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Bioorganic & Medicinal Chemistry Letters Jun 2013High throughput screening identified the pyrazole-4-acetic acid substructure as CRTh2 receptor antagonists. Optimisation of the compounds uncovered a tight SAR but also...
High throughput screening identified the pyrazole-4-acetic acid substructure as CRTh2 receptor antagonists. Optimisation of the compounds uncovered a tight SAR but also identified some low nanomolar inhibitors.
Topics: Acetates; Animals; Half-Life; High-Throughput Screening Assays; Protein Binding; Pyrazoles; Rats; Receptors, Immunologic; Receptors, Prostaglandin; Structure-Activity Relationship
PubMed: 23601708
DOI: 10.1016/j.bmcl.2013.03.093 -
Bioorganic & Medicinal Chemistry Letters Jun 2021Myeloperoxidase (MPO), a critical enzyme in antimicrobial host-defense, has been implicated in chronic inflammatory diseases such as coronary artery disease. The design...
Myeloperoxidase (MPO), a critical enzyme in antimicrobial host-defense, has been implicated in chronic inflammatory diseases such as coronary artery disease. The design and evaluation of MPO inhibitors for the treatment of cardiovascular disease are reported herein. Starting with the MPO and triazolopyridine 3 crystal structure, novel inhibitors were designed incorporating a substituted pyrazole, which allowed for substituents to interact with hydrophobic and hydrophilic patches in the active site. SAR exploration of the substituted pyrazoles led to piperidine 17, which inhibited HOCl production from activated neutrophils with an IC value of 2.4 μM and had selectivity against thyroid peroxidase (TPO). Optimization of alkylation chemistry on the pyrazole nitrogen facilitated the preparation of many analogs, including macrocycles designed to bridge two hydrophobic regions of the active site. Multiple macrocyclization strategies were pursued to prepare analogs that optimally bound to the active site, leading to potent macrocyclic MPO inhibitors with TPO selectivity, such as compound 30.
Topics: Dose-Response Relationship, Drug; Enzyme Inhibitors; Humans; Macrocyclic Compounds; Molecular Structure; Peroxidase; Pyrazoles; Small Molecule Libraries; Structure-Activity Relationship
PubMed: 33811992
DOI: 10.1016/j.bmcl.2021.128010 -
Molecular Diversity Nov 2013A convenient and efficient synthesis of multi-substituted dihydropyrano[2,3-c]pyrazole derivatives is reported. The four-component reaction of 4-hydrazinobenzoic acid,...
A convenient and efficient synthesis of multi-substituted dihydropyrano[2,3-c]pyrazole derivatives is reported. The four-component reaction of 4-hydrazinobenzoic acid, β-keto esters, aromatic aldehydes, and malononitrile using 10 mol% CAN catalyst in water under ultrasound irradiation produced the target compounds in good-to-excellent yields. This method has advantages over conventional methods in being economic, non-toxic, and environmentally compatible due to its use of efficient and eco-friendly CAN catalyst and water solvent.
Topics: Catalysis; Cerium; Molecular Structure; Nitrates; Pyrazoles; Solvents; Sonication
PubMed: 23918005
DOI: 10.1007/s11030-013-9465-7 -
Mini Reviews in Medicinal Chemistry 2019Bis-heterocycles especially those containing pyrazole moiety display much better antibacterial activity than mono heterocycles.
BACKGROUND
Bis-heterocycles especially those containing pyrazole moiety display much better antibacterial activity than mono heterocycles.
OBJECTIVE
Herein, we synthesised a series of new bis-pyrazoles and investigated their antimicrobial agents.
METHODS
A novel series of bis-pyrazole derivatives have been synthesized in good yield by coupling reaction of cyanoacetic acid {4-[(2-cyano-acetyl)-hydrazonomethyl]-benzylidene}-hydrazide with a number of diazonium salts of aromatic amines in DMF in the presence of NaOH. Refluxing of the produced hydrazones with hydrazine-hydrate in ethanolic solution afforded the respective bis-pyrazoles. On the other hand, the reaction of bis(cyanoacetic acid hydrazide) derivative with a diversity of hydrazonoyl chlorides in dioxane under reflux gave bis-pyrazoles.
RESULTS
The structures of all the products were discussed and assured from all possible spectral data as well as for the elemental analysis. In addition, the results of the antimicrobial activity examination of selected derivatives revealed a high strength of some tested compounds compared to standard bactericides and fungicides utilized. Molecular docking of the newly synthesized compounds into the Enoyl ACP reductase active site supported the in vitro antimicrobial activity. All the tested compounds could fit in the enzyme binding pocket with significant binding affinities (-7.040 to -9.141 Kcal/mol).
CONCLUSION
The good results of the antimicrobial examination of the newly synthesized bis-pyrazoles comprise the considerable evidence of the importance of bis-heterocyclic compounds which encourages us to continue designing and synthesising a novel series with potent biological activity in the future.
Topics: Anti-Bacterial Agents; Antifungal Agents; Aspergillus niger; Dose-Response Relationship, Drug; Geotrichum; Gram-Negative Bacteria; Gram-Positive Bacteria; Microbial Sensitivity Tests; Molecular Docking Simulation; Molecular Structure; Pyrazoles; Structure-Activity Relationship
PubMed: 30864524
DOI: 10.2174/1389557519666190313095545 -
Bioorganic & Medicinal Chemistry Letters Aug 2015High-throughput screening was used to find selective inhibitors of human 15-lipoxygenase-1 (15-LOX-1). One hit, a 1-benzoyl substituted pyrazole-3-carboxanilide (1a),...
High-throughput screening was used to find selective inhibitors of human 15-lipoxygenase-1 (15-LOX-1). One hit, a 1-benzoyl substituted pyrazole-3-carboxanilide (1a), was used as a starting point in a program to develop potent and selective 15-LOX-1 inhibitors.
Topics: Amides; Arachidonate 15-Lipoxygenase; Humans; Lipoxygenase Inhibitors; Pyrazoles
PubMed: 26037319
DOI: 10.1016/j.bmcl.2015.05.007 -
Bioorganic & Medicinal Chemistry Letters Apr 2010Utilizing a pharmacophore hypothesis, previously described gamma-secretase inhibiting HTS hits were evolved into novel tricyclic sulfonamide-pyrazoles, with high in...
Utilizing a pharmacophore hypothesis, previously described gamma-secretase inhibiting HTS hits were evolved into novel tricyclic sulfonamide-pyrazoles, with high in vitro potency, good brain penetration, low metabolic stability, and high clearance.
Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Animals; Crystallography, X-Ray; Humans; Inhibitory Concentration 50; Models, Molecular; Pyrazoles; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Sulfonamides
PubMed: 20206516
DOI: 10.1016/j.bmcl.2010.02.050 -
Bioorganic & Medicinal Chemistry Letters Aug 2022The synthesis of eight novel pyrazole-tetrazole compounds are presented. Their structures are identified by NMR and FTIR spectroscopy, mass spectrometry as well as...
The synthesis of eight novel pyrazole-tetrazole compounds are presented. Their structures are identified by NMR and FTIR spectroscopy, mass spectrometry as well as elemental analysis. Their in-vitro α-amylase inhibition and haemoglobin antiglycation activity were examined by spectrophotometric methods. All compounds possess both activities, especially molecules entitled 2-(1-((5-methyl-1H-pyrazol-3-yl)methyl)-1H-tetrazol-5-yl)pyridine 4 and 2-(1-((1-ethyl-5-methyl-1H-pyrazol-3-yl)methyl)-1H-tetrazol-5-yl)pyridine 8 which were found to be extremely potent compared to the positive controls. The SAR study proved the influence of the alkylation position of pyrazole derivative on the tetrazole ring, the nature of substituent on the tetrazolic carbon atom and the nature of the group at the nitrogen atom of the pyrazole ring on both α-amylase and glycation inhibition activity. Compounds 4 and 8 could be a good drug candidate to treat Type 2 diabetes.
Topics: Diabetes Mellitus, Type 2; Humans; Pyrazoles; Pyridines; Tetrazoles; alpha-Amylases
PubMed: 35569687
DOI: 10.1016/j.bmcl.2022.128785 -
Chemical Research in Toxicology Aug 2021Cytochrome P450 2C8 (CYP2C8) is a major drug-metabolizing enzyme in humans and is responsible for the metabolism of ∼5% drugs in clinical use. Thus, inhibition of...
Cytochrome P450 2C8 (CYP2C8) is a major drug-metabolizing enzyme in humans and is responsible for the metabolism of ∼5% drugs in clinical use. Thus, inhibition of CYP2C8, which causes potential adverse drug events, cannot be neglected. The in vitro drug interaction studies guidelines for industry issued by the FDA also point out that it needs to be determined whether investigated drugs are CYP2C8 inhibitors before clinical trials. However, current studies mainly focus on predicting the inhibitors of other major P450 enzymes, and the importance of CYP2C8 inhibition has been overlooked. Therefore, there is a need to develop models for identifying potential CYP2C8 inhibition. In this study, in silico classification models for predicting CYP2C8 inhibition were built by five machine-learning methods combined with nine molecular fingerprints. The performance of the models built was evaluated by test and external validation sets. The best model had AUC values of 0.85 and 0.90 for the test and external validation sets, respectively. The applicability domain was analyzed based on the molecular similarity and exhibited an impact on the improvement of prediction accuracy. Furthermore, several representative privileged substructures such as 1-benzo[]imidazole, 1-phenyl-1-pyrazole, and quinoline were identified by information gain and substructure frequency analysis. Overall, our results would be helpful for the prediction of CYP2C8 inhibition.
Topics: Computer Simulation; Cytochrome P-450 CYP2C8; Cytochrome P-450 CYP2C8 Inhibitors; Drug Discovery; Humans; Imidazoles; Machine Learning; Molecular Docking Simulation; Pyrazoles
PubMed: 34255486
DOI: 10.1021/acs.chemrestox.1c00078 -
Journal of Hazardous Materials Nov 2010In this study, 3,4,5-trinitro-1H-pyrazole (R20), 3,4,5-trinitro-1H-pyrazol-1-amine (R21), 1-methyl-3,4,5-trinitro-1H-pyrazole (R22), and 1,3,4,5-tetranitro-1H-pyrazole...
In this study, 3,4,5-trinitro-1H-pyrazole (R20), 3,4,5-trinitro-1H-pyrazol-1-amine (R21), 1-methyl-3,4,5-trinitro-1H-pyrazole (R22), and 1,3,4,5-tetranitro-1H-pyrazole (R23) have been considered as potential candidates for high-energy density materials by quantum chemical treatment. The geometric and electronic structures, band gap, thermodynamic properties, crystal density and detonation properties were studied using density functional theory at the B3LYP/aug-cc-pVDZ level. The calculated energy of explosion, density, and detonation performance of model compounds are comparable to 1,3,5-trinitro-1,3,5-triazinane (RDX), and 1,3,5,7-tetranitro-1,3,5,7-tetrazocane (HMX). Atoms-in-molecules (AIM) analyses have also been carried to understand the nature of intramolecular interactions and the strength of trigger bonds.
Topics: Explosions; Models, Molecular; Models, Theoretical; Molecular Structure; Pyrazoles; Structure-Activity Relationship; Thermodynamics
PubMed: 20728272
DOI: 10.1016/j.jhazmat.2010.07.106 -
ChemMedChem Sep 2021Pyrazole-thiazole core-containing compound KP-40 and 20 novel derivatives were designed and synthesized through traditional SAR analysis. These molecules displayed...
Pyrazole-thiazole core-containing compound KP-40 and 20 novel derivatives were designed and synthesized through traditional SAR analysis. These molecules displayed adjunctive activity with meropenem against Gram-negative bacteria evidenced by a range of fractional inhibitory concentration (FIC=0.5-0.25) and minimum adjunctive concentration (MAC=128-32 μM) values. Of this series of molecules, four compounds displayed notable adjunctive potential, with FIC and MAC values of 0.25 and 32 μM, respectively. Moreover, the solubility of these compounds was improved to an acceptable range. Further analysis using our "in house" permeation and efflux multi parameter optimization (PEMPO) algorithm revealed key physicochemical properties that may be critical for the development of active Gram-negative antibacterials. Taking PEMPO scores into consideration prior to executing synthesis of analogs may be a simple, yet rapid and effective strategy that can be used in conjunction with traditional SAR approaches to aid in the design of potent Gram-negative antibacterials.
Topics: Anti-Bacterial Agents; Carbapenem-Resistant Enterobacteriaceae; Dose-Response Relationship, Drug; Meropenem; Microbial Sensitivity Tests; Molecular Structure; Pyrazoles; Structure-Activity Relationship; Thiazoles
PubMed: 34096189
DOI: 10.1002/cmdc.202100321