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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 -
Drug News & Perspectives Mar 2006Liver fibrosis is the result of an unbalanced wound healing response to a chronic hepatic injury. Transforming growth factor-beta (TGF-beta) plays a major role in this... (Review)
Review
Liver fibrosis is the result of an unbalanced wound healing response to a chronic hepatic injury. Transforming growth factor-beta (TGF-beta) plays a major role in this process via the activation of hepatic stellate cells. Various approaches have been tested in animal models of fibrosis to block the effects of TGF-beta, including antibodies and soluble receptors. Here, we discuss the potential use of TGF-beta signaling inhibitors, acting at the TGF-beta type I receptor kinase (ALK5) level, as a possible therapy for liver fibrosis. Thus far, there is only one ALK5 inhibitor (GW6604) for which activity in models of liver fibrosis has been described, showing clear antifibrotic effects resulting in liver function improvement. However, due to the pleiotropic effects of TGF-beta, the beneficial antifibrotic effects of ALK5 inhibition should be carefully balanced against the potential risk of unwanted effects stemming from chronic treatment.
Topics: Activin Receptors, Type I; Animals; Disease Models, Animal; Humans; Liver Cirrhosis; Protein Serine-Threonine Kinases; Pyrazoles; Pyridines; Receptor, Transforming Growth Factor-beta Type I; Receptors, Transforming Growth Factor beta; Transforming Growth Factor beta
PubMed: 16628263
DOI: 10.1358/dnp.2006.19.2.977444 -
Molecules (Basel, Switzerland) Oct 2022COX-2 can be considered as a clinically relevant molecular target for adjuvant, in particular radiosensitizing treatments. In this regard, using selective COX-2...
COX-2 can be considered as a clinically relevant molecular target for adjuvant, in particular radiosensitizing treatments. In this regard, using selective COX-2 inhibitors, e.g., in combination with radiotherapy or endoradiotherapy, represents an interesting treatment option. Based on our own findings that nitric oxide (NO)-releasing and celecoxib-derived COX-2 inhibitors (COXIBs) showed promising radiosensitizing effects in vitro, we herein present the development of a series of eight novel NO-COXIBs differing in the peripheral substitution pattern and their chemical and in vitro characterization. COX-1 and COX-2 inhibition potency was found to be comparable to the lead NO-COXIBs, and NO-releasing properties were demonstrated to be mainly influenced by the substituent in 4-position of the pyrazole (Cl vs. H). Introduction of the -propionamide at the sulfamoyl residue as a potential prodrug strategy lowered lipophilicity markedly and abolished COX inhibition while NO-releasing properties were not markedly influenced. NO-COXIBs were tested in vitro for a combination with single-dose external X-ray irradiation as well as [Lu]LuCl treatment in HIF2α-positive mouse pheochromocytoma (MPC-HIF2a) tumor spheroids. When applied directly before X-ray irradiation or Lu treatment, NO-COXIBs showed radioprotective effects, as did celecoxib, which was used as a control. Radiosensitizing effects were observed when applied shortly after X-ray irradiation. Overall, the NO-COXIBs were found to be more radioprotective compared with celecoxib, which does not warrant further preclinical studies with the NO-COXIBs for the treatment of pheochromocytoma. However, evaluation as radioprotective agents for healthy tissues could be considered for the NO-COXIBs developed here, especially when used directly before irradiation.
Topics: Adrenal Gland Neoplasms; Animals; Anti-Inflammatory Agents, Non-Steroidal; Celecoxib; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Mice; Nitric Oxide; Pheochromocytoma; Prodrugs; Pyrazoles; Radiation-Protective Agents; Radiation-Sensitizing Agents
PubMed: 36235124
DOI: 10.3390/molecules27196587 -
Bioorganic & Medicinal Chemistry Letters Aug 2017In 2014, a published report of the high-throughput screen of>42,000 kinase inhibitors from GlaxoSmithKline against T. brucei identified 797 potent and selective hits....
In 2014, a published report of the high-throughput screen of>42,000 kinase inhibitors from GlaxoSmithKline against T. brucei identified 797 potent and selective hits. From this rich data set, we selected NEU-0001101 (1) for hit-to-lead optimization. Through our preliminary compound synthesis and SAR studies, we have confirmed the previously reported activity of 1 in a T. brucei cell proliferation assay and have identified alternative groups to replace the pyridyl ring in 1. Pyrazole 24 achieves improvements in both potency and lipophilicity relative to 1, while also showing good in vitro metabolic stability. The SAR developed on 24 provides new directions for further optimization of this novel scaffold for anti-trypanosomal drug discovery.
Topics: Cell Line; Cell Proliferation; Drug Design; Humans; Pyrazoles; Quinazolinones; Structure-Activity Relationship; Trypanocidal Agents; Trypanosoma brucei brucei; Trypanosomiasis, African
PubMed: 28729055
DOI: 10.1016/j.bmcl.2017.07.032 -
Scientific Reports Jan 2024In this study, a two pyrazole derivatives; 2-(5-methyl-1H-pyrazole-3-carbonyl)-N-phenylhydrazine-1-carboxamide (Pyz-1) and...
Synthesis, structural characterizations, in vitro biological evaluation and computational investigations of pyrazole derivatives as potential antidiabetic and antioxidant agents.
In this study, a two pyrazole derivatives; 2-(5-methyl-1H-pyrazole-3-carbonyl)-N-phenylhydrazine-1-carboxamide (Pyz-1) and 4-amino-5-(5-methyl-1H-pyrazol-3-yl)-4H-1,2,4-triazole-3-thiol (Pyz-2) were synthesized and characterized by C-NMR, H-NMR, FT-IR, and mass spectrometry. A complete molecular structures optimization, electronic and thermodynamic properties of Pyz-1 and Pyz-2 in gas phase and aqueous solution were predicted by using hybrid B3LYP method with the 6-311++G** basis sets. Pyz-1 and Pyz-2 were evaluated in vitro for their anti-diabetic, antioxidant and xanthine oxidase inhibition activities. For anti-diabetic activity, Pyz-1 and Pyz-2 showed a potent α-glucosidase and α-amylase inhibition with IC values of 75.62 ± 0.56, 95.85 ± 0.92 and 119.3 ± 0.75, 120.2 ± 0.68 µM, respectively, compared to Acarbose (IC = 72.58 ± 0.68 µM, IC = 115.6 ± 0.574 µM). In xanthine oxidase assay, Pyz-1 and Pyz-2 exhibited remarkable inhibitory ability with IC values 24.32 ± 0.78 and 10.75 ± 0.54 µM, respectively. The result of antioxidant activities showed that the title compounds have considerable antioxidant and radical scavenger abilities. In addition, molecular docking simulation was used to determine the binding modes and energies between the title compounds and α-glucosidase and α-amylase enzymes.
Topics: Humans; Hypoglycemic Agents; Glycoside Hydrolase Inhibitors; Antioxidants; Molecular Docking Simulation; alpha-Glucosidases; Xanthine Oxidase; Spectroscopy, Fourier Transform Infrared; Diabetes Mellitus; Molecular Structure; Pyrazoles; alpha-Amylases; Structure-Activity Relationship
PubMed: 38225280
DOI: 10.1038/s41598-024-51290-6 -
Bioorganic & Medicinal Chemistry Letters Dec 2016Chemical synthesis was performed to produce a series of 6-amino-1,3-disubstituted-4-phenyl-1,4-dihydro pyrano[2,3-c]pyrazole-5-carbonitrile compounds (14-57) which were...
Chemical synthesis was performed to produce a series of 6-amino-1,3-disubstituted-4-phenyl-1,4-dihydro pyrano[2,3-c]pyrazole-5-carbonitrile compounds (14-57) which were characterized by H NMR, C NMR and LC/MS-MS. These compounds were assessed for their effect on the in vitro anchorage independent growth of human lung cancer cell line H2122 and IC values calculated. Two of the more potent compounds, BQU057 40 and BQU082 57 also displayed a dose dependent effect on RalA and RalB activity in H2122 spheroids using the common RalBP1 pull-down assay. Mouse PK and tissue distribution studies on 40 and 57 were performed and demonstrated that parent drug was present in tumor 3.0h post ip (50mg/Kg) dose.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Drug Discovery; Humans; Lung; Lung Neoplasms; Mice; Nitriles; Pyrazoles; Tissue Distribution; ral GTP-Binding Proteins
PubMed: 27825764
DOI: 10.1016/j.bmcl.2016.10.021 -
ChemMedChem May 2021A fragment-based drug-discovery approach was used on a pyrazoloadenine fragment library to uncover new molecules that target the RET (REarranged during Transfection)...
A fragment-based drug-discovery approach was used on a pyrazoloadenine fragment library to uncover new molecules that target the RET (REarranged during Transfection) oncoprotein, which is a driver oncoprotein in ∼2 % of non-small-cell lung cancers. The fragment library was screened against the RET kinase and LC-2/ad (RET-driven), KM-12 (TRKA-driven matched control) and A549 (cytotoxic control) cells to identify selective scaffolds that could inhibit RET-driven growth. An unsubstituted pyrazoloadenine fragment was found to be active on RET in a biochemical assay, but reduced cell viability in non-RET-driven cell lines (EC =1 and 3 μM, respectively). To increase selectivity for RET, the pyrazoloadenine was modeled in the RET active site, and two domains were identified that were probed with pyrazoloadenine fragment derivatives to improve RET affinity. Scaffolds at each domain were merged to generate a novel lead compound, 8 p, which exhibited improved activity and selectivity for the RET oncoprotein (A549 EC =5.92 μM, LC-2/ad EC =0.016 μM, RET IC =0.000326 μM).
Topics: Adenine; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Discovery; Humans; Molecular Structure; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-ret; Pyrazoles; Structure-Activity Relationship
PubMed: 33559353
DOI: 10.1002/cmdc.202100013 -
Bioorganic & Medicinal Chemistry Feb 2020The apelinergic system comprises the apelin receptor and its cognate apelin and elabela peptide ligands of various lengths. This system has become an increasingly...
The apelinergic system comprises the apelin receptor and its cognate apelin and elabela peptide ligands of various lengths. This system has become an increasingly attractive target for pulmonary and cardiometabolic diseases. Small molecule regulators of this receptor with good drug-like properties are needed. Recently, we discovered a novel pyrazole based small molecule agonist 8 of the apelin receptor (EC = 21.5 µM, K = 5.2 µM) through focused screening which was further optimized to initial lead 9 (EC = 0.800 µM, K = 1.3 µM). In our efforts to synthesize more potent agonists and to explore the structural features important for apelin receptor agonism, we carried out structural modifications at N1 of the pyrazole core as well as the amino acid side-chain of 9. Systematic modifications at these two positions provided potent small molecule agonists exhibiting EC values of <100 nM. Recruitment of β-arrestin as a measure of desensitization potential of select compounds was also investigated. Functional selectivity was a feature of several compounds with a bias towards calcium mobilization over β-arrestin recruitment. These compounds may be suitable as tools for in vivo studies of apelin receptor function.
Topics: Animals; Apelin Receptors; CHO Cells; Cricetulus; Dose-Response Relationship, Drug; Humans; Microsomes, Liver; Molecular Structure; Pyrazoles; Structure-Activity Relationship
PubMed: 31948845
DOI: 10.1016/j.bmc.2019.115237 -
Molecules (Basel, Switzerland) Jan 2019Three types of pyrazole-fused heterobicycles, i.e., 1,5-, 1,7-, and 2,5-dihydropyrano[3,2-]pyrazoles, were synthesized from 4-allyloxy-1-pyrazoles. A sequence of the...
Three types of pyrazole-fused heterobicycles, i.e., 1,5-, 1,7-, and 2,5-dihydropyrano[3,2-]pyrazoles, were synthesized from 4-allyloxy-1-pyrazoles. A sequence of the Claisen rearrangement of 4-allyloxy-1-pyrazoles, ruthenium-hydride-catalyzed double bond migration, -allylation, and ring-closing metathesis was employed in this study.
Topics: Catalysis; Chemistry Techniques, Synthetic; Molecular Structure; Pyrazoles; Ruthenium
PubMed: 30650589
DOI: 10.3390/molecules24020296 -
Scientific Reports Feb 2018Microtubules are highly dynamic structures that form spindle fibres during mitosis and are one of the most validated cancer targets. The success of drugs targeting...
Microtubules are highly dynamic structures that form spindle fibres during mitosis and are one of the most validated cancer targets. The success of drugs targeting microtubules, however, is often limited by the development of multidrug resistance. Here we describe the discovery and characterization of SSE15206, a pyrazolinethioamide derivative [3-phenyl-5-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide] that has potent antiproliferative activities in cancer cell lines of different origins and overcomes resistance to microtubule-targeting agents. Treatment of cells with SSE15206 causes aberrant mitosis resulting in G2/M arrest due to incomplete spindle formation, a phenotype often associated with drugs that interfere with microtubule dynamics. SSE15206 inhibits microtubule polymerization both in biochemical and cellular assays by binding to colchicine site in tubulin as shown by docking and competition studies. Prolonged treatment of cells with the compound results in apoptotic cell death [increased Poly (ADP-ribose) polymerase cleavage and Annexin V/PI staining] accompanied by p53 induction. More importantly, we demonstrate that SSE15206 is able to overcome resistance to chemotherapeutic drugs in different cancer cell lines including multidrug-resistant KB-V1 and A2780-Pac-Res cell lines overexpressing MDR-1, making it a promising hit for the lead optimization studies to target multidrug resistance.
Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Multiple; Drug Resistance, Neoplasm; G2 Phase Cell Cycle Checkpoints; Humans; Microtubules; Mitosis; Neoplasms; Pyrazoles
PubMed: 29459693
DOI: 10.1038/s41598-018-21642-0