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European Journal of Medicinal Chemistry May 2021In this research, rational design, synthesis, carbonic anhydrases (CAs) inhibitory effects, and cytotoxicities of the...
Comprehensive study on potent and selective carbonic anhydrase inhibitors: Synthesis, bioactivities and molecular modelling studies of 4-(3-(2-arylidenehydrazine-1-carbonyl)-5-(thiophen-2-yl)-1H-pyrazole-1-yl) benzenesulfonamides.
In this research, rational design, synthesis, carbonic anhydrases (CAs) inhibitory effects, and cytotoxicities of the 4-(3-(2-arylidenehydrazine-1-carbonyl)-5-(thiophen-2-yl)-1H-pyrazole-1-yl)benzenesulfonamides 1-20 were reported. Compound 18 (Ki = 7.0 nM) was approximately 127 times more selective cancer-associated hCA IX inhibitor over hCA I, while compound 17 (Ki = 10.6 nM) was 47 times more selective inhibitor of hCA XI over hCA II compared to the acetazolamide. Compounds 11 (CC = 5.2 μM) and 20 (CC = 1.6 μM) showed comparative tumor-specificity (TS= > 38.5; >128.2) with doxorubicin (TS > 43.0) towards HSC-2 cancer cell line. Western blot analysis demonstrated that 11 induced slightly apoptosis whereas 20 did not induce detectable apoptosis. A preliminary analysis showed that some correlation of tumor-specificity of 1-20 with the chemical descriptors that reflect hydrophobic volume, dipole moment, lowest hydrophilic energy, and topological structure. Molecular docking simulations were applied to the synthesized ligands to elucidate the predicted binding mode and selectivity profiles towards hCA I, hCA II, and hCA IX.
Topics: Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Cell Line; Dose-Response Relationship, Drug; Humans; Isoenzymes; Models, Molecular; Molecular Structure; Pyrazoles; Structure-Activity Relationship; Sulfonamides; Benzenesulfonamides
PubMed: 33744685
DOI: 10.1016/j.ejmech.2021.113351 -
Drug Testing and Analysis Sep 2016This study presents the identification of N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-(cyclohexylmethyl)-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide that was termed...
The synthesis and characterization of the 'research chemical' N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-(cyclohexylmethyl)-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (3,5-AB-CHMFUPPYCA) and differentiation from its 5,3-regioisomer.
This study presents the identification of N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-(cyclohexylmethyl)-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide that was termed 3,5-AB-CHMFUPPYCA. This compound was obtained from a UK-based Internet vendor, who erroneously advertised this 'research chemical' as AZ-037 and which would have been associated with (S)-N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-(5-fluoropentyl)-5-(4-fluorophenyl)-1H-pyrazole-3-carboxamide. The presence of the pyrazole core indicates a bioisosteric replacement of an indazole ring that is frequently associated with synthetic cannabinoids of the PINACA, FUBINACA, and CHMINACA series. The pyrazole ring system present in 3,5-AB-CHMFUPPYCA gives rise to the regioisomer N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-(cyclohexylmethyl)-5-(4-fluorophenyl)-1H-pyrazole-3-carboxamide (named 5,3-AB-CHMFUPPYCA) and both isomers were synthesized using two specific routes which supported the correct identification of the 'research chemical' as 3,5-AB-CHMFUPPYCA. Both isomers could be conveniently differentiated. Interestingly, a route specific chlorine-containing by-product also was observed during the synthesis of 3,5-AB-CHMFUPPYCA and identified as N-(1-amino-3-methyl-1-oxobutan-2-yl)-4-chloro-1-(cyclohexylmethyl)-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide. An extensive analytical characterization included chromatographic, spectroscopic, mass spectrometric platforms as well as crystal structure analysis. The syntheses and analytical characterizations of both AB-CHMFUPPYCA isomers are reported for the first time and serves as a reminder that the possibility of mislabeling of 'research chemicals' cannot be excluded. The pharmacological activities of both AB-CHMFUPPYCA isomers remain to be explored. Copyright © 2015 John Wiley & Sons, Ltd.
Topics: Cannabinoids; Chromatography, Liquid; Crystallography, X-Ray; Gas Chromatography-Mass Spectrometry; Illicit Drugs; Internet; Magnetic Resonance Spectroscopy; Models, Molecular; Psychotropic Drugs; Pyrazoles; Spectrometry, Mass, Electrospray Ionization
PubMed: 26360802
DOI: 10.1002/dta.1864 -
Bioorganic Chemistry Nov 2021Microbial resistance is a big concern worldwide, making the development of new antimicrobial drugs difficult. The thiazole and pyrazole rings are important heterocyclic...
Hydrazonoyl bromide precursors as DHFR inhibitors for the synthesis of bis-thiazolyl pyrazole derivatives; antimicrobial activities, antibiofilm, and drug combination studies against MRSA.
Microbial resistance is a big concern worldwide, making the development of new antimicrobial drugs difficult. The thiazole and pyrazole rings are important heterocyclic compounds utilized to produce a variety of antimicrobial medications. As a result, a series of new bis-thiazolyl-pyrazole derivatives 3, 4a-c, 5a, b, and 6a-c was synthesized by reacting bis hydrazonoyl bromide with several active methylene reagents in a one-pot reaction. The assigned structure was characterized entirely based on elemental and spectral analyses. The antimicrobial activity represented by MIC was performed using a resazurin-based turbidimetric (TB) assay. The results exhibited good antimicrobial activity against gram-positive strains, especially S. aureus (ATCC6538) while showing poor to moderate activity against gram-negative and fungal strains. Furthermore, the most active derivatives 3, 4a, 4c, and 5b were evaluated for MIC, MBC, antibiofilm, hemolytic assay, and drug combination testing against two S. aureus (ATCC6538) and MRSA (ACL18) strains. Additionally, bis-thiazolyl pyrazole 3, 4c, and 5b exhibited more potent inhibitory activity for DHFR with IC values (6.34 ± 0.26, 7.49 ± 0.28, and 3.81 ± 0.16 µM), respectively, compared with Trimethoprim (8.34 ± 0.11 µM). The bis-1-(substituted-thiazol-2-yl)-1H-pyrazole-4-carbonitrile derivative 5b was the most active member with MIC values ranging from (0.12-0.25 µM) compared to Vancomycin (1-2 µM), and MBC values ranging from (0.5-1 µM) for S. aureus (ATCC6538) and MRSA (ACL18). Surprisingly, compound 5b displayed bactericidal behavior, synergistic effect with three commercial antibiotics, and inhibited DHFR with 2.1 folds higher than Trimethoprim. Finally, good findings were obtained from in silico investigations incorporating toxicity prediction and molecular docking simulation.
Topics: Anti-Bacterial Agents; Antifungal Agents; Biofilms; Dose-Response Relationship, Drug; Enzyme Inhibitors; Fungi; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Microbial Sensitivity Tests; Molecular Structure; Pyrazoles; Structure-Activity Relationship; Tetrahydrofolate Dehydrogenase
PubMed: 34530234
DOI: 10.1016/j.bioorg.2021.105339 -
Journal of Peptide Science : An... Sep 2017A series of model compounds containing 3-amino-1H-pyrazole-5-carboxylic acid residue with N-terminal amide/urethane and C-terminal amide/hydrazide/ester groups were...
A series of model compounds containing 3-amino-1H-pyrazole-5-carboxylic acid residue with N-terminal amide/urethane and C-terminal amide/hydrazide/ester groups were investigated by using NMR, Fourier transform infrared, and single-crystal X-ray diffraction methods, additionally supported by theoretical calculations. The studies demonstrate that the most preferred is the extended conformation with torsion angles ϕ and ψ close to ±180°. The studied 1H-pyrazole with N-terminal amide/urethane and C-terminal amide/hydrazide groups solely adopts this energetically favored conformation confirming rigidity of that structural motif. However, when the C-terminal ester group is present, the second conformation with torsion angles ϕ and ψ close to ±180° and 0°, respectively, is accessible. The conformational equilibrium is observed in NMR and Fourier transform infrared studies in solution in polar environment as well as in the crystal structures of other related compounds. The observed conformational preferences are clearly related to the presence of intramolecular interactions formed within the studied residue. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.
Topics: Amino Acids; Crystallography, X-Ray; Hydrogen Bonding; Magnetic Resonance Spectroscopy; Pyrazoles
PubMed: 28608410
DOI: 10.1002/psc.3018 -
Steroids Dec 2021A series of thirty-six steroidal pyrazole amides, divided into two categories based on their main skeletons were designed and synthesized via a five-step synthetic...
A series of thirty-six steroidal pyrazole amides, divided into two categories based on their main skeletons were designed and synthesized via a five-step synthetic route. The final product is obtained through Pinnick oxidation of pyrazole aldehydes to yield the corresponding acids, which then underwent amidation to afford the target products efficiently under mild reaction conditions. Structures of the desired compounds were confirmed by H NMR, C NMR, high resolution mass spectrometry; X-ray structural characterization of compound 16n was also obtained. The synthesized compounds were screened for their antiproliferative activity against four cancer cell lines (Pc-3 A549, Hela, HepG2) using the SRB method. Amides 10n, 16n, and 16p-16t exhibited moderate to high cytotoxic activities with IC values ranging from 2.05 to 8.73 μM. Of note, the hydrochloride derivative 16p displayed the highest activity towards PC-3 cells with IC values of 2.05 μM. Analysis of structure-activity relationships indicated that the presence of the diamine moiety and the aqueous solubility of the derivatives were vital factors for antiproliferative potency. Furthermore, molecule 16p induced PC-3 cells apoptosis and arrested cell cycle at G1 phase in a dose-dependent manner.
Topics: Amides; Antineoplastic Agents; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Molecular Conformation; Pyrazoles; Stereoisomerism; Steroids; Structure-Activity Relationship
PubMed: 34655595
DOI: 10.1016/j.steroids.2021.108931 -
Bioorganic & Medicinal Chemistry Letters Jun 2011The synthesis and biological evaluation of non-oxime pyrazole based B-Raf inhibitors is reported. Several oxime replacements have been prepared and have shown excellent...
The synthesis and biological evaluation of non-oxime pyrazole based B-Raf inhibitors is reported. Several oxime replacements have been prepared and have shown excellent enzyme activity. Further optimization of fused pyrazole 2a led to compound 38, a selective and potent B-Raf inhibitor.
Topics: Animals; Crystallography, X-Ray; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme Inhibitors; Inhibitory Concentration 50; Mice; Molecular Structure; Oximes; Proto-Oncogene Proteins B-raf; Pyrazoles
PubMed: 21536432
DOI: 10.1016/j.bmcl.2010.12.038 -
Molecules (Basel, Switzerland) Mar 2017With the aim of developing novel anti-inflammatory scaffolds, a new series of pyrazole-substituted various nitrogenous heterocyclic ring systems at C-4 position were...
With the aim of developing novel anti-inflammatory scaffolds, a new series of pyrazole-substituted various nitrogenous heterocyclic ring systems at C-4 position were synthesized through different chemical reactions and validated by means of spectral and elemental data. The new obtained compounds were investigated for their anti-inflammatory activity using the carrageenan-induced paw edema standard technique and revealed that, compound showed increased potency with % inhibition of edema 85.23 ± 1.92 and 85.78 ± 0.99, respectively, higher than the standard reference drugs indomethacin and celebrex (72.99% and 83.76%). Molecular modeling studies were initiated herein to validate the attained pharmacological data and provide understandable evidence for the observed anti-inflammatory behavior.
Topics: Animals; Anti-Inflammatory Agents; Carrageenan; Celecoxib; Cyclooxygenase Inhibitors; Drug Design; Edema; Heterocyclic Compounds; Injections; Male; Molecular Docking Simulation; Piperidines; Pyrazoles; Rats; Rimonabant
PubMed: 28338602
DOI: 10.3390/molecules22040512 -
Bioorganic & Medicinal Chemistry Letters Aug 2011A series of indazoles have been discovered as KHK inhibitors from a pyrazole hit identified through fragment-based drug discovery (FBDD). The optimization process guided...
A series of indazoles have been discovered as KHK inhibitors from a pyrazole hit identified through fragment-based drug discovery (FBDD). The optimization process guided by both X-ray crystallography and solution activity resulted in lead-like compounds with good pharmaceutical properties.
Topics: Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Discovery; Fructokinases; Indazoles; Models, Molecular; Molecular Structure; Pyrazoles; Stereoisomerism; Structure-Activity Relationship
PubMed: 21767952
DOI: 10.1016/j.bmcl.2011.06.067 -
Comptes Rendus Des Seances de La... 1964
Topics: Anaphylaxis; Blood Pressure; Blood Pressure Determination; Kallidin; Peptides; Pharmacology; Phenylbutazone; Pyrazoles; Rabbits; Research
PubMed: 14145440
DOI: No ID Found -
Journal of Computational Chemistry Dec 2021Pyrazole derivatives correspond to a family of heterocycle molecules with important pharmacological and physiological applications. At present, we perform a density...
Pyrazole derivatives correspond to a family of heterocycle molecules with important pharmacological and physiological applications. At present, we perform a density functional theory (DFT) calculations and a quantitative structure-activity relationship (QSAR) evaluation on a series of 1-(4,5-dihydro-1H-pyrazol-1-yl) ethan-1-one and 4,5-dihydro-1H-pyrazole-1-carbothioamide derivatives as an epidermal growth factor receptor (EGFR) inhibitory activity. We thus propose a virtual screening protocol based on a machine-learning study. This theoretical model relates the studied compounds' biological activity to their calculated physicochemical descriptors. Moreover, the linear regression function is used to validate the model via the evaluation of Q and Q parameters for external and internal validations, respectively. Our QSAR model shows a good correlation between observed activities IC and predicted ones. Our model allows us to mitigate time-consuming problems and waste chemical and biological products in the preclinical phases.
Topics: Density Functional Theory; ErbB Receptors; Humans; Models, Molecular; Pyrazoles; Quantitative Structure-Activity Relationship
PubMed: 34609748
DOI: 10.1002/jcc.26761