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European Journal of Medicinal Chemistry Mar 2019A series of hybrids 10a-v based on coumarin/pyrazole oxime have been synthesized, and exhibit good to excellent antitumor activities. Compound 10n has shown remarkable...
A series of hybrids 10a-v based on coumarin/pyrazole oxime have been synthesized, and exhibit good to excellent antitumor activities. Compound 10n has shown remarkable anticancer effect on SMMC-7721 cells (IC = 2.08 μM), which is considerably lower than 5-FU (IC = 37.8 μM) and similar to ADM (IC = 2.67 μM), with little effect on normal hepatic cells LO2. Notably, the suppression experiments of metastatic activities reveal that 10n also displays significant anti-metastasis effects through inhibiting cell migration and invasion in highly metastatic SMMC-7721 cell line, and dose-dependently reverses TGF-β1-induced epithelial-mesenchymal transition (EMT) procedure better than ADM. Finally, 10n also possesses low acute toxicity and potent tumor growth inhibitory property against SMMC-7721 cell lines in vivo. Our findings suggest that novel coumarin/pyrazole oxime hybrids are promising therapeutic agent candidates for further research.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Coumarins; Epithelial-Mesenchymal Transition; Humans; Neoplasm Invasiveness; Neoplasm Metastasis; Oximes; Pyrazoles; Structure-Activity Relationship; Transforming Growth Factor beta1
PubMed: 30739827
DOI: 10.1016/j.ejmech.2019.01.070 -
Angewandte Chemie (International Ed. in... Mar 2017We have developed a method for palladium-catalyzed, pyrazole-directed sp C-H bond arylation by aryl iodides. The reaction employs a Pd(OAc) catalyst at 5-10 mol %...
We have developed a method for palladium-catalyzed, pyrazole-directed sp C-H bond arylation by aryl iodides. The reaction employs a Pd(OAc) catalyst at 5-10 mol % loading and silver(I) oxide as a halide-removal agent, and it proceeds in acetic acid or acetic acid/hexafluoroisopropanol solvent. Ozonolysis of the pyrazole moiety affords pharmaceutically important β-phenethylamines.
Topics: Catalysis; Iodides; Oxides; Palladium; Phenethylamines; Pyrazoles; Silver Compounds
PubMed: 28233918
DOI: 10.1002/anie.201611407 -
Chemical Biology & Drug Design Jan 2017The molecular modification and synthesis of compounds is vital to discovering drugs with desirable pharmacological and toxicity profiles. In response to pyrazole...
The molecular modification and synthesis of compounds is vital to discovering drugs with desirable pharmacological and toxicity profiles. In response to pyrazole compounds' antipyretic, analgesic, and anti-inflammatory effects, this study sought to evaluate the analgesic, anti-inflammatory, and vasorelaxant effects, as well as the mechanisms of action, of a new pyrazole derivative, 5-[1-(4-fluorophenyl)-1H-pyrazol-4-yl]-2H-tetrazole. During the acetic acid-induced abdominal writhing test, treatments with 5-[1-(4-fluorophenyl)-1H-pyrazol-4-yl]-2H-tetrazole reduced abdominal writhing, while during the formalin test, 5-[1-(4-fluorophenyl)-1H-pyrazol-4-yl]-2H-tetrazole reduced licking times in response to both neurogenic pain and inflammatory pain, all without demonstrating any antinociceptive effects, as revealed during the tail flick test. 5-[1-(4-fluorophenyl)-1H-pyrazol-4-yl]-2H-tetrazole also reduced carrageenan-induced paw edema and cell migration during the carrageenan-induced pleurisy test. As demonstrated by the model of the isolated organ, 5-[1-(4-fluorophenyl)-1H-pyrazol-4-yl]-2H-tetrazole exhibits a vasorelaxant effect attenuated by Nω-nitro-l-arginine methyl ester, 1H-[1,2,4]oxadiazolo[4,3-alpha]quinoxalin-1-one, tetraethylammonium or glibenclamide. 5-[1-(4-fluorophenyl)-1H-pyrazol-4-yl]-2H-tetrazole also blocked CaCl -induced contraction in a dose-dependent manner. Suggesting a safe toxicity profile, 5-[1-(4-fluorophenyl)-1H-pyrazol-4-yl]-2H-tetrazole reduced the viability of 3T3 cells at higher concentrations and was orally tolerated, despite signs of toxicity in doses of 2000 mg/kg. Lastly, the compounds' analgesic activity might be attributed to the involvement of the NO/cGMP pathway and K channels observed in the vasorelaxant effect.
Topics: Analgesics; Animals; Anti-Inflammatory Agents; Antipyretics; In Vitro Techniques; Male; Mice; Pyrazoles; Rats; Rats, Wistar
PubMed: 27526659
DOI: 10.1111/cbdd.12838 -
European Journal of Medicinal Chemistry Jan 20061H-pyrazole-4-carbohydrazides were synthesized and their leishmanicidal in vitro activities and cytotoxic effects were investigated. The drugs prototypes of these new...
1H-pyrazole-4-carbohydrazides were synthesized and their leishmanicidal in vitro activities and cytotoxic effects were investigated. The drugs prototypes of these new compounds (ketoconazole, benznidazole, allopurinol and pentamidine) were also tested. It was found that among all the 1H-pyrazole-4-carbohydrazides derivatives examined, the most active compounds were those with X = Br, Y = NO2 (27) and X = NO2, Y = Cl (15) derivatives which showed to be most effective on promastigotes forms of L. amazonensis than on L. chagasi and L. braziliensis species. When tested against murine peritoneal macrophages as mammalian host cell controls of toxicity, 1-(4-Br-phenyl)-N'-[(4-NO(2)-phenyl)methylene]-1H-pyrazole-4-carbohydrazides (27) (EC50 = 50 microM l(-1)) and 1-(4-NO2-phenyl)-N'-[(4-Cl-phenyl)methylene]-1H-pyrazole-4-carbohydrazides (15) EC50 = 80 microM l(-1))] was reasonably toxic. However, both compounds were less toxic than pentamidine and ketoconazole. These results provide new perspectives on the development of drugs with activities against Leishmania parasite.
Topics: Animals; Antiprotozoal Agents; Cell Survival; Cells, Cultured; Drug Evaluation, Preclinical; Hydrazines; Leishmania; Leishmaniasis; Macrophages, Peritoneal; Mice; Mice, Inbred BALB C; Molecular Structure; Parasitic Sensitivity Tests; Pyrazoles; Structure-Activity Relationship
PubMed: 16300859
DOI: 10.1016/j.ejmech.2005.10.007 -
Dalton Transactions (Cambridge, England... Dec 2018Synthesis of an entirely new series of arene ruthenium complexes [Ru(η6-C6H6)(L1)Cl]PF6, (1), [Ru(η6-C10H14)(L1)Cl]PF6 (2), [Ru(η6-C6H6)(L2)Cl]PF6 (3) and...
Synthesis of an entirely new series of arene ruthenium complexes [Ru(η6-C6H6)(L1)Cl]PF6, (1), [Ru(η6-C10H14)(L1)Cl]PF6 (2), [Ru(η6-C6H6)(L2)Cl]PF6 (3) and [Ru(η6-C10H14)(L2)Cl]PF6 (4) involving 5-[2-(1H-pyrazol-1-yl)quinoline]-BODIPY (L1) and 5-[6-methoxy-2-(1H-pyrazol-1-yl)quinoline]-BODIPY (L2) was described. The ligands and complexes were thoroughly characterized by various physicochemical techniques and the structures of L1, 1 and 4 were determined by X-ray single crystal analyses. Photo-/ and electrochemical property, DNA binding, cytotoxicity, cellular uptake and apoptotic studies on 1-4 were performed by various methods, while singlet oxygen-mediated cytotoxicity via photo-irradiation by visible light was supported by 1,3-diphenylisobenzofuran titration studies. Binding of the complexes in the minor groove of CT-DNA via van der Waals forces and electrostatic interactions was affirmed by molecular docking studies. In vitro antiproliferative activity and photocytotoxicity of 1-4 were examined against the human cervical cancer cell line (HeLa) which clearly showed that these are extremely photocytotoxic under visible light (400-700 nm, 10 J cm-2; IC50 49.15, 1; 25.18, 2; 15.85, 3; 12.87, 4), less toxic in the dark (IC50 > 100 μM) and preferentially accumulate in the lysosome of the HeLa cells. Further, these complexes behave as a potential theranostic agent and their ability to kill cancer cells under visible light lies in the order 4 > 3 > 2 > 1.
Topics: Animals; Antineoplastic Agents; Boron Compounds; Cattle; Cell Proliferation; Cell Survival; Circular Dichroism; Coordination Complexes; DNA; Density Functional Theory; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Electrochemical Techniques; HeLa Cells; Humans; Hydrolysis; Lysosomes; Molecular Docking Simulation; Molecular Structure; Pyrazoles; Quinolines; Reactive Oxygen Species; Ruthenium; Structure-Activity Relationship
PubMed: 30507985
DOI: 10.1039/c8dt02947d -
Molecules (Basel, Switzerland) Aug 2022Elaboration of a convenient route towards donor-substituted pyrazoles from heteropropargyl precursors is challenging due to a number of thermodynamically favorable side...
Elaboration of a convenient route towards donor-substituted pyrazoles from heteropropargyl precursors is challenging due to a number of thermodynamically favorable side reactions (e.g., acetylene-allene isomerization and Glaser homocoupling). In this work, Sonogashira cross-coupling conditions of 4--butylphenyl propargyl ether with benzoyl chloride followed by tandem Michael addition/cyclocondensation with hydrazine into 3,5-disubstituted pyrazole (kinetic control), as well as cycloisomerization conditions of ketoacetylene intermediate into 2,5-disubstituted furan (thermodynamic control), were established through a variation of the catalyst loading, solvent polarity, excess of triethylamine, and time of reaction. During the optimization of process parameters, a number of by-products represented by a monophosphine binuclear complex (PPhPdI) with two bridging iodine atoms and diyne were identified and isolated in the pure form. The quantum-chemical calculations and solution-state H/C NMR spectroscopy suggested that the 5(3)-(4--butylphenyloxy)methoxy-3(5)-phenyl-1-pyrazole exists in the tautomeric equilibrium in a polar methanol solvent and that individual tautomers could be characterized in case aprotic solvents employed. The pyrazole features a unique tetramer motif in the crystal phase formed by alternating 3(5)-phenyl-1-pyrazole tautomers, which was stabilized by N-H···N bonds and stacking interactions of pyrazole rings, whereas pyrazole dimers were identified in the gas phase.
Topics: Furans; Pyrazoles; Solvents; Thermodynamics
PubMed: 36014420
DOI: 10.3390/molecules27165178 -
Acta Crystallographica. Section C,... Sep 2014The title substituted pyrazole derivatives, C17H15N5O3 and C18H15F3N4O, share most of their molecular features, in particular the hydrazinylidene (-HN-N=) rather than...
On substituted pyrazole derivatives. I. 3-Methyl-4-[(Z)-2-(4-methylphenyl)hydrazin-1-ylidene]-1-(3-nitrophenyl)-1H-pyrazol-5(4H)-one and 3-methyl-4-[(Z)-2-(4-methylphenyl)hydrazin-1-ylidene]-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-5(4H)-one.
The title substituted pyrazole derivatives, C17H15N5O3 and C18H15F3N4O, share most of their molecular features, in particular the hydrazinylidene (-HN-N=) rather than the diazene (-N=N-) tautomeric form, and differ only in the substituents (NO2 and CF3) on one of the outer phenyl rings. The molecular units are basically planar, with the rotation of the phenyl rings being hindered by the presence of two intramolecular hydrogen bonds having the keto O atom as acceptor. In both structures, the packing is governed by weak C-H...O, C-H...π and π-π interactions. The subtle way in which minor structural differences lead to rather different supramolecular structures is analysed.
Topics: Crystallography, X-Ray; Hydrogen Bonding; Imides; Molecular Structure; Nitro Compounds; Pyrazoles; Pyrazolones
PubMed: 25186353
DOI: 10.1107/S2053229614017173 -
Bioorganic & Medicinal Chemistry May 2014Idiopathic or immune thrombocytopenia (ITP) is a serious clinical disorder involving the destruction of platelets by macrophages. Small molecule therapeutics are highly...
Idiopathic or immune thrombocytopenia (ITP) is a serious clinical disorder involving the destruction of platelets by macrophages. Small molecule therapeutics are highly sought after to ease the burden on current therapies derived from human sources. Earlier, we discovered that dimers of five-membered heterocycles exhibited potential to inhibit phagocytosis of human RBCs by macrophages. Here, we reveal a structure-activity relationship of the bis-pyrazole class of molecules with -C-C-, -C-N- and -C-O- linkers, and their evaluation as inhibitors of phagocytosis of antibody-opsonized human RBCs as potential therapeutics for ITP. We have uncovered three potential candidates, 37, 47 and 50, all carrying a different linker connecting the two pyrazole moieties. Among these compounds, hydroxypyrazole derivative 50 is the most potent compound with an IC50 of 14 ± 9 μM for inhibiting the phagocytosis of antibody-opsonized human RBCs by macrophages. None of the compounds exhibited significant potential to induce apoptosis in peripheral blood mononuclear cells (PBMCs). Current study has revealed specific functional features, such as up to 2-atom spacer arm and alkyl substitution at one of the N(1) positions of the bivalent pyrazole core to be important for the inhibitory activity.
Topics: Antibodies; Erythrocytes; Humans; Leukocytes, Mononuclear; Phagocytosis; Purpura, Thrombocytopenic, Idiopathic; Pyrazoles; Structure-Activity Relationship
PubMed: 24685704
DOI: 10.1016/j.bmc.2014.03.016 -
Bioorganic Chemistry Sep 2021In this study, a new series of quinazolinone-pyrazole hybrids were designed, synthesized and screened for their α-glucosidase inhibitory activity. The results of the in...
Design and synthesis of novel quinazolinone-pyrazole derivatives as potential α-glucosidase inhibitors: Structure-activity relationship, molecular modeling and kinetic study.
In this study, a new series of quinazolinone-pyrazole hybrids were designed, synthesized and screened for their α-glucosidase inhibitory activity. The results of the in vitro screening indicated that all the molecular hybrids exhibited more inhibitory activity (IC values ranging from 60.5 ± 0.3 µM-186.6 ± 20 μM) in comparison to standard acarbose (IC = 750.0 ± 10.0 µM). Limited structure-activity relationship suggested that the variation in the inhibitory activities of the compounds affected by different substitutions on phenyl rings of diphenyl pyrazole moiety. The enzyme kinetic studies of the most potent compound 9i revealed that it inhibited α-glucosidase in a competitive mode with a Ki of 56 μM. Molecular docking study was performed to predict the putative binding interaction. As expected, all pharmacophoric moieties used in the initial structure design playing a pivotal role in the interaction with the binding site of the enzyme. In addition, by performing molecular dynamic investigation and MM-GBSA calculation, we investigated the difference in structural perturbation and dynamic behavior that is observed over α-glycosidase in complex with the most active compound and acarbose relative to unbound α-glycosidase enzyme.
Topics: Dose-Response Relationship, Drug; Drug Design; Glycoside Hydrolase Inhibitors; Kinetics; Models, Molecular; Molecular Structure; Pyrazoles; Quinazolinones; Saccharomyces cerevisiae; Structure-Activity Relationship; alpha-Glucosidases
PubMed: 34246971
DOI: 10.1016/j.bioorg.2021.105127 -
Bioorganic & Medicinal Chemistry Letters Jan 2014A novel series of 2-(5-methyl-1,3-diphenyl-1H-pyrazol-4-yl)-5-phenyl-1,3,4-oxadiazoles 7(a-m) were synthesized either by cyclization of...
A novel series of 2-(5-methyl-1,3-diphenyl-1H-pyrazol-4-yl)-5-phenyl-1,3,4-oxadiazoles 7(a-m) were synthesized either by cyclization of N'-benzoyl-5-methyl-1,3-diphenyl-1H-pyrazole-4-carbohydrazide 4a using POCl3 at 120°C or by oxidative cyclization of hydrazones derived from various arylaldehyde and (E)-N'-benzylidene-5-methyl-1,3-diphenyl-1H-pyrazole-4-carbohydrazide 5(a-d) using chloramine-T as oxidant. Newly synthesized compounds were characterized by analytical and spectral (IR, (1)H NMR, (13)C NMR and LC-MS) methods. The synthesized compounds were evaluated for their antimicrobial activity and were compared with standard drugs. The compounds demonstrated potent to weak antimicrobial activity. Among the synthesized compounds, compound 7m emerged as an effective antimicrobial agent, while compounds 7d, 7f, 7i and 7l showed good to moderate activity. The minimum inhibitory concentration of the compounds was in the range of 20-50μgmL(-1) against bacteria and 25-55μgmL(-1) against fungi. The title compounds represent a novel class of potent antimicrobial agents.
Topics: Anti-Bacterial Agents; Antifungal Agents; Bacteria; Dose-Response Relationship, Drug; Fungi; Microbial Sensitivity Tests; Molecular Structure; Oxadiazoles; Pyrazoles; Structure-Activity Relationship
PubMed: 24316123
DOI: 10.1016/j.bmcl.2013.11.029