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As nitrogen-containing five-membered heterocyclic structural units, the substituted pyrazole derivatives have a broad spectrum of pharmacological activities, especially 4,5-dihydro-1H-pyrazoles that also commonly known as 2-pyrazolines. Since 2010, considerable studies have been found that the 2-pyrazoline derivatives possess potent anticancer activities. In the present review, it covers the pyrazoline derivatives reported by literature from 2010 till date (2010-2019). This review aims to establish the relationship between the anticancer activities variation and different substituents introduced into a 2-pyrazoline core, which could provide important pharmacophore clues for the discovery of new anticancer agents containing 2-pyrazoline scaffold.
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Antineoplásicos , Antineoplásicos/farmacología , Humanos , Relación Estructura-ActividadRESUMEN
BACKGROUND: The reactivity of 4-(dicyanomethylene)-3-methyl-l-phenyl-2-pyrazoline-5-one DCNP 1 and its derivatives makes it valuable as a building block for the synthesis of heterocyclic compounds like pyrazolo- imidazoles, -thiazoles, spiropyridines, spiropyrroles, spiropyrans, and others. As a number of publications have reported on the reactivity of DCNP and its derivatives, we compiled some features of this interesting molecule. OBJECTIVE: This article aims to review the preparation of DCNP, its reactivity, and application in heterocyclic and dyes synthesis. CONCLUSION: In this review, we have provided an overview of recent progress in the chemistry of DCNP and its significance in the synthesis of various classes of heterocyclic compounds and dyes. The unique reactivity of DCNP offers unprecedentedly mild reaction conditions for the generation of versatile cynomethylene dyes from a wide range of precursors, including amines, α-aminocarboxylic acids, their esters, phenols, malononitriles, and azacrown ethers. We anticipate that more innovative transformations involving DCNP will continue to emerge in the near future.
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Compuestos Heterocíclicos , Nitrilos , Colorantes , ImidazolesRESUMEN
AIM AND OBJECTIVE: This work presents the synthetic capability and the exploitation of 1,3-diphenyl- 1H-pyrazole-4-carboxladehyde 1 and 5-diphenyl pyrazolyl-2-pyrazoline analogue 8 to serve as excellent precursors for the synthesis of substituted indol-2,3-dione, trizolo[3,4-a]benzazoles, thiazolo[2,3- a]benzimidazole-3-one, substituted 2-pyrazoline and pyrazole-substituted-pyrazolines using various reagents. MATERIALS AND METHODS: Using chemicals from Aldrich, Fluka, or Merck, and pure solvents, we apply the synthetic procedures for the synthesis of novel heterocycles. The melting points of these compounds were determined using APP. Digital ST 15 melting point apparatus. SP3-100 spectrophotometer recorded FT-IR spectra (KBr) (cm-1). NMR spectra (δ, ppm) were recorded on 400 MHz AVANCE-III High-Performance FT-NMR Spectrometer BRUCKER (Switzerland) and some 1H NMR spectra were recorded on Varian EM-360L NMR Spectrophotometer (90 MHz) (USA) in CDCl3 or DMSO-d6 as a solvent. Elemental analyses were carried out at a Vario EL C, H, N, and S Analyzer. Bromine was determined using direct titration method after carius combustion. RESULTS: The structures of the compounds were confirmed by IR, 1H NMR, 13C NMR, and elemental analyses. CONCLUSION: 1,3-Diphenyl-1H-pyrazole-4-carboxladehyde 1 and 2-pyrazoline derivative 9 confirmed their importance in the synthetic organic chemistry. Depending on the formyl group of aldehyde 1 and active methylene of pyrazoline 8, we synthesized new series of heterocycles; indol-2,3-dione, trizolo[3,4-a]benzazole, thiazolo[2,3-a]benzimidazole-3-one and pyrazolyl-pyrazoline derivatives expecting their pharmacological applications. The targeted compounds were substantiated from its spectral data.
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AIM AND OBJECTIVE: A series of new 2-pyrazoline analogues were synthesized. The structures of the synthesized compounds were elucidated by the analytical and spectroscopic data. Some selected compounds were screened for the anti-inflammatory activity by using animal model of carrageenan-induced paw edema in mice. Additionally, the analgesic and acute toxicity of these compounds were evaluated and exhibited reasonable results. The anti-oxidant and anti-inflammatory effects of these compounds were established by measuring the contents of malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide (NO), and tumor necrosis factor alpha (TNF-α) in the edema paw tissue. MATERIALS AND METHODS: All chemicals and reagents used in current study were of analytical grade. Melting points were determined using APP. Digital ST 15 melting point apparatus and are uncorrected. FT-IR spectra were recorded on a Pye-Unicam SP3-100 spectrophotometer in KBr pellet. All 1H and 13C NMR spectra were recorded on AVANCE-III (400 MHz) High Performance FT-NMR Spectrometer Brucker (Switzerland) and some 1H NMR spectra were recorded on Varian EM-360L NMR Spectrophotometer (60 MHz) (USA) in CDCl3 or DMSO-d6 as solvent. Chemical shifts are reported in δ units and the coupling constants (J) are reported in hertz. C, H, N and S analyses were performed with a Vario EL C, H, N, S Analyzer. Carrageenan (product number C1013) was obtained from Sigma-Aldrich (USA). RESULTS: The structures of the compounds were confirmed by IR, 1H NMR, 13C NMR, and elemental analyses. The results of pharmacological activity revealed that compounds 5, 6, 7, and 15 could be recognized as potential multi-potent anti-inflammatory. CONCLUSION: A simple and suitable method for the synthesis of new pharmacophore was reported. We have designed nineteen heterocycles related to pyrazoline ring, and evaluated eleven of them for their antiinflammatory, analgesic and acute toxicity activities. Compounds 5, 6, 7, and 15 proved to be the interesting compounds, they have high anti-inflammatory activity. However, all the selected compounds show remarkable analgesic activity.
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Analgésicos/uso terapéutico , Antiinflamatorios/uso terapéutico , Indoles/uso terapéutico , Inflamación/tratamiento farmacológico , Dolor/tratamiento farmacológico , Pirazoles/uso terapéutico , Analgésicos/síntesis química , Analgésicos/toxicidad , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/toxicidad , Carragenina , Edema/inducido químicamente , Femenino , Historia Medieval , Indoles/síntesis química , Indoles/toxicidad , Inflamación/inducido químicamente , Masculino , Ratones , Pirazoles/síntesis química , Pirazoles/toxicidad , Ratas WistarRESUMEN
A new racemic pyrazoline derivative was synthesized and resolved to its enantiomers using analytic and semipreparative high-pressure liquid chromatography. The absolute configuration of both fractions was established using vibrational circular dichroism. The in vitro monoamine oxidase (MAO) inhibitory profiles were evaluated for the racemate and both enantiomers separately for the two isoforms of the enzyme. The racemic compound and both enantiomers were found to inhibit hMAO-A selectively and competitively. In particular, the R enantiomer was detected as an exceptionally potent and a selective MAO-A inhibitor (Ki = 0.85 × 10-3 ± 0.05 × 10-3 µM and SI: 2.35 × 10-5 ), whereas S was determined as poorer compound than R in terms of Ki and SI (0.184 ± 0.007 and 0.001). The selectivity of the enantiomers was explained by molecular modeling docking studies based on the PDB enzymatic models of MAO isoforms.
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Inhibidores de la Monoaminooxidasa/química , Inhibidores de la Monoaminooxidasa/farmacología , Pirazoles/química , Pirazoles/farmacología , Dicroismo Circular , Células Hep G2 , Humanos , Cinética , Modelos Moleculares , Simulación del Acoplamiento Molecular , Estructura Molecular , Monoaminooxidasa/genética , Monoaminooxidasa/metabolismo , Inhibidores de la Monoaminooxidasa/síntesis química , Pirazoles/síntesis química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Parkinson's disease (PD) is a chronic, progressive, and age-related neurodegenerative disorder characterized by the loss of midbrain dopaminergic neurons caused by the accumulation of free radicals and oxidative stress. Based on the neuroprotective properties of 2-pyrazoline derivatives, in the current work, 1-(phenyl/4-substituted phenyl)-3-(2-furanyl/thienyl)-5-aryl-2-pyrazolines (3aâ»i, 4aâ»i) were synthesized via the cyclization of the chalcones (1, 2) with suitable phenylhydrazine hydrochloride derivatives. All these compounds were investigated for their neuroprotective effects using an in vitro 6-hydroxydopamine (6-OHDA)-induced neurotoxicity model of PD in the rat pheochromocytoma (PC-12) Adh cell line. In addition, some different pharmacokinetic parameters of all compounds were in silico predicted by the QikProp module of Schrödinger's Maestro molecular modeling package. 4-Methylsulfonylphenyl substituted compounds 3h (20%) and 4h (23%) were determined as the most promising neuroprotective agents related to their inductive roles in cell viability when compared with the 6-OHDA-positive control group (43% and 42%, respectively). Moreover, in silico pharmacokinetic results indicated that all compounds were within the acceptable range intended for human use. According to both in vitro and in silico studies, compounds 3h and 4h draw attention as potential orally bioavailable therapeutic drug candidates against neurodegeneration in PD.
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Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo/efectos de los fármacos , Oxidopamina/efectos adversos , Pirazoles/química , Pirazoles/farmacología , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Técnicas de Química Sintética , Diseño de Fármacos , Espectroscopía de Resonancia Magnética , Estructura Molecular , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fármacos Neuroprotectores/síntesis química , Pirazoles/síntesis química , Ratas , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
A novel series of pyrazoline derivatives were synthesized and their spectral properties were characterized via FT-IR, 1H, and 13C NMR. The electronic transitions and fluorescence properties were tracked via UV-Vis and emission spectrometry. The density functional theory (DFT) calculations have been also computed to get spot onto the geometry, electronic transitions and spectroscopic properties theoretically that has been compared with the encountered experimental ones. Moreover, the dipole moment, optimized energy, HOMO - LUMO energies and band gaps were calculated for novel candidates pyrazoline derivatives with highly fluorescence quantum yield.
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Sensitive analysis of glycans by liquid chromatography/mass spectrometry is significantly hampered by the lack of chromogenic or fluorescent groups on the glycan structures, as well as, their poor ionization properties. In the present, a heterobifunctional chromogenic reagent 3-amino-1-phenyl-2-pyrazoline-5-ketone (PAP) bearing amino and active methylene groups, which readily reacts with reducing glycans, was used for detection of the pre-column-labeled glycans via high-performance liquid chromatography/electrospray ionization mass spectrometry (HPLC/ESI-MS). The PAP derivatives with active methylene and amino groups were obtained via reductive amination in acidic medium and condensation of an active PAP methylene group with the reducing end of glycans in alkaline medium, respectively, and the PAP derivatives could be further functionalized, e.g., via glycan microarray preparation. The conditions for the two reaction modes were optimized, the HPLC separation method of PAP derivatives was investigated, and the PAP derivatives of some glycans derived from biological samples were obtained and analyzed by ESI-MS and LC-MS. Using this new reagent, reducing glycans can be selectively derivatized by different reaction mechanisms, having great importance for functional glycomics studies.
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Polisacáridos/análisis , Pirazolonas/química , Espectrometría de Masa por Ionización de Electrospray/métodos , Cromatografía Liquida/métodos , HumanosRESUMEN
AIM AND OBJECTIVE: MAO inhibitors have a significant effect on the nervous system since they act in regulation of neurotransmitter concentrations. Neurotransmitter levels are critical for a healthy nervous system. MAO inhibitors can be used in the treatment of neurological disorders such as depression, Parkinson's disease and Alzheimer's disease, as the increase or decrease of some neurotransmitter concentrations is associated with these neurological disorders. This study was conducted to discover new and active MAO inhibitor drug candidates. MATERIALS AND METHODS: New pyrazoline derivatives have been designed with the molecular docking approach and interactions of our compounds with the MAO enzyme have been investigated using the Autodock 4.2 program. The designed pyrazoline derivative compounds were synthesized by the reaction of the chalcones and hydrazides in ethanol. hMAO inhibitory activities of the newly synthesized compounds were investigated by fluorimetric method. In vitro cytotoxicity of five most potent inhibitors were tested in HepG2 cells. RESULTS: (3-(5-bromo-2-hydroxyphenyl)-5-(4-methoxyphenyl)-4,5-dihydropyrazol-1-yl)(phenyl) methanone (5i) and (3-(2-hydroxy-4-methoxy phenyl)-5-p-tolyl-4,5-dihydropyrazol-1-yl)(phenyl) methanone (5l) inhibited hMAO-A more potently than moclobemide (Ki values are 0.004±0.001 and 0.005±0.001, respectively). The same two compounds, 5i and 5l, inhibited hMAO-A more selectively than moclobemide (SI values are 5.55x10-5 and 0.003, respectively). Both of these compounds were found non toxic at 1 µM, 5 µM and 25µM concentrations. CONCLUSION: Two of the newly synthesized compounds, (3-(5-bromo-2-hydroxyphenyl)-5-(4- methoxyphenyl)-4,5-dihydropyrazol-1-yl)(phenyl)methanone and (3-(2-hydroxy-4-methoxy phenyl)- 5-p-tolyl-4,5-dihydropyrazol-1-yl)(phenyl) methanone were found to be promising MAO-A inhibitors due to their high inhibitory potency, high selectivity and low toxicity.
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Diseño de Fármacos , Inhibidores de la Monoaminooxidasa/síntesis química , Inhibidores de la Monoaminooxidasa/farmacología , Monoaminooxidasa/metabolismo , Pirazoles/síntesis química , Pirazoles/farmacología , Relación Dosis-Respuesta a Droga , Células Hep G2 , Ensayos Analíticos de Alto Rendimiento , Humanos , Modelos Moleculares , Estructura Molecular , Inhibidores de la Monoaminooxidasa/química , Pirazoles/química , Relación Estructura-ActividadRESUMEN
AIM AND OBJECTIVE: Depression is a momentous disease that can greatly reduce the quality of life and cause death. In depression, neurotransmitter levels such as serotonine, dopamine and noradrenaline are impaired. Monoamine oxidases (MAO) are responsible for oxidative catalysis of these monoamine neurotransmitters. Because of this relation, MAO-A inhibitors show antidepressant activity by regulating neurotransmitter levels. This study was carried out to investigate the design, synthesis and activity of new antidepressant compounds in pyrazoline and hydrazone structure. MATERIAL AND METHOD: Chalcones and hydrazides were heated under reflux to give new pyrazoline and hydrazone derivatives. Docking simulations were performed using AutoDock4.2. hMAO activities were determined by a fluorimetric method. To determine cell viability, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay was used. Behavioral activities of the three compounds were determined by using Forced Swim Test, Step-Through Passive Avoidance Test, Elevated Plus Maze and Open Field Arena Tests. RESULTS: According to in vitro tests, all of the synthesized compounds were found more potent than moclobemide and six of the synthesized compounds were found more selective than moclobemide. Three of the synthesized compounds were investigated for their behavioral activities comparing with moclobemide after 7 days of i.p. treatment at 30 mg/kg. One of the three compounds elicited significant antidepressant properties. CONCLUSION: All of the synthesized compounds were found potent hMAO-A inhibitors in in vitro screening tests. Only one of the in vivo tested three compounds, (3-(2-hydroxy-5-methylphenyl)-5- p-tolyl-4,5-dihydropyrazol-1-yl)(pyridin-4-yl) methanone indicated significant antidepressant activity. This article opens a window for further development of new pyrazoline and hydrazone derivatives as antidepressant agents.
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Antidepresivos/farmacología , Ensayos Analíticos de Alto Rendimiento , Hidrazonas/farmacología , Inhibidores de la Monoaminooxidasa/farmacología , Monoaminooxidasa/metabolismo , Pirazoles/farmacología , Animales , Antidepresivos/síntesis química , Antidepresivos/química , Conducta Animal , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Células Hep G2 , Humanos , Hidrazonas/síntesis química , Hidrazonas/química , Masculino , Ratones , Simulación del Acoplamiento Molecular , Estructura Molecular , Inhibidores de la Monoaminooxidasa/síntesis química , Inhibidores de la Monoaminooxidasa/química , Pirazoles/síntesis química , Pirazoles/química , Ratas , Relación Estructura-Actividad , NataciónRESUMEN
Super-activation of cholinesterases (acetylcholinesterase and butyrylcholinesterase) are linked to various neurological problems most precisely Alzheimer's disease (AD), which leads to senile dementia. Therefore, cholinesterases (AChE & BChE) inhibition are considered as a promising strategy for the treatment of Alzheimer's disease. FDA approved drugs for the treatment of AD, belong to a group of cholinesterase inhibitors. However, none of them is able to combat or completely abrogate the disease progression. Herein, we report a series of newly synthesized chalcone derivatives with anti-AD potential. For this purpose, a series of piperidyl-thienyl and 2-pyrazoline derivatives of chalcones were tested for their cholinesterases (AChE & BChE) inhibitory activity. All compounds were found as selective inhibitor of AChE. In piperidyl chalcones derivatives compound 1e having IC50 of 0.16 ± 0.008 µM and 2m in 2-pyrazoline chalcones with IC50 of 0.13 ± 0.006 µM, were found to be the most potent inhibitors of AChE, exhibiting ≈142 and ≈ 173-fold greater inhibitory potential compared to the reference inhibitor i.e., Neostigmine (IC50 ± SEM = 22.2 ± 3.2 µM). Molecular docking studies of most potent inhibitors were carried out to investigate the binding interactions inside the active site. Molecular docking study revealed that potent compounds and co-crystalized ligand had same binding orientation within the active site of target enzyme. Most of these compounds are selective inhibitors of AChE with a potential use against progressive neurodegenerative disorder and age related problems.
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Acetilcolinesterasa/metabolismo , Butirilcolinesterasa/metabolismo , Chalconas/química , Chalconas/farmacología , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/enzimología , Animales , Electrophorus , Humanos , Simulación del Acoplamiento Molecular , Pirazoles/química , Pirazoles/farmacologíaRESUMEN
A group of 3,5-diaryl-2-pyrazoline and hydrazone derivatives was prepared via the reaction of various chalcones with hydrazide compounds in ethanol. Twenty original compounds were synthesized. Ten of these original compounds have a pyrazoline structure, nine of these original compounds have a hydrazone structure, and one of these original compounds has a chalcone structure. Structural elucidation of the compounds was performed by IR, (1)H NMR, (13)C NMR, mass spectral data, and elemental analyses. These compounds were tested for their inhibitory activities toward the A and B isoforms of human monoamine oxidase (MAO). Except for 3k and 6c, all compounds were found to be competitive, reversible, and selective inhibitors for either one of the isoforms (hMAO-A or MAO-B). Compounds 3k and 6c were found to be competitive, reversible, but non-selective MAO inhibitors. Compound 6h showed hMAO-B inhibitory activity whereas the others potently inhibited hMAO-A. Compound 5c showed higher selectivity than the standard drug moclobemide. According to the experimental K(i) values, compounds 6i, 6d, and 6a exhibited the highest inhibitory activity toward hMAO-A. The AutoDock 4.2 program was employed to perform automated molecular docking. The calculated results obtained computationally were in good agreement with the experimental values.
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Hidrazonas/síntesis química , Hidrazonas/farmacología , Inhibidores de la Monoaminooxidasa/síntesis química , Inhibidores de la Monoaminooxidasa/farmacología , Monoaminooxidasa/metabolismo , Pirazoles/síntesis química , Pirazoles/farmacología , Diseño de Fármacos , Humanos , Cinética , Moclobemida/farmacología , Simulación del Acoplamiento Molecular , Monoaminooxidasa/química , Conformación Proteica , Relación Estructura-ActividadRESUMEN
A series of 5-(benzo[d][1,3]dioxol-5-yl)-3-tert-butyl-1-substituted-4,5-dihydropyrazole derivatives 4a-e and 6a-g have been synthesized and spectrally characterized. The antibacterial activity of the novel candidates has been screened using the agar diffusion test. These compounds were endowed with high antibacterial activity against different Gram +ve and Gram -ve bacteria when compared with standard antibacterial drugs. In the light of zone of inhibition and MIC results, Sarcina and Staphylococcus aureus are the most sensitive bacteria where pyrrolidinomethanone derivative 4e showed MICs at 80 and 110 nM, respectively. While hydroxypiperidinoethanone derivative 6c showed MIC at 90 nM for Sarcina.
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A novel series of 2-pyrazoline and hydrazone derivatives were synthesized and investigated for their human monoamine oxidase (hMAO) inhibitory activity. All compounds inhibited the hMAO isoforms (MAO-A or MAO-B) competitively and reversibly. With the exception of 5i, which was a selective MAO-B inhibitor, all derivatives inhibited hMAO-A potently and selectively. According to the experimental Ki values, compounds 6e and 6h exhibited the highest inhibitory activity towards the hMAO-A, whereas compound 5j, which carries a bromine atom at R(4) of the A ring of the pyrazoline, appeared to be the most selective MAO-A inhibitor. Tested compounds were docked computationally into the active site of the hMAO-A and hMAO-B isozymes. The computationally obtained results were in good agreement with the corresponding experimental values.
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Hidrazonas/farmacología , Inhibidores de la Monoaminooxidasa/farmacología , Monoaminooxidasa/metabolismo , Pirazoles/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Hidrazonas/síntesis química , Hidrazonas/química , Modelos Moleculares , Estructura Molecular , Inhibidores de la Monoaminooxidasa/síntesis química , Inhibidores de la Monoaminooxidasa/química , Pirazoles/síntesis química , Pirazoles/química , Relación Estructura-ActividadRESUMEN
A series of biologically active N-thiocarbamoyl pyrazoline derivatives have been synthesized using anhydrous potassium carbonate as the catalyst. All the synthesized compounds were characterized by FT-IR, (1)H NMR, (13)C NMR spectral studies, LCMS, CHN Analysis and X-ray diffraction analysis (compound 7). In order to supplement the XRD parameters, molecular modelling was carried out by Gaussian 03W. From the optimized structure, the energy, dipolemoment and HOMO-LUMO energies of all the systems were calculated.