against a human breast cancer cell line (MCF-7) and a human liver cell line (HepG2). Spiro compound 8c was the most active member among the synthesized candidates, with exceptional cytotoxicity against the MCF-7 and HepG2 cell lines, with IC50 values of 0.189 ± 0.01 and 1.04 ± 0.21 µM, respectively. The candidate 8c exhibited more potent activity (10.10- and 2.27-fold) than the standard drug roscovitine (IC50 = 1.91 ± 0.17 µM (MCF-7) and 2.36 ± 0.21 µM (HepG2)). Compound 8c was investigated for epidermal growth factor receptor (EGFR) inhibition; it exhibited promising IC50 values of 96.6 nM compared with 67.3 nM for erlotinib. The IC50 value of 8c (34.98 nM) exhibited cyclin-dependent kinase 2 (CDK-2) inhibition, being more active than roscovitine the (IC50 = 140 nM) in targeting the CDK-2 kinase enzyme. Additionally, for apoptosis induction of compound 8c in MCF-7, it upregulated the expression levels of proapoptotic genes for P53, Bax, caspases-3, 8, and 9 at up to 6.18, 4.8, 9.8, 4.6, 11.3 fold-change, respectively, and downregualted the level of the antiapoptotic gene for Bcl-2 by 0.14-fold. Finally, a molecular docking study of the most active compound 8c highlighted a good binding affinity with Lys89 as the key amino acid for CDK-2 inhibition.

In Vivo and In Vitro Evaluation of Some New Pyrazole Derivatives in Comparison with Celecoxib

Abstract: In the present work, a series of 3-indolyldihydropyrimidine thione containing pyrazole, thiadiazole, and/or benzothiazole were prepared in the form of sulfonamide and sulfohydrazide derivatives in either conventional conditions or under microwave irradiation and evaluated as potential non-steroidal cyclooxygenase-2(COX-2) inhibitors. On subjecting the key synthon 1-[4-(1H-Indol-3-yl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-5-yl]-3,3-dimercaptopropene 1 to the reaction with phenylhydrazine; pyrazole condensed to indolyldihydropyrimidine 2 formed and used as a starting material for synthesizing pyrazoles sulfohydrazides and pyrazole sulfonamides moieties. The newly synthesized target compounds have been examined as in vitro antimicrobial agents and in vivo anti-inflammatory and analgesic according to carrageenan-induced paw edema in comparison with celecoxib as a standard drug; promising activities were obtained. All newly obtained compounds have been characterized by means of elemental and spectral analyses, e.g. FT-IR, Mass spectra, 1H NMR, and 13C NMR.

Synthesis, Molecular Docking, and Antitumor Activity of 1,3,4‐Thiadiazole‐Based Heterocycles against Hepatocellular Carcinoma

AbstractNumerous aminothiadiazole‐based compounds have been extensively employed as pharmaceuticals to treat a variety of ailments, leading to a flurry of new discoveries. It takes novel synthetic techniques to prepare new aminothiadiazole derivatives from enaminonitrile derivative 4, which was formerly an important step in the synthesis of pyrazole, isoxazole, and pyrimidine derivatives (6, 8, and 10). For the production of triazolo, imidazolo, and pyrazolo pyrimidine derivatives, enaminonitrile 4 also has shown chemical activity toward various N‐nucleophiles, such as heterocyclic amines (12, 14, and 16). As a result of cyclo‐condensing enaminonitrile precursor 4 with a variety of carbon and oxygen nucleophiles, certain complex, polyfunctional substituted fused 2‐pyridone and chromenone derivatives containing thiadiazole molecules were produced (18, 20, 22, and 25). Next, the cytotoxic effect of the entitled compounds against HepG2 and MCF7 has been reported, followed by an in‐vivo study on hepatocellular carcinoma (HCC) HepG2 with the compounds that showed the lowest IC50 values. In addition to molecular docking into the FGFR 4 active site (PDB: 4XCU), the bioavailability of the active compounds in accordance with Lipinski's rule of five has been shown.

Modern Non-Steroidal Anti-Inflammatory Drugs

Over the past decade, employees of the departments of pharmacology, general and bioorganic chemistry of the Tashkent State Medical Institute (since 1990, I Tashkent State Medical Institute) have been conducting targeted research to find, study new, more advanced anti-inflammatory drugs in a number of new pyrazole derivatives and related compounds (in general, nutrition more than 300 new drugs were exposed). These studies revealed a number of highly active and low-toxic compounds, and also established the dependence of the anti-inflammatory activity of these compounds on the chemical structure.

Investigation of chalcone cyclized pyrazole derivatives as an anti-inflammatory agent: In-vivo and in-silico molecular docking approach

A novel pyrazole condensed with chalcone and pyrazoline derivatives have been synthesized and evaluated against anti-inflammatory activity using a standard method of acute carrageenan-induced rat paw edema in vivo. NJD1 would be the most potent compound (30.10 ± 0.02%) found to be inhibitory in rats and exhibiting activity similar to celecoxib as a reference standard. Molecular docking studies have been conducted on PDB: 1TD7, the 3D X-ray crystallographic structure of group I protein phospholipase A2 (PLA2), -5.609 kcal/mol is the binding affinity of the standard celecoxib. The synthesized derivatives NJD1 and NJD2 (-6.283, -6.057 kcal/mol) has exhibited greater binding affinity, respectively.

Synthesis, molecular docking study, and in vivo biological evaluation of pyrazolopyridines derived from monocarbonyl curcumin analogues as potential anti-inflammatory agents

Background: Pyrazolopyridines are heterocyclic compounds with nitrogen atoms in the ring, and they have been used as one of the important pharmacophores in drug design. Pyrazole derivatives have been synthesised and applied in the pharmaceutical industry as active drugs. The recent commercial success of pyrazole COX-2 inhibitors has brought even more attention to the significance of this heterocyclic ring in medicinal chemistry. Objective: This study aimed to synthesise new compounds as anti-inflammatory candidates from the pyrazolopyridine group. Method: Synthesis was carried out using the Claisen-Schmidt reaction through condensation of substituted benzaldehyde and 4-piperidone to produce mono-ketone curcumin analogues, which were then cyclised with phenylhydrazine. The results of the synthesis were characterised using FT-IR, 1H-NMR, and MS. Docking analysis was performed on the 3LN1 protein with MOE 2021.0901. Furthermore, an in vivo anti-inflammatory test was applied using a plethysmometer. Results: The synthesis results obtained two pyrazolopyridine compounds, and the docking results showed that both of these synthesised compounds could interact with the COX-2 receptor binding site. Conclusion: Compound 2 demonstrated good anti-inflammatory activities. This strategy is in the preliminary stages of identifying novel substances that may be used as anti-inflammatory agents in the future.

Synthesis, spectroscopic characterization and dyeing performance of novel bis azo dyes derived from benzidine

Benzidine was coupled with ethyl cyanoacetate, and malononitrile, to give azo-hydrazo products which in turn were cyclized by using hydrazine and phenyl hydrazine to give 4,4'-([1,1'-biphenyl]-4,4'-diylbis(hydrazin-2-yl-1-ylidene))bis pyrazole derivatives 5–7. These compounds were identified by various spectral analysis. The examination of 0.1 M NaOH and 0.1 M HCl in DMF revealed that the λmax of the synthesized dyes are quite sensitive to pH variation and slightly affected by the coupler moieties. Utilizing the dispersion agent DYEWELL-002, polyester fabric (PE-F) was dyed in water. The color strength (K/S), its summation (K/Ssum), dye exhaustion (%E) and reflectance values were measured and discussed. The DFT method estimates the chemical descriptor parameters of the titled dyes, using B3LYP/6-31G(d,p) level to investigate the performance of dyes as well as to postulate a mechanism of dyeing process.

Synthesis, in silico modelling, and in vitro biological evaluation of substituted pyrazole derivatives as potential anti-skin cancer, anti-tyrosinase, and antioxidant agents

Twenty-five azole compounds (P1–P25) were synthesised using regioselective base-metal catalysed and microwave-assisted approaches, fully characterised by high-resolution mass spectrometry (HRMS), nuclear magnetic resonance (NMR), and infrared spectra (IR) analyses, and evaluated for anticancer, anti-tyrosinase, and anti-oxidant activities in silico and in vitro. P25 exhibited potent anticancer activity against cells of four skin cancer (SC) lines, with selectivity for melanoma (A375, SK-Mel-28) or non-melanoma (A431, SCC-12) SC cells over non-cancerous HaCaT-keratinocytes. Clonogenic, scratch-wound, and immunoblotting assay data were consistent with anti-proliferative results, expression profiling therewith implicating intrinsic and extrinsic apoptosis activation. In a mushroom tyrosinase inhibition assay, P14 was most potent among the compounds (half-maximal inhibitory concentration where 50% of cells are dead, IC50 15.9 μM), with activity greater than arbutin and kojic acid. Also, P6 exhibited noteworthy free radical-scavenging activity. Furthermore, in silico docking and absorption, distribution, metabolism, excretion, and toxicity (ADMET) simulations predicted prominent-phenotypic actives to engage diverse cancer/hyperpigmentation-related targets with relatively high affinities. Altogether, promising early-stage hits were identified – some with multiple activities – warranting further hit-to-lead optimisation chemistry with further biological evaluations, towards identifying new skin-cancer and skin-pigmentation renormalising agents.

Design, synthesis, molecular docking and biological evaluation of novel pyrazole derivatives bearing quinoxalinone moiety as multi-targeted anticancer agents

Based on a multitarget-directed drug design technique, a series of new quinoxalinone-based pyrazole derivatives (4a-h) were designed and synthesized. The potency of newly synthesized molecules to inhibit the antiproliferation of the human cancer cell lines MCF-7 (breast), HCT-116 (colon), and A549 (lung) was examined. The most effective compounds against the examined cancer cell lines were 4e, 4f, 4 g, and 4 h. Among these, compounds 4e and 4 h had a strong anticancer activity that was equivalent to sorafenib. The capacity of the potent compounds (4e, 4f, 4 g, and 4 h) to inhibit the in vitro activity of the thymidylate synthase (TS) enzyme, BRaf, and EGFR kinases was also tested. With IC50 values for the TS enzyme, BRaf kinase, and EGFR kinase ranging from 1.16 to 2.97 μM, 1.28 to 3.69 μM, and 1.93 to 4.28 μM, respectively, all the investigated compounds showed a noticeable inhibitory action. Among the synthesized hybrids, compound 4 h showed IC50 value of 2.04, 2.69 and 1.93 μM against MCF-7, HCT-116, and A549 cell line, respectively, and 1.16, 1.28 and 1.93 nM against TS, BRaf and EGFR kinase enzyme, respectively. All of the synthesized hybrids adhered to Lipinski's guidelines, which suggested that they would have favorable oral drug-like qualities. To determine the probable interaction between the potent compounds and the TS active site, molecular docking study was conducted.

Design, synthesis and antitumor activity of coumarin, isoxazole, pyrazole, pyridine and pyrimidine compounds: 3β-hydroxypregn-5-ene-20-one derivatives

In continuation of our reserach for synthesizing heterocyclic derivatives with a broad range of biological activities, the current research was performed to synthesize 3β-hydroxypregn-5-ene-20-one derivatives of coumarin, isoxazole, pyrazole, pyridine and pyrimidine and screen for antitumor activity. Synthesis of amino-thiopephen derivatives (1a-1b) was performed through reaction of 3β-hydroxypregn-5-ene-20-one with ethyl cyanoacetate or malononitrile and sulphur. 3β-Hydroxypregn-5-ene-20-one was reacted with ethyl cyanoacetate in the presence of hydrazine, urea or thiourea to obtain aminopyrazole (3), aminopyrimidine (4a-4b) derivatives, respectively. The amino-thiophene derivatives (1a-1b) further reacted with either phenylisothiocyanate or benzoylisothiocyanate to form fused thienopyrimidine derivatives (5a-5d). The products 1a and 1b were also treated with ethyl cyanoacetate to afford cyanoacetamidothiophene derivatives (6a-6b) which were converted to fused thienopyridone derivatives (7a-7b) through cyclization reaction. The compounds 6a and 6b were allowed to react with different carbonyl compounds including salicyaldehyde, cyclopentanone-sulphur mixture, acetylacetone and malonaldehyde to prepare coumarin (8a-8b), cyclopentylthiophene (9a-9b) and 2-pyridinone (10a-10d) derivatives respectively. Furthermore, the reactions of hydroxylamine hydrochloride and benzoylacetonitrile with the compounds 6a-6b separately afforded new aminoisoxazole (12a-12b) and phenylpyridone (14a-14b) derivatives, respectively. The structures of new products were established through IR, 1H NMR, 13C NMR spectroscopic and mass spectrometric analysis. The synthesized compounds (1a-1b to 14a-14b) displayed in-vitro antitumor activity against human cell-lines, including MCF-7 (breast adenocarcinoma), SF-268 (CNS cancer) and NCI-H460 (non-small lung cancer cell). The results suggested that all the screened products exhibited cell growth inhibitory activity in a dose-dependents manner. However, the compound 12a showed highest level of inhibition against all three cell-lines.

Synthesis and Pharmacological Activities of Pyrazole and Oxadiazole Derivatives: a Review

Synthesis and Pharmacological Activities of Pyrazole and Oxadiazole Derivatives: a Review