Pyrazole Carboxylic Acid Research Articles

Self-assembly and structures of new transition metal complexes with phenyl substituted pyrazole carboxylic acid and N-donor co-ligands

Five new transition metal complexes, [Ni(HL1)2(2,2′-bipy)]·3H2O (1), [Ni(HL1)2(4,4′-bipy)] (2), [Co(HL1)2(4,4′-bipy)]·5H2O (3), [Ni2(HL2)4·(4,4′-bipy)·(H2O)2]·4H2O (4), [Co(HL2)2·(4,4′-bipy)] (5) (H2L1=5-phenyl-1H-pyrazole-3-carboxylic acid; H2L2=3-phenyl-1H-pyrazole-4-carboxylic acid; 2,2′-bipy=2,2′-bipyridine; 4,4′-bipy=4,4′-bipyridine) have been synthesized and characterized. Complex 1 exhibits a monomeric structure, 2 and 3 display 1D chain structures, 4 and 5 possess 3D metal-organic frameworks with 1D channels, and all extend to 3D supramolecular networks via rich hydrogen bonds. Complex 4 shows a new (4,6)-connected network with (44·58·63)(54·6·8) topology, while 5 exhibits a NaCl-like network with (412·63) topology. The thermal stabilities of complexes 1–5 and powder XRD of 4 and 5 were investigated. Furthermore, the antibacterial activities of the title complexes against the tested bacteria were studied and compared to the activities of the corresponding free ligands.

An efficient 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU)-mediated synthesis of 5-(trifluoromethyl)-N-alkyl-1-(3-phenylisoquinoline-1-yl)-1H-pyrazole-4-carboxamides

A series of 5-(trifluoromethyl)-N-alkyl-1-(3-phenylisoquinoline-1-yl)-1H-pyrazole-4-carboxamides 4 has been effectively achieved in high yield and purity from the reaction of pyrazole carboxylic acid 2 with amines 3 in the presence of TBTU as a catalyst and diisopropyl ethylamine as a base in acetonitrile at room temperature.

Modified method for the synthesis of isomeric N-substituted (1H-pyrazolyl)propane-1,3-diones

The condensation reaction of isomeric N-substituted (1H-pyrazol-4-yl)ethanones with the ethyl esters of pyrazole carboxylic acids and fluoroacetic acids has been studied using NaH as the base. Under optimized conditions, it proved to be a convenient and preparative method for the synthesis of N-substituted (1H-pyrazolyl)propane-1,3-diones and (1H-pyrazolyl)-4-polyfluorobutane-1,3-diones.

A 1D Cu(II) coordination polymer exhibiting ferromagnetic interactions and a mononuclear Cu(II) complex of substituted pyrazole carboxylic acids: Synthesis, characterization and crystal structure

Reaction of 2 equiv. amount of copper(II) nitrate hexahydrate with 1 equiv. of 5-methyl-1-pyridin-2-yl-1 H-pyrazole-3-carboxylic acid (PyPzCA) in presence of triethyl amine base afforded a 1D coordination polymeric compound [Cu 2(PyPzCA) 2(H 2O) 3(NO 3)]NO 3·H 2O ( 1). Whereas, the same reaction when repeated with 1-(4,6-dimethyl-pyrimidin-2-yl)-5-methyl-1 H-pyrazole-3-carboxylic acid (PymPzCA) instead of PyPzCA, a mononuclear compound [Cu(PymPzCA)]·2H 2O·NEt 3 ( 2) is formed. Both the complexes are crystallographically characterized. In 1, both the copper atoms (Cu1 and Cu2) have distorted square pyramidal geometry with N 2O 3 chromophore while, in 2, the central copper atom has a distorted trigonal bipyramidal geometry with N 4O chromophore. Complex 1, is a 1D coordination polymer where the metal centers being far apart and are involved in a weak ferromagnetic interaction which is quite unexpected.

Synthesis, characterization and antiglaucoma activity of some novel pyrazole derivatives of 5-amino-1,3,4-thiadiazole-2-sulfonamide

Pyrazole carboxylic acid derivatives of 5-amino-1,3,4-thiadiazole-2-sulfonamide (inhibitor 1) were synthesized from ethyl 3-(chlorocarbonyl)-1-(3-nitrophenyl)-5-phenyl-1H-pyrazole-4-carboxylate compound. The inhibitory effects of inhibitor 1, acetazolamide ( AAZ) and of 11 newly synthesized amides ( 5a– b, 6, 7a– g, and 8) on hydratase and esterase activities of carbonic anhydrase isoenzymes (hCA-I and hCA-II) have been studied in vitro. The comparison of newly synthesized amides to inhibitor 1 and to AAZ indicated that the new derivatives inhibit CA isoenzymes and they are more potent inhibitors than the parent inhibitor 1 and AAZ.

Pyrazole acids as niacin receptor agonists for the treatment of dyslipidemia

Niacin is an effective drug for raising HDL cholesterol and reducing coronary risks, but patients show low compliance with treatment due to severe facial flushing upon taking the drug. A series of bicyclic pyrazole carboxylic acids were synthesized and tested for their ability to activate the niacin receptor. One analog, 23, showed improved potency and lacked flushing at doses that effectively altered the lipid profile of rats.

Effects of new 5-amino-1,3,4-thiadiazole-2-sulfonamide derivatives on human carbonic anhydrase isozymes

Pyrazole carboxylic acid amides of 5-amino-1,3,4-thiadiazole-2-sulfonamide 1 (inhibitor 1) were synthesized from 4-benzoyl-1-(4-nitrophenyl)-5-phenyl-1 H-pyrazole-3-carbonyl chloride and 4-benzoyl-1-(3-nitrophenyl)-5-phenyl-1 H-pyrazole-3-carbonyl chloride compounds. Human carbonic anhydrase isoenzymes (hCA-I and hCA-II) were purified from erythrocyte cells by the affinity chromatography. The inhibitory effects of inhibitor 1, acetazolamide ( AAZ), and of 16 newly synthesized amides ( 8–11, 12a– f, 13a– c, 14a– b, and 15) on hydratase and esterase activities of these isoenzymes have been studied in vitro. The average IC 50 values of the new compounds ( 8–11, 12a– f, 13a– c, 14a– b, and 15) for hydratase activity ranged from 3.25 to 4.75 μM for hCA-I and from 0.055 to 2.6 μM for hCA-II. The mean IC 50 values of the same inhibitors for esterase activity were in the range of 2.7–6.6 μM for hCA-I (with the exception of inhibitor 10, which did not inhibit the esterase activity of hCA-I) and of 0.013–4.2 μM for hCA-II. The K i values for new compounds ( 8–11, 12a– f, 13a– c, 14a– b, and 15) were observed well below that of the parent compound inhibitor 1 and were also comparable to that of AAZ under the same experimental conditions. The comparison of newly synthesized amides to inhibitor 1 and to AAZ indicated that the new derivatives preferentially inhibit hCA-II and are more potent inhibitors of hCA-II than the parent inhibitor 1 and AAZ.

Methylation of 4-nitro-3(5)-pyrazolecarboxylic acid

Reactions of 4-nitro-3(5)-pyrazolecarboxylic acid dipotassium salt with different methylating agents in various solvents have been investigated to improve the synthesis of isomeric 1-methyl-4-nitro-3- and -5-pyrazolecarboxylic acids.

Electrosynthesis of 4-chloropyrazolecarboxylic acids

4-Chlorosubstituted pyrazolecarboxylic acids were synthesized via chlorination of the corresponding acids at the Pt anode in NaCl aqueous solutions under conditions of divided galvanostatic electrolysis. The efficiency of the process depends on the structures of the initial pyrazolecarboxylic acids, particularly, on the donor-acceptor properties of the substituents and on their position in the pyrazole ring. The yields of the 4-chlorosubstituted products of chlorination of pyrazole-3(5)-carboxylic acid, 1-methylpyrazole-5-carboxylic acid, 1-methyl-pyrazole-3-carboxylic acid, 1-ethylpyrazole-3-carboxylic acid, and 1-methyl-3-nitropyrazole- 5-carboxylic acid are 92, 93, 69, 80, and 4%, respectively.

Medium and structural effects on the ionization constants of some pyrazole carboxylic acid derivatives

Stoichiometric ionization constants of some pyrazole carboxylic acids [4-benzoyl-1-(3-nitrophenyl)-5-phenyl-1H-pyrazole-3-carboxylic acid, 4-benzoyl-1-(4-nitrophenyl)-5-phenyl-1H-pyrazole-3-carboxylic acid, 4-(ethoxycarbonyl)-1,5-diphenyl-1H-pyrazole-3-carboxylic acid, 4-(ethoxycarbonyl)-1-(3-nitrophenyl)-5-phenyl-1H-pyrazole-3-carboxylic acid, 4-(ethoxycarbonyl)-1-(4-nitrophenyl)-5-phenyl-1H-pyrazole-3-carboxylic acid] were determined in ethanol–water mixtures of 50, 60, 70% ethanol (v/v) by a potentiometric titration method. Titrations were performed in an ionic strength of 0.10 M NaCl at 25.0 ± 0.1 °C using an Orion 960 automatic titrator under a nitrogen atmosphere. Using the potentiometric titration data, ionization constants were calculated in three different ways. The effects of structure and solvent on the acidity of pyrazole carboxylic acids are also discussed.

ChemInform Abstract: Pyrazole Carboxamides and Carboxylic Acids as Protein Kinase Inhibitors in Aberrant Eukaryotic Signal Transduction: Induction of Growth Arrest in MCF‐7 Cancer Cells.

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Syntheses and crystal structures of the metal complexes based on pyrazolecarboxylic acid ligands

This paper aims at introducing five new metal complexes, Co(HL 1) 2(H 2O) 2 ( 1), {[Cu(HL 1) 2] · (H 2O)} n ( 2), {[Zn(HL 2)(H 2O) 3] · 2H 2O} n ( 3), {[Co(HL 2)(H 2O) 3] · 2H 2O} n ( 4) and [K(H 2L 2)] n ( 5), (in which H 2L 1 is 3-methyl-5-pyrazolecarboxylic acid and H 3L 2 is 3,5-pyrazoledicarboxylic acid, respectively), which have been synthesized under hydrothermal conditions or by using diffusion methods. Their molecular structures have been characterized by elemental analyses, IR spectroscopy and single-crystal X-ray diffraction analyses. The X-ray analyses reveal that complex 1 has a mononuclear structure, which is further assembled to a three-dimensional (3-D) framework through intermolecular hydrogen bonds; complex 2 is a 1-D coordinated polymer, which is further assembled to a 2-D layer through intermolecular hydrogen bonds and π–π interactions; both complexes 3 and 4 possess similar 1-D chain structures, and the adjacent chains are further linked by hydrogen bonds to form 2-D supramolecular networks; complex 5 exhibits a 3-D structure, in which, the metal–metal weak interaction, K–K, plays an important role.

Amide derivatives with pyrazole carboxylic acids of 5-amino-1,3,4-thiadiazole 2-sulfonamide as new carbonic anhydrase inhibitors: Synthesis and investigation of inhibitory effects

Pyrazole carboxylic acid amides of 5-amino-1,3,4-thiadiazole-2-sulfonamide were synthesized from 4-benzoyl-1,5-diphenyl-1H-pyrazole-3-carbonyl chloride and 4-benzoyl-1-(3-nitrophenyl)-5-phenyl-1H-pyrazole-3-carbonyl chloride. Carbonic anhydrase isoenzymes (hCA-I and hCA-II) were purified from human erythrocyte cells by the affinity chromatography method. The inhibitory effects of 5-amino-1,3,4-thiadiazole-2-sulfonamide 1, acetazolamide 2 and new synthesized amides on these isozymes have been studied in vitro. The I50 concentrations (the concentration of inhibitor producing a 50% inhibition of CA activity) against hydratase activity ranged from 1.2 to 2.2 nM for hCA-I and from 0.4 to 2 nM for hCA-II. The I50 values against esterase activity ranged from 1.4 to 8 nM for hCA-I and from 1.3 to 6 nM for hCA-II. The Ki values were observed between 8.2·10− 5 to 6.2·10− 4 M for hCA-I and between 2.9·10− 4 to 8.2·10− 4 M for hCA-II. The comparison of new synthesized amides to 5-amino-1,3,4-thiadiazole-2-sulfonamide 1, acetazolamide 2 indicated that the new synthesized compounds (18–23) inhibit CA activity more potently than the parent compounds.

Synthesis and Biological Activities of New Triphenyl Organotin (IV) Based on the Pyrazole Carboxylic Acids

The synthesis of new triphenyltin derivatives with (N-substituted-pyrazol-3-yl) carboxylic acid fragments is described. The in vitro antibacterial activity of the new agents was evaluated against two fungal strains (Saccharomyces cerevisiae and Fusarium oxysporum f.sp albedinis) and against bacterial strains (Echerichia coli). A considerable activity was recorded with respect to the three studied micro-organisms. Structure activity relationship studies (SAR) reflect the effect of substituted pyrazolic fragment.

Pyrazole carboxamides and carboxylic acids as protein kinase inhibitors in aberrant eukaryotic signal transduction: induction of growth arrest in MCF-7 cancer cells

Densely functionalised pyrazole carboxamides and carboxylic acids were synthesised in an expedient manner through saponification and transamidation, respectively, of ester-functionalised pyrazoles. This synthetic protocol allowed for three diversifying steps in which appendages on the pyrazole scaffold were adjusted to optimise inhibition of protein kinases. Thirty-five analogues were tested in CK2, AKT1, PKA, PKCalpha, and SAPK2a (p38) kinase inhibition bioassays. Blocking of these kinases may lead to effective therapies for treating inflammatory diseases and cancer. In order to investigate potential biological activity, MCF-7 human breast cancer cells were incubated with the most promising derivatives. Two analogues caused changes in MCF-7 cell growth, one of them through cell cycle arrest demonstrated by cell cycle analysis.

Methoxy- and Fluorine-Substituted Analogs of O-1302: Synthesis and in Vitro Binding Affinity for the CB1 Cannabinoid Receptor

Methoxy and fluorine analogs substituted on the terminal carbon of the pentyl chain of N-(piperidinyl)-1-(2,4-dichlorophenyl)-4-methyl-5-(4-pentylphenyl)-1H-pyrazole-3-carboxamide (O-1302) were synthesized in a multi-step process from 5-phenyl-1-pentanol, which was based on the 1,5-diarylpyrazole core template of N-(piperidinyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716) through condensation of the respective amine with pyrazole carboxylic acid, in order to develop tracers for medical imaging. Their potency for inhibiting the binding of the CB1 antagonist [(3)H]SR141716 was evaluated with the aim of developing positron emission tomography (PET) ligands for the cerebral cannabinoid CB1 receptor. These analogs bearing a piperidinyl carboxamide at the C(3) of the pyrazole ring exhibited affinities comparable to those of the CB1 reference antagonist SR141716, which warrants further investigation using the radiolabeled form for biological imaging studies. A morpholine ring substituted at the C(3) of the pyrazole ring resulted in a reduction of the CB1 affinity.

Design and synthesis of substituted pyridine derivatives as HIF-1α prolyl hydroxylase inhibitors

Structure-guided de novo drug design led to the identification of a novel series of substituted pyridine derivatives as HIF-1α prolyl hydroxylase inhibitors. Pyridine carboxyamide derivatives bearing a substituted aryl group at the 5-position of the pyridine ring show appreciable activity, while constraining the side chain by placing a pyrazole carboxylic acid generated a potent lead series with consistent activity against EGLN-1.

Antimicrobial study of pyrazine, pyrazole and imidazole carboxylic acids and their hydrazinium salts

Some new hydrazinium salts of 2-pyrazinecarboxylate, 2,3-pyrazinedicarboxylate, 3,5-pyrazoledicarboxylate and 4,5-imidazoledicarboxylate have been prepared. The in vitro antibacterial screening of the free acids and their hydrazinium salts has been carried out against Escherichia coli, Salmonella typhiiand Vibrio cholerae. The antibacterial activities of the prepared hydrazinium salts show more promising activity than the corresponding free acids and the standard positive control antibiotic, Co-trimoxazole.

PEG-supported synthesis of pyrazole oligoamides with peptide beta-sheet affinity.

Pyrazole amino acid oligoamides were prepared on polyethylene glycol starting from nitro pyrazole carboxylic acids or protected pyrazole amino acids. The polymer support facilitates product isolation during synthesis and makes the target oligoamides soluble in chloroform and water. This allows the determination of their binding properties towards peptides. Moderate affinity, which increases with the number of pyrazole units, is observed in chloroform and water.

Protein Tyrosine Phosphatase 1B Inhibitors: Heterocyclic Carboxylic Acids

Several series of compounds (benzoic acids, pyrazolecarboxylic acids, phenoxyacetic acids, and quinolinoxyacetic acids) were prepared and evaluated for their inhibitory activity against PTP-1B. Several compounds showed submicromolar inhibitory activity.