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Combinatorial Chemistry & High... 2021Microwave-assisted condensation of acetophenone 1 and aromatic aldehydes 2 gave chalcone analogs 3, which were cyclized to pyrazole derivatives 6a-f via the reaction...
AIMS AND OBJECTIVES
Microwave-assisted condensation of acetophenone 1 and aromatic aldehydes 2 gave chalcone analogs 3, which were cyclized to pyrazole derivatives 6a-f via the reaction with hydrazine hydrate and oxalic acid in the presence of the catalytic amount of acetic acid in ethanol.
MATERIALS AND METHODS
The structural features of the synthesized compounds were characterized by melting point, FT-IR, H, C NMR and elemental analysis.
RESULTS
The antibacterial activities of the synthesized pyrazoles were evaluated against three gram-positive bacteria, such as Enterococcus durans, Staphylococcus aureus, Bacillus subtilis and two gram-negative bacteria such as Escherichia coli and Salmonella typhimurium.
CONCLUSION
All the synthesized pyrazoles showed relatively high antibacterial activity against S. aureus strain, and none of them demonstrated antibacterial activity against E. coli.
Topics: Anti-Bacterial Agents; Bacillus subtilis; Enterococcus; Escherichia coli; Microbial Sensitivity Tests; Microwaves; Pyrazoles; Salmonella typhimurium; Staphylococcus aureus
PubMed: 33076806
DOI: 10.2174/1386207323666201019152206 -
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 -
International Journal of Nanomedicine 2019It is well known that the grafted multiwalled carbon nanotubes (MWCNTs) have antibacterial activity and lower cytotoxicity. Moreover, pyrazole derivatives have a broad...
INTRODUCTION
It is well known that the grafted multiwalled carbon nanotubes (MWCNTs) have antibacterial activity and lower cytotoxicity. Moreover, pyrazole derivatives have a broad spectrum of biological activity due to their fertile template for many medicinal drugs. On view of these findings we report herein the hybridization between MWCNTs and some pyrazole derivatives as antibacterial agents.
MATERIALS AND METHODS
Pyrazole and pyrazolone derivatives were grafted onto the surface of carboxylated MWCNTs via the reaction of carboxylated MWCNTs and the diazonium salts of pyrazoles and pyrazolones using mixed acid treatment. The insertion of the pyrazole and pyrazolone moieties was characterized by Fourier transform infrared (FTIR) spectroscopy, energy dispersion spectroscopy, transmission electron microscopy, X-ray diffraction and thermogravimetric (TGA).
RESULTS
The results indicate that pyrazole and pyrazolone moieties successfully attached on carboxylated MWCNTs surface. The neat pyrazole and pyrazolone derivatives and their corresponding carbon nanotubes were tested against , and bacteria, and fungi. The results showed that the grafted carbon nanotubes of pyrazole and pyrazolone derivatives have better antimicrobial activity than the neat pyrazole and pyrazolone derivatives. The molecular docking studies were performed on the most potent antimicrobial compounds to investigate the existence of the interactions between the most active inhibitors and Farnesyl pyrophosphate synthase (FPPS).
CONCLUSION
The surface of the carboxylated MWCNTs was successfully grafted with some pyrazole derivatives. The antibacterial activity was investigated for the newly synthesized compounds and indicated that the grafted MWCNTs have good antibacterial activity toward some pathogenic types of bacteria.
Topics: Anti-Bacterial Agents; Bacteria; Catalytic Domain; Fungi; Ligands; Microbial Sensitivity Tests; Molecular Docking Simulation; Nanotubes, Carbon; Pyrazoles; Spectroscopy, Fourier Transform Infrared; Thermogravimetry; X-Ray Diffraction
PubMed: 31686804
DOI: 10.2147/IJN.S182699 -
European Journal of Medicinal Chemistry Oct 2013We recently discovered and reported dual inhibitor 5 of AChE and BACE1 with N-benzylpiperidine ethyl as C-terminus. Compound 5 showed potent inhibitory activities for...
We recently discovered and reported dual inhibitor 5 of AChE and BACE1 with N-benzylpiperidine ethyl as C-terminus. Compound 5 showed potent inhibitory activities for BACE1, and could reduce endogenous Aβ1-40 production in APP transgenic mice. In present work, we rapidly identified substituted triazole as the C-terminus of compound 5 by replacing the benzylpiperidine ethyl group with click chemistry and tested these synthesized compounds by in situ screening assay. As revealed by the crystal structures of BACE1 in complex with our triazole compound 12, we found that Pro70 and Thr72 located in the flap region were the critical components for binding with these inhibitors. With the aid of the crystal structure, a new series of five-membered heterocyclic compounds was prepared in order to explore the structure-activity relationship (SAR) of this class of molecules. From these efforts, pyrazole was discovered as a novel C-terminus of BACE1 inhibitors. After further modification of pyrazole with variable substituents, compound 37 exhibited good potency in enzyme inhibition assay (IC50=0.025 μM) and compound 33 showed moderate inhibition effects on Aβ production of APP transfected HEK293 cells. Moreover, these pyrazole derivatives demonstrated good selectivity versus cathepsin D. Our results indicated that the vicinity of Pro70 and Thr72 might be utilized as a subsite, and the discovered pyrazole derivatives might provide useful hints for developing novel BACE1 inhibitors as anti-AD drugs.
Topics: Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Cells, Cultured; Crystallography, X-Ray; Drug Discovery; Enzyme Activation; Humans; Inhibitory Concentration 50; Mice; Mice, Transgenic; Protease Inhibitors; Pyrazoles; Structure-Activity Relationship
PubMed: 23988410
DOI: 10.1016/j.ejmech.2013.06.027 -
Parasitology Aug 2017The synthesis and antiprotozoal activity of some simple dialkyl pyrazole-3,5-dicarboxylates (compounds 2-6) and their sodium salts (pyrazolates) (compounds 7-9) against...
The synthesis and antiprotozoal activity of some simple dialkyl pyrazole-3,5-dicarboxylates (compounds 2-6) and their sodium salts (pyrazolates) (compounds 7-9) against Trypanosoma cruzi, Leishmania infantum and Leishmania braziliensis are reported. In most cases the studied compounds showed, especially against the clinically significant amastigote forms, in vitro activities higher than those of the reference drugs (benznidazole for T. cruzi and glucantime for Leishmania spp.); furthermore, the low non-specific cytotoxicities against Vero cells and macrophages shown by these compounds led to good selectivity indexes, which are 8-72 times higher for T. cruzi amastigotes and 15-113 times higher for Leishmania spp. amastigotes than those of the respective reference drugs. The high efficiency of diethyl ester 3 and its sodium salt 8 against the mentioned protozoa was confirmed by further in vitro assays on infection rates and by an additional in vivo study in a murine model of acute and chronic Chagas disease. The inhibitory capacity of compounds 3 and 8 on the essential iron superoxide dismutase of the aforementioned parasites may be related to the observed anti-trypanosomatid activity. The low acute toxicity of compounds 3 and 8 in mice is also reported in this article.
Topics: Animals; Chagas Disease; Chlorocebus aethiops; Dicarboxylic Acids; Female; Leishmania braziliensis; Leishmania infantum; Macrophages; Mice; Mice, Inbred BALB C; Parasitemia; Pyrazoles; Trypanocidal Agents; Trypanosoma cruzi; Vero Cells
PubMed: 28367781
DOI: 10.1017/S0031182017000415 -
Journal of Enzyme Inhibition and... Dec 20203-alkyl-5-aryl-1-pyrimidyl-1-pyrazole derivatives were designed and synthesised as selective inhibitors of JNK3, a target for the treatment of neurodegenerative...
3-alkyl-5-aryl-1-pyrimidyl-1-pyrazole derivatives were designed and synthesised as selective inhibitors of JNK3, a target for the treatment of neurodegenerative diseases. Following previous studies, we have designed JNK3 inhibitors to reduce the molecular weight and successfully identified a lead compound that exhibits equipotent activity towards JNK3. Kinase profiling results also showed high selectivity for JNK3 among 38 kinases. Among the derivatives, the IC value of ()-2-(1-(2-((1-(cyclopropanecarbonyl)pyrrolidin-3-yl)amino)pyrimidin-4-yl)-5-(3,4-dichlorophenyl)-1-pyrazol-3-yl)acetonitrile exhibited 227 nM, showing the highest inhibitory activity against JNK3.
Topics: Dose-Response Relationship, Drug; Drug Discovery; Humans; Mitogen-Activated Protein Kinase 10; Molecular Docking Simulation; Molecular Structure; Protein Kinase Inhibitors; Pyrazoles; Structure-Activity Relationship
PubMed: 31856610
DOI: 10.1080/14756366.2019.1705294 -
Molecules (Basel, Switzerland) Jul 2018In this study, a series of novel pyrazole-hydrazone derivatives containing an isoxazole moiety were synthesized. Antiviral bioassays indicated that some of the title...
In this study, a series of novel pyrazole-hydrazone derivatives containing an isoxazole moiety were synthesized. Antiviral bioassays indicated that some of the title compounds exhibited better in vivo antiviral activities against tobacco mosaic virus (TMV). In particular, compounds , and exhibited the best curative activity, protection activity, and inactivation activity against TMV, respectively, which were superior to those of Ningnanmycin. This study demonstrated that this series of novel pyrazole-hydrazone derivatives containing an isoxazole amide moiety could effectively control TMV.
Topics: Antiviral Agents; Chemistry Techniques, Synthetic; Drug Design; Hydrazones; Isoxazoles; Magnetic Resonance Spectroscopy; Microbial Sensitivity Tests; Pyrazoles; Structure-Activity Relationship; Tobacco Mosaic Virus
PubMed: 30037021
DOI: 10.3390/molecules23071798 -
Journal of Medicinal Chemistry May 2024-myristoyltransferase (NMT) is a promising antimalarial drug target. Despite biochemical similarities between and human NMTs, our recent research demonstrated that high...
-myristoyltransferase (NMT) is a promising antimalarial drug target. Despite biochemical similarities between and human NMTs, our recent research demonstrated that high selectivity is achievable. Herein, we report NMT-inhibiting compounds aimed at identifying novel mechanisms of selectivity. Various functional groups are appended to a pyrazole moiety in the inhibitor to target a pocket formed beneath the peptide binding cleft. The inhibitor core group polarity, lipophilicity, and size are also varied to probe the water structure near a channel. Selectivity index values range from 0.8 to 125.3. Cocrystal structures of two selective compounds, determined at 1.97 and 2.43 Å, show that extensions bind the targeted pocket but with different stabilities. A bulky naphthalene moiety introduced into the core binds next to instead of displacing protein-bound waters, causing a shift in the inhibitor position and expanding the binding site. Our structure-activity data provide a conceptual foundation for guiding future inhibitor optimizations.
Topics: Pyrazoles; Plasmodium vivax; Acyltransferases; Structure-Activity Relationship; Antimalarials; Enzyme Inhibitors; Crystallography, X-Ray; Humans; Models, Molecular; Binding Sites
PubMed: 38680035
DOI: 10.1021/acs.jmedchem.4c00168 -
Novel pyrazole derivatives as neutral CB₁ antagonists with significant activity towards food intake.European Journal of Medicinal Chemistry Apr 2013In spite of rimonabant's withdrawal from the European market due to its adverse effects, interest in the development of drugs based on CB1 antagonists is revamping on...
In spite of rimonabant's withdrawal from the European market due to its adverse effects, interest in the development of drugs based on CB1 antagonists is revamping on the basis of the peculiar properties of this class of compounds. In particular, new strategies have been proposed for the treatment of obesity and/or related risk factors through CB1 antagonists, i.e. by the development of selectively peripherally acting agents or by the identification of neutral CB1 antagonists. New compounds based on the lead CB1 antagonist/inverse agonist rimonabant have been synthesized with focus on obtaining neutral CB1 antagonists. Amongst the new derivatives described in this paper, the mixture of the two enantiomers (±)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-(2-cyclohexyl-1-hydroxyethyl)-4-methyl-1H-pyrazole ((±)-5), and compound 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-[(Z)-2-cyclohexyl-1-fluorovinyl]-4-methyl-1H-pyrazole ((Z)-6), showed interesting pharmacological profiles. According to the preliminary pharmacological evaluation, these novel pyrazole derivatives showed in fact both neutral CB1 antagonism behaviour and significant in vivo activity towards food intake.
Topics: Animals; Dose-Response Relationship, Drug; Eating; Male; Mice; Molecular Structure; Pyrazoles; Receptor, Cannabinoid, CB1; Structure-Activity Relationship
PubMed: 23357307
DOI: 10.1016/j.ejmech.2012.12.056 -
Bioorganic & Medicinal Chemistry Letters Jul 2021A series of novel pyrazole-benzimidazole derivatives (6-42) have been designed, synthesized and evaluated for their in vitro antiproliferative activity against the...
A series of novel pyrazole-benzimidazole derivatives (6-42) have been designed, synthesized and evaluated for their in vitro antiproliferative activity against the HCT116, MCF-7 and Huh-7 cell lines. Among them, compounds 17, 26 and 35 showed significant antiproliferative activity against HCT116 cell lines with the IC values of 4.33, 5.15 and 4.84 μM, respectively. Moreover, fluorescent staining studies showed compound 17 could induce cancer cells apoptosis. The flow cytometry assay revealed that compound 17 could induce cell cycle arrest at G0/G1 phase. All in all, these consequences suggest that pyrazole-benzimidazole derivatives could serve as promising compounds for further research to develop novel and highly potent cancer therapy agents.
Topics: Antineoplastic Agents; Benzimidazoles; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Pyrazoles; Structure-Activity Relationship
PubMed: 33979690
DOI: 10.1016/j.bmcl.2021.128097