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Molecules (Basel, Switzerland) Jul 2022In silico evaluation of various regioisomeric 5- and 3-hydroxy-substituted alkyl 1-aryl-1-pyrazole-4-carboxylates and their acyclic precursors yielded promising results...
In silico evaluation of various regioisomeric 5- and 3-hydroxy-substituted alkyl 1-aryl-1-pyrazole-4-carboxylates and their acyclic precursors yielded promising results with respect to their binding in the active site of dihydroorotate dehydrogenase of (DHODH). Consequently, four ethyl 1-aryl-5-hydroxy-1-pyrazole-4-carboxylates and their 3-hydroxy regioisomers were prepared by two-step syntheses via enaminone-type reagents or key intermediates. The synthesis of 5-hydroxy-1-pyrazoles was carried out using the literature protocol comprising acid-catalyzed transamination of diethyl [(dimethylamino)methylene]malonate with arylhydrazines followed by base-catalyzed cyclization of the intermediate hydrazones. For the synthesis of isomeric methyl 1-aryl-3-hydroxy-1-pyrazole-4-carboxylates, a novel two-step synthesis was developed. It comprises acylation of hydrazines with methyl malonyl chloride followed by cyclization of the hydrazines with -butoxy-bis(dimethylamino)methane. Testing the pyrazole derivatives for the inhibition of DHODH showed that 1-(naphthalene-2-yl)-5-hydroxy-1-pyrazole-4-carboxylate and 1-(naphthalene-2-yl)-, 1-(2,4,6-trichlorophenyl)-, and 1-[4-(trifluoromethyl)phenyl]-3-hydroxy-1-pyrazole-4-carboxylates (~30% inhibition) were slightly more potent than a known inhibitor, diethyl α-{[(1-indazol-5-yl)amino]methylidene}malonate (19% inhibition).
Topics: Carboxylic Acids; Dihydroorotate Dehydrogenase; Hydrazines; Malonates; Naphthalenes; Plasmodium falciparum; Pyrazoles
PubMed: 35897941
DOI: 10.3390/molecules27154764 -
Organic & Biomolecular Chemistry Jun 2014Selective synthesis of 4-(sulfonyl)-methyl-1H-pyrazoles and (E)-4,5-dihydro-1H-pyrazoles from N-allenic sulfonylhydrazones with sulfonyl group migrations has been...
Selective synthesis of 4-(sulfonyl)-methyl-1H-pyrazoles and (E)-4,5-dihydro-1H-pyrazoles from N-allenic sulfonylhydrazones with sulfonyl group migrations has been developed. A key feature of these reactions is that the migrations of the sulfonyl groups to different positions can be controlled by changing the Lewis acids.
Topics: Chemistry, Organic; Cyclization; Hydrazones; Pyrazoles
PubMed: 24781849
DOI: 10.1039/c4ob00550c -
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 -
Bioorganic & Medicinal Chemistry Letters May 2021Methicillin-resistant Staphylococcus aureus (MRSA) infections are a significant burden both clinically and economically worldwide. Increasing resistance to current...
Methicillin-resistant Staphylococcus aureus (MRSA) infections are a significant burden both clinically and economically worldwide. Increasing resistance to current antibiotics requires an urgent investigation into novel classes of antimicrobial agents. This study presents a structure-activity relationship (SAR) rationale for pyrazole linked phenylthiazole analogues as new antibacterial agents. A library of 23 novel pyrazole linked phenylthiazole compounds were synthesised, followed by screening for antimicrobial activity against five bacterial species and two fungi. The most active compound 14b has shown promising antibacterial activity against the Gram-positive methicillin-resistant Staphylococcus aureus (MRSA, ATCC 43300) strain (MIC 4 μg/mL). Furthermore, the active pyrazole linked phenylthiazole compound exhibited a better toxicity profile than standard antibiotics. In summary, these results demonstrate that a pyrazole linked phenylthiazole scaffold has potential as a lead for further investigation to afford novel antibacterial agents.
Topics: Anti-Bacterial Agents; Dose-Response Relationship, Drug; Drug Design; HEK293 Cells; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Molecular Structure; Pyrazoles; Structure-Activity Relationship; Thiazoles
PubMed: 33609657
DOI: 10.1016/j.bmcl.2021.127853 -
Molecules (Basel, Switzerland) Jun 2022An efficient synthetic route to construct diverse pyrazole-based chalcones from 1-phenyl-1-pyrazol-3-ols bearing a formyl or acetyl group on the C4 position of pyrazole...
An efficient synthetic route to construct diverse pyrazole-based chalcones from 1-phenyl-1-pyrazol-3-ols bearing a formyl or acetyl group on the C4 position of pyrazole ring, employing a base-catalysed Claisen-Schmidt condensation reaction, is described. Isomeric chalcones were further reacted with -hydroxy-4-toluenesulfonamide and regioselective formation of 3,5-disubstituted 1,2-oxazoles was established. The novel pyrazole-chalcones and 1,2-oxazoles were characterized by an in-depth analysis of NMR spectral data, which were obtained through a combination of standard and advanced NMR spectroscopy techniques.
Topics: Chalcone; Chalcones; Magnetic Resonance Spectroscopy; Oxazoles; Pyrazoles
PubMed: 35744875
DOI: 10.3390/molecules27123752 -
Current Drug Discovery Technologies 2023In the present study, a new series of 1,2,4-triazole linked to pyrazole derivatives (8a-j) of...
BACKGROUND
In the present study, a new series of 1,2,4-triazole linked to pyrazole derivatives (8a-j) of 4-(((7-amino-7H-[1,2,4]triazolo[4,3-b][1,2,4]triazol-6-yl)methyl)amino)-1,5-dimethyl- 2-phenyl-1H-pyrazol-3(2H)-one were synthesized and assessed for their antibacterial and anticancer activity.
OBJECTIVE
Encouraged by these results, these analogues 4-(((7-amino-7H-[1,2,4]triazolo[4,3- b][1,2,4]triazol-6-yl)methyl)amino)-1,5-dimethyl-2-phenyl-1H-pyrazol-3(2H)-ones 8 have been synthesized and their inhibitory potential activity against different bacterial microorganisms and cancer cell lines was discussed.
METHODS
All the synthesized final scaffolds were characterized by H NMR, C NMR, IR, mass and elemental analysis. All the synthesized 1,2,4-triazole linked to pyrazole compounds were evaluated for their antimicrobial sensitivity by using the agar dilution technique. The anticancer activity of these compounds has been assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide colorimetric assay and docking results are described by Autodock 4.2.
RESULTS
In vitro analysis suggests that compounds 8h, 8f, and 8b demonstrated excellent antibacterial activity against S. aureus, P. aeruginosa, S. epidermidis with MICs of 8, 8, 11 μg/mL respectively, while the remaining compounds showed moderate to good inhibitory potential. Some of them exhibited potent cytotoxicity against MCF-7 and P388 cancer cell lines and compounds 8c, 8f, and 8d reveal the highest potency against MCF-7 with IC values 2.8 ± 0.4, 3.1 ± 0.4, 3.5 ± 0.2 μM, respectively. Especially 8c, 8i and 8f showed better interaction patterns with amino acids Ala197 (N-N), Lys168 (N-N), Asn163 (O-N) at 3.13, 3.09, 3.00 A° as reported in DNA (Topo II) complex (1ZXM).
CONCLUSION
New findings have established the fact that fused 1,2,4-triazoles linked to pyrazole contributed great significance in the field of medicinal chemistry due to their various biological properties.
Topics: Humans; Structure-Activity Relationship; Staphylococcus aureus; Triazoles; Anti-Bacterial Agents; Neoplasms; Pyrazoles; Molecular Structure; Antineoplastic Agents
PubMed: 36437730
DOI: 10.2174/1570163820666221125121625 -
Angewandte Chemie (International Ed. in... Sep 2021A novel metal-organic framework (MOF) containing one-dimensional, Fe chains bridged by dipyrazolate linkers and N,N-dimethylformamide (DMF) ligands has been synthesized....
A novel metal-organic framework (MOF) containing one-dimensional, Fe chains bridged by dipyrazolate linkers and N,N-dimethylformamide (DMF) ligands has been synthesized. The unusual chain-type metal nodes feature accessible coordination sites on adjacent metal centers, resulting in motifs that are reminiscent of the active sites in non-heme diiron enzymes. The MOF facilitates direct reduction of nitric oxide (NO), producing nearly quantitative yields of nitrous oxide (N O) and emulating the reactivity of flavodiiron nitric oxide reductases (FNORs). The ferrous form of the MOF can be regenerated via a synthetic cycle involving reduction with cobaltocene (CoCp ) followed by reaction with trimethylsilyl triflate (TMSOTf).
Topics: Biomimetic Materials; Ferrous Compounds; Metal-Organic Frameworks; Molecular Structure; Nitric Oxide; Oxidation-Reduction; Pyrazoles
PubMed: 34342117
DOI: 10.1002/anie.202108095 -
Chemistry & Biodiversity Nov 2023Pyrazolic hybrids appended with naphthalene, p-chlorobenzene, o-phenol and toluene have been synthesized using Claisen Schmidt condensation reaction of...
Pyrazolic hybrids appended with naphthalene, p-chlorobenzene, o-phenol and toluene have been synthesized using Claisen Schmidt condensation reaction of 1-benzyl-3,5-dimethyl-1H-pyrazole-4-carbaldehyde. All compounds were characterized by various spectroscopic techniques. Compound (E)-3-(1-benzyl-3,5-dimethyl-1H-pyrazol-4-yl)-1-(4-chlorophenyl)prop-2-en-1-one crystallizes in monoclinic crystal system with C2/c space group. These synthesized compounds were tested for cytotoxic activity and among these compounds 4b and 5a shows prominent cytotoxic activity against triple-negative breast cancer (TNBC) cells MDA-MB-231 with IC50 values 47.72 μM and 24.25 μM, respectively. Distinguishing morphological changes were noticed in MDA-MB-231 cells treated with pyrazole hybrids contributing to apoptosis action. To get more insight into cytotoxic activity, in silico molecular docking of these compounds were performed and the results suggested that (E)-3-(1-benzyl-3,5-dimethyl-1H-pyrazol-4-yl)-1-(p-tolyl)prop-2-en-1-one and 1-(1'-benzyl-5-(4-chlorophenyl)-3',5'-dimethyl-3,4-dihydro-1'H,2H-[3,4'-bipyrazol]-2-yl)ethan-1-one binds to the prominent domain of Akt2 indicating their potential ability as Akt2 inhibitor. Moreover, from in silico ADME studies clearly demonstrated that these compounds may be regarded as a drug candidate for sub-lingual absorption based on log p values (2.157-4.924). These compounds also show promising antitubercular activity. The overall results suggest that pyrazolic hybrids with substitution at less sterically hindered positions have appealing potent cytotoxic activity and antituberculosis activity due to which they may act as multidrug candidate.
Topics: Molecular Docking Simulation; Molecular Structure; MDA-MB-231 Cells; Cell Line, Tumor; Antineoplastic Agents; Pyrazoles; Structure-Activity Relationship
PubMed: 37702285
DOI: 10.1002/cbdv.202300799 -
Organic & Biomolecular Chemistry Aug 20133-(4-Chlorophenyl)-4-substituted pyrazole derivatives were synthesised and tested for their in vitro antifungal activity. Some compounds showed very good antifungal...
3-(4-Chlorophenyl)-4-substituted pyrazole derivatives were synthesised and tested for their in vitro antifungal activity. Some compounds showed very good antifungal activity against four pathogenic strains of fungi. The same compounds exhibited an interesting activity against the tested strain of Mycobacterium tuberculosis H37Rv. The results suggest that 1,3,4-oxadiazoles and 5-pyrazolinones bearing a core pyrazole scaffold may be promising antifungal and antitubercular agents.
Topics: Antifungal Agents; Aspergillus; Candida; Cryptococcus neoformans; Dose-Response Relationship, Drug; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium tuberculosis; Pyrazoles; Structure-Activity Relationship
PubMed: 23779132
DOI: 10.1039/c3ob27290g -
European Journal of Medicinal Chemistry Dec 2017A number of diarylpyrazolylquinoline derivatives were synthesized and evaluated for their anti-dengue virus (DENV) activity. Among them,...
A number of diarylpyrazolylquinoline derivatives were synthesized and evaluated for their anti-dengue virus (DENV) activity. Among them, 6-fluoro-2-(1-(4-fluorophenyl)-3- (4-methoxyphenyl)-1H-pyrazol-5-yl)quinoline (11c), 2-[1,3-bis(4-methoxyphenyl)-1H-pyrazol- 5-yl]-6-fluoroquinoline (12c), and 4-[5-(6-fluoroquinolin-2-yl)-3-(4-methoxyphenyl)-1H-pyrazol- 1-yl]benzenesulfonamide (13c) exhibited approximately 10-folds more active anti-DENV-2 activity (IC of 1.36, 1.09 and 0.81 μM, respectively) than that of ribavirin (IC = 12.61 μM). Compound 13c was also potent inhibited other sero-types of DENV. It reduced DENV replication in both viral protein and mRNA levels, and no significant cell cytotoxicity was detected, with greater than 50% viability of Huh-7-DV-Fluc cells at a concentration of 200 μM. Furthermore, compound 13c can effectively protect mice from DENV infection by reducing disease symptoms and mortality of DENV-infected mice. It represents a potential antiviral agent to block DENV replication in vitro and in vivo. Structural optimization of the initial lead compound, 13c, and the detailed molecular mechanism of action are ongoing.
Topics: Animals; Antiviral Agents; Cell Line, Tumor; Cell Survival; Dengue; Dengue Virus; Dose-Response Relationship, Drug; Drug Discovery; Humans; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Molecular Structure; Pyrazoles; Quinolines; Structure-Activity Relationship
PubMed: 29031073
DOI: 10.1016/j.ejmech.2017.10.001