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Acta Poloniae Pharmaceutica 2013The enaminone 2 was reacted with hydrazonyl halides 3a-d to afford the corresponding pyrazole derivatives (6a-d) which reacted with hydrazine hydrate to afford the new...
The enaminone 2 was reacted with hydrazonyl halides 3a-d to afford the corresponding pyrazole derivatives (6a-d) which reacted with hydrazine hydrate to afford the new pyrazolo[3,4-d]pyridazine derivatives 7a-d, respectively. In addition, compound 2 was reacted with some primary aromatic amines to afford the corresponding secondary enaminones 10a-c and reacted with sulfapyridine or sulfapyrimidine to afford the corresponding sulfonamide derivatives 12a and 12b. Evaluation of these new compounds against rotavirus Wa strain and adenovirus type 7 showed promising antiviral activity.
Topics: Adenoviridae; Antiviral Agents; Cell Line; Cytopathogenic Effect, Viral; Humans; Molecular Structure; Pyrazoles; Pyridazines; Rotavirus; Tetrahydronaphthalenes
PubMed: 23610964
DOI: No ID Found -
Nature Mar 2019Carbon-hydrogen (C-H) and carbon-carbon (C-C) bonds are the main constituents of organic matter. Recent advances in C-H functionalization technology have vastly expanded...
Carbon-hydrogen (C-H) and carbon-carbon (C-C) bonds are the main constituents of organic matter. Recent advances in C-H functionalization technology have vastly expanded our toolbox for organic synthesis. By contrast, C-C activation methods that enable editing of the molecular skeleton remain limited. Several methods have been proposed for catalytic C-C activation, particularly with ketone substrates, that are typically promoted by using either ring-strain release as a thermodynamic driving force or directing groups to control the reaction outcome. Although effective, these strategies require substrates that contain highly strained ketones or a preinstalled directing group, or are limited to more specialist substrate classes. Here we report a general C-C activation mode driven by aromatization of a pre-aromatic intermediate formed in situ. This reaction is suitable for various ketone substrates, is catalysed by an iridium/phosphine combination and is promoted by a hydrazine reagent and 1,3-dienes. Specifically, the acyl group is removed from the ketone and transformed to a pyrazole, and the resulting alkyl fragment undergoes various transformations. These include the deacetylation of methyl ketones, carbenoid-free formal homologation of aliphatic linear ketones and deconstructive pyrazole synthesis from cyclic ketones. Given that ketones are prevalent in feedstock chemicals, natural products and pharmaceuticals, these transformations could offer strategic bond disconnections in the synthesis of complex bioactive molecules.
Topics: Acylation; Carbon; Hydrazines; Iridium; Ketones; Phosphines; Pyrazoles
PubMed: 30758326
DOI: 10.1038/s41586-019-0926-8 -
Journal of Enzyme Inhibition and... Dec 2023Design and synthesis of three novel series of aryl enaminones (- and -) and pyrazole () linked compounds with sulphonamides, sulfaguanidine, or carboxylic acid...
Effect of hydrophobic extension of aryl enaminones and pyrazole-linked compounds combined with sulphonamide, sulfaguanidine, or carboxylic acid functionalities on carbonic anhydrase inhibitory potency and selectivity.
Design and synthesis of three novel series of aryl enaminones (- and -) and pyrazole () linked compounds with sulphonamides, sulfaguanidine, or carboxylic acid functionalities were reported as carbonic anhydrase inhibitors (CAIs) using the "tail approach" strategy in their design to achieve the most variable amino acids in the middle/outer rims of the hCAs active site. The synthesised compounds were assessed for their inhibitory activity against the following human (h) isoforms, hCA I, II, IX, and XII using stopped-flow CO hydrase assay. Enaminone sulphonamide derivatives (-) potently inhibited the target tumour-associated isoforms hCA IX and hCA XII (KIs 26.2-63.7 nM) and hence compounds and were further screened for their cytotoxic activity against MCF-7 and MDA-MB-231 cancer cell lines under normoxic and hypoxic conditions. Derivative showed comparable potency against both MCF-7 and MDA-MB-231 cancer cell lines under both normoxic ((IC = 4.918 and 12.27 µM, respectively) and hypoxic (IC = 1.689 and 5.898 µM, respectively) conditions compared to the reference drug doxorubicin under normoxic (IC = 3.386 and 4.269 µM, respectively) and hypoxic conditions (IC = 1.368 and 2.62 µM, respectively). Cell cycle analysis and Annexin V-FITC and propidium iodide double staining methods were performed to reinforce the assumption that may act as a cytotoxic agent through the induction of apoptosis in MCF-7 cancer cells.
Topics: Humans; Carbonic Anhydrases; Carbonic Anhydrase IX; Sulfaguanidine; Structure-Activity Relationship; Carboxylic Acids; Sulfonamides; Antineoplastic Agents; Carbonic Anhydrase Inhibitors; Pyrazoles; Molecular Structure
PubMed: 37078174
DOI: 10.1080/14756366.2023.2201403 -
Food and Chemical Toxicology : An... Dec 2023Tartrazine (E102, FD&C Yellow 5) is a vibrant yellow azo dye added to many processed foods. The safety of this ubiquitous chemical has not been fully elucidated, and it...
Tartrazine (E102, FD&C Yellow 5) is a vibrant yellow azo dye added to many processed foods. The safety of this ubiquitous chemical has not been fully elucidated, and it has been linked to allergic reactions and ADHD in some individuals. In our study, bacterial species isolated from human stool decolourised tartrazine and, upon exposure to air, a purple compound formed. Tartrazine is known to undergo reduction in the gut to sulfanilic acid and 4-amino-3-carboxy-5-hydroxy-1-(4-sulfophenyl)pyrazole (SCAP). These metabolites and their derivatives are relevant to the toxicology of tartrazine. The toxicity of sulfanilic acid has been studied before, but the oxidative instability of SCAP has previously prevented full characterisation. We have verified the chemical identity of SCAP and confirmed that the purple-coloured oxidation derivative is 4-(3-carboxy-5-hydroxy-1-(4-sulfophenyl)-1H-pyrazol-4-yl)imino-5-oxo-1-(4-sulfophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid (purpurazoic acid, PPA), as proposed by Westöö in 1965. A yellow derivative of SCAP is proposed to be the hydrolysed oxidation product, 4,5-dioxo-1-(4-sulfophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid. SCAP and PPA are moderately toxic to human cells (IC 89 and 78 μM against HEK-293, respectively), but had no apparent effect on Escherichia coli and Bacillus subtilis bacteria. These results prompt further analyses of the toxicology of tartrazine and its derivatives.
Topics: Humans; Tartrazine; Azo Compounds; HEK293 Cells; Oxidation-Reduction; Carboxylic Acids; Pyrazoles
PubMed: 37980979
DOI: 10.1016/j.fct.2023.114193 -
Malaria Journal Aug 2022The search for pharmacologically effective agents among molecules bearing multiple functionalities is commonly practiced. In continuation of the search for new...
BACKGROUND
The search for pharmacologically effective agents among molecules bearing multiple functionalities is commonly practiced. In continuation of the search for new anti-malarial agents, new pyrazole-hydrazine coupled Schiff-base derivatives previously synthesized were screened for anti-malarial property.
METHODS
Here, in vivo prophylactic and curative activities of the compounds were assessed while their binding affinity for falcipain-2, a crucial enzyme in Plasmodium survival, was done using computational techniques.
RESULTS
The two derivatives (BepINH and BepBeH) respectively led to a significant (p < 0.05) reduction in parasitaemia count (0.76 ± 1.11 and 0.79 ± 1.19) at day 3 post-treatment relative to the negative control (16.37 ± 1.25). For the prophylactic study, it was observed that the highest parasitaemia suppression level of 95.35% and 95.17% for BepINH and BepBeH at 15 mg/kg was slightly comparable to that obtained for ACT-Lonart (99.38%). In addition, their haematological profiles indicate that they are potentially beneficial in suppressing haemolytic damage to RBC, thereby protecting the body against infection-induced anaemia. Docking calculations on the derivatives toward the Plasmodium falciparum falcipain-2 revealed that they favourably interacted with a binding affinity higher than that of a known cocrystallized inhibitor.
CONCLUSION
This study confirms the relevance of multi-functional molecules in the search for new and effective anti-plasmodial agent and lay the foundation for further development of these compound series to potent anti-plasmodial agent that interacts with falcipain-2.
Topics: Antimalarials; Hydrazines; Plasmodium falciparum; Pyrazoles; Schiff Bases
PubMed: 35996135
DOI: 10.1186/s12936-022-04266-8 -
Molecules (Basel, Switzerland) Jun 2021Two penta-coordinated ; and ; complexes with the -pyrazolyl--triazine pincer ligands and were synthesized and characterized. Both and act as NNN-tridentate pincer...
Syntheses and Structural Investigations of Penta-Coordinated Co(II) Complexes with -Pyrazolo--Triazine Pincer Ligands, and Evaluation of Their Antimicrobial and Antioxidant Activities.
Two penta-coordinated ; and ; complexes with the -pyrazolyl--triazine pincer ligands and were synthesized and characterized. Both and act as NNN-tridentate pincer chelates coordinating the Co(II) center with one short Co-N(-triazine) and two longer Co-N(pyrazole) bonds. The coordination number of Co(II) is five in both complexes, and the geometry around Co(II) ion is a distorted square pyramidal in while shows more distortion. In both complexes, the packing is dominated by Cl…H, C-H…π, and Cl…C (anion-π stacking) interactions in addition to O…H interactions, which are found only in . The UV-Vis spectral band at 564 nm was assigned to metal-ligand charge transfer transitions based on TD-DFT calculations. Complexes and showed higher antimicrobial activity compared to the respective free ligand and which were not active. MIC values indicated that had better activity against , and than . DPPH free radical scavenging assay revealed that all the studied compounds showed weak to moderate antioxidant activity where the nature of the substituent at the -triazine core has a significant impact on the antioxidant activity.
Topics: Anti-Bacterial Agents; Antioxidants; Cobalt; Coordination Complexes; Crystallography, X-Ray; Ligands; Microbial Sensitivity Tests; Models, Molecular; Pyrazoles; Triazines
PubMed: 34198604
DOI: 10.3390/molecules26123633 -
Molecules (Basel, Switzerland) Jan 2019To find novel antitumor agents, a series of 1-benzofuro[3,2-]pyrazole derivatives were designed and synthesized. The treatment of 6-methoxybenzofuran-3(2)-one with...
To find novel antitumor agents, a series of 1-benzofuro[3,2-]pyrazole derivatives were designed and synthesized. The treatment of 6-methoxybenzofuran-3(2)-one with LiHMDS in anhydrous tetrahydrofuran (THF) followed by reaction with 3-substitued phenyl isothiocyanate gave the thioamide intermediates, which underwent condensation with hydrazine monohydrate in dioxane/EtOH (1:1) to provide the benzofuropyrazole derivatives ⁻ as well as the unexpected pyrazole derivatives ⁻. In tumor cell growth inhibitory assay, all the benzofuropyrazole derivatives were not active against the breast tumor MCF-7 cell, only was highly active and more potent than ABT-751 against the leukemia K562 (GI = 0.26 μM) and lung tumor A549 cells (GI = 0.19 μM), while other benzofuropyrazoles showed very weak inhibitory activity. In contrast, the pyrazoles were in general more potent than the benzofuropyrazoles ⁻. Compound exhibited a similar tendency to that of with high potency against K562 and A549 cells but weak effects on MCF-7 cell. Both pyrazoles and exhibited high inhibitory activities against K562, MCF-7 and A549 cells. The most active compound was much more potent than ABT-751 against K562 and A549 cells with GI values of 0.021 and 0.69 M, respectively. Moreover, was identified as a novel tubulin polymerization inhibitor with an IC of 7.30 M.
Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Humans; Pyrazoles; Tubulin Modulators
PubMed: 30642134
DOI: 10.3390/molecules24020279 -
Journal of Medicinal Chemistry Nov 2017We report the discovery and medicinal chemistry optimization of a novel series of pyrazole-based inhibitors of human lactate dehydrogenase (LDH). Utilization of a...
We report the discovery and medicinal chemistry optimization of a novel series of pyrazole-based inhibitors of human lactate dehydrogenase (LDH). Utilization of a quantitative high-throughput screening paradigm facilitated hit identification, while structure-based design and multiparameter optimization enabled the development of compounds with potent enzymatic and cell-based inhibition of LDH enzymatic activity. Lead compounds such as 63 exhibit low nM inhibition of both LDHA and LDHB, submicromolar inhibition of lactate production, and inhibition of glycolysis in MiaPaCa2 pancreatic cancer and A673 sarcoma cells. Moreover, robust target engagement of LDHA by lead compounds was demonstrated using the cellular thermal shift assay (CETSA), and drug-target residence time was determined via SPR. Analysis of these data suggests that drug-target residence time (off-rate) may be an important attribute to consider for obtaining potent cell-based inhibition of this cancer metabolism target.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Crystallography, X-Ray; Drug Discovery; Drug Screening Assays, Antitumor; Enzyme Inhibitors; High-Throughput Screening Assays; Humans; L-Lactate Dehydrogenase; Male; Membranes, Artificial; Mice; Microsomes, Liver; Permeability; Pyrazoles; Rats; Solubility; Structure-Activity Relationship; Thiazoles
PubMed: 29120638
DOI: 10.1021/acs.jmedchem.7b00941 -
Molecules (Basel, Switzerland) Mar 2023Glycogen phosphorylase (GP) is a key regulator of glucose levels and, with that, an important target for the discovery of novel treatments against type 2 diabetes....
Glycogen phosphorylase (GP) is a key regulator of glucose levels and, with that, an important target for the discovery of novel treatments against type 2 diabetes. β-d-Glucopyranosyl derivatives have provided some of the most potent GP inhibitors discovered to date. In this regard, -β-d-glucopyranosyl azole type inhibitors proved to be particularly effective, with 2- and 4-β-d-glucopyranosyl imidazoles among the most potent designed to date. His377 backbone C=O hydrogen bonding and ion-ion interactions of the protonated imidazole with Asp283 from the 280s loop, stabilizing the inactive state, were proposed as crucial to the observed potencies. Towards further exploring these features, 4-amino-3-(β-d-glucopyranosyl)-5-phenyl-1-pyrazole () and 3-(β-d-glucopyranosyl)-4-guanidino-5-phenyl-1-pyrazole () were designed and synthesized with the potential to exploit similar interactions. Binding assay experiments against rabbit muscle GPb revealed as a moderate inhibitor (IC = 565 µM), but displayed no inhibition at 625 µM concentration. Towards understanding the observed inhibitions, docking and post-docking molecular mechanics-generalized Born surface area (MM-GBSA) binding free energy calculations were performed, together with Monte Carlo and density functional theory (DFT) calculations on the free unbound ligands. The computations revealed that while was predicted to hydrogen bond with His377 C=O in its favoured tautomeric state, the interactions with Asp283 were not direct and there were no ion-ion interactions; for , the most stable tautomer did not have the His377 backbone C=O interaction and while ion-ion interactions and direct hydrogen bonding with Asp283 were predicted, the conformational strain and entropy loss of the ligand in the bound state was significant. The importance of consideration of tautomeric states and ligand strain for glucose analogues in the confined space of the catalytic site with the 280s loop in the closed position was highlighted.
Topics: Pyrazoles; Glycogen Phosphorylase; Density Functional Theory; Molecular Docking Simulation; Monte Carlo Method; Molecular Conformation; Glucose; Diabetes Mellitus, Type 2
PubMed: 37049768
DOI: 10.3390/molecules28073005 -
Journal of Enzyme Inhibition and... Dec 2023New thymol - 1,5-disubstitutedpyrazole hybrids were synthesised as dual COX-2/5-LOX inhibitors. Compounds , , and displayed inhibitory activity against COX-2 (IC=...
New thymol - 1,5-disubstitutedpyrazole hybrids were synthesised as dual COX-2/5-LOX inhibitors. Compounds , , and displayed inhibitory activity against COX-2 (IC= 0.043, 0.045, 0.063, and 0.068 µM nearly equal to celecoxib (IC= 0.045 µM with high SI (316, 268, 204, and 151, respectively) comparable to celecoxib (327). All target compounds, and , showed 5-LOX inhibitory activity higher than reference quercetin. Besides, they possessed inhibition of formalin-induced paw oedema higher than celecoxib. In addition, compounds and showed superior gastrointestinal safety profile (no ulceration) as celecoxib and diclofenac sodium in the population of fasted rats. In conclusion, compounds , and achieved the target goal. They elicited dual inhibition of COX-2/5-LOX higher than celecoxib and quercetin, potent anti-inflammatory activity higher than celecoxib and superior gastrointestinal safety profile (no ulceration) as celecoxib.
Topics: Rats; Animals; Cyclooxygenase 2 Inhibitors; Cyclooxygenase 2; Thymol; Lipoxygenase Inhibitors; Celecoxib; Quercetin; Molecular Docking Simulation; Anti-Inflammatory Agents; Pyrazoles
PubMed: 36408833
DOI: 10.1080/14756366.2022.2147164