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Molecules (Basel, Switzerland) Aug 2021Pyrazoles are considered privileged scaffolds in medicinal chemistry. Previous reviews have discussed the importance of pyrazoles and their biological activities;... (Review)
Review
Pyrazoles are considered privileged scaffolds in medicinal chemistry. Previous reviews have discussed the importance of pyrazoles and their biological activities; however, few have dealt with the chemistry and the biology of heteroannulated derivatives. Therefore, we focused our attention on recent topics, up until 2020, for the synthesis of pyrazoles, their heteroannulated derivatives, and their applications as biologically active moieties. Moreover, we focused on traditional procedures used in the synthesis of pyrazoles.
Topics: Chemistry Techniques, Synthetic; Humans; Pyrazoles
PubMed: 34443583
DOI: 10.3390/molecules26164995 -
Scientific Reports Mar 2020Bipyrazone, 1,3-dimethyl-4-(2-(methylsulfonyl)-4-(trifluoromethyl) benzoyl)-1H-pyrazol-5-yl 1,3-dimethyl-1H-pyrazole- 4-carboxylate, is a 4-hydroxyphenylpyaunate...
Bipyrazone, 1,3-dimethyl-4-(2-(methylsulfonyl)-4-(trifluoromethyl) benzoyl)-1H-pyrazol-5-yl 1,3-dimethyl-1H-pyrazole- 4-carboxylate, is a 4-hydroxyphenylpyaunate dioxygenase (HPPD)-inhibiting herbicide. Greenhouse and field experiments were conducted to explore the potential of post-emergence (POST) application of bipyrazone in wheat fields in China. In the greenhouse study, bipyrazone at 10 and 20 g active ingredient (a.i.) ha effectively controlled Descurainia sophia L., Capsella bursa-pastoris (L.) Medic., Lithospermum arvense L. and Myosoton aquaticum L. Whereas, all tested 16 wheat cultivars showed high degree of tolerance to bipyrazone at 375 and 750 g a.i. ha. In a dose-response experiment carried on the Shannong 6 wheat cultivar and five weed biotypes, bipyrazone was safe to the wheat cultivar, and C. bursa-pastoris, M. aquaticum and D. sophia were sensitive to this herbicide. The selectivity index (SI) between the Shannong 6 and weeds ranged from 34 to 39. The field experiments confirmed that a mixture of bipyrazone and fluroxypyr-mepthyl is practical for controlling broadleaf weeds, and bipyrazone applied alone at 30 to 40 g a.i. ha can also provide satisfactory control of sensitive broadleaf weeds. These findings suggest that bipyrazone POST application has good potential for broadleaf weed management in wheat fields.
Topics: 4-Hydroxyphenylpyruvate Dioxygenase; Crops, Agricultural; Greenhouse Effect; Herbicide Resistance; Herbicides; Molecular Structure; Plant Proteins; Plant Weeds; Pyrazoles; Triticum
PubMed: 32218463
DOI: 10.1038/s41598-020-62116-6 -
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 -
International Journal of Molecular... Oct 2023A variety of ribo-, 2'-deoxyribo-, and 5'-norcarbocyclic derivatives of the 8-aza-7-deazahypoxanthine fleximer scaffolds were designed, synthesized, and screened for...
A variety of ribo-, 2'-deoxyribo-, and 5'-norcarbocyclic derivatives of the 8-aza-7-deazahypoxanthine fleximer scaffolds were designed, synthesized, and screened for antibacterial activity. Both chemical and chemoenzymatic methods of synthesis for the 8-aza-7-deazainosine fleximers were compared. In the case of the 8-aza-7-deazahypoxanthine fleximer, the transglycosylation reaction proceeded with the formation of side products. In the case of the protected fleximer base, 1-(4-benzyloxypyrimidin-5-yl)pyrazole, the reaction proceeded selectively with formation of only one product. However, both synthetic routes to realize the fleximer ribonucleoside () worked with equal efficiency. The new compounds, as well as some 8-aza-7-deazapurine nucleosides synthesized previously, were studied against Gram-positive and Gram-negative bacteria and . It was shown that 1-(β-D-ribofuranosyl)-4-(2-aminopyridin-3-yl)pyrazole () and 1-(2',3',4'-trihydroxycyclopent-1'-yl)-4-(pyrimidin-4(3H)-on-5-yl)pyrazole () were able to inhibit the growth of mc2 155 by 99% at concentrations (MIC) of 50 and 13 µg/mL, respectively. Antimycobacterial activities were revealed for 4-(4-aminopyridin-3-yl)-1H-pyrazol () and 1-(4'-hydroxy-2'-cyclopenten-1'-yl)-4-(4-benzyloxypyrimidin-5-yl)pyrazole (). At concentrations (MIC) of 40 and 20 µg/mL, respectively, the compounds resulted in 99% inhibition of growth.
Topics: Humans; Anti-Bacterial Agents; Nucleosides; Gram-Negative Bacteria; Gram-Positive Bacteria; Mycobacterium tuberculosis; Tuberculosis; Pyrazoles; Microbial Sensitivity Tests; Structure-Activity Relationship
PubMed: 37895100
DOI: 10.3390/ijms242015421 -
Journal of Alzheimer's Disease : JAD 2018Generation of amyloid-β peptides (Aβs) by proteolytic cleavage of the amyloid-β protein precursor (AβPP), especially increased production of Aβ42/Aβ43 over Aβ40,...
Generation of amyloid-β peptides (Aβs) by proteolytic cleavage of the amyloid-β protein precursor (AβPP), especially increased production of Aβ42/Aβ43 over Aβ40, and their aggregation as oligomers and plaques, represent a characteristic feature of Alzheimer's disease (AD). In familial AD (FAD), altered Aβ production originates from specific mutations of AβPP or presenilins 1/2 (PS1/PS2), the catalytic subunits of γ-secretase. In sporadic AD, the origin of altered production of Aβs remains unknown. We hypothesize that the 'human chemical exposome' contains products able to favor the production of Aβ42/Aβ43 over Aβ40 and shorter Aβs. To detect such products, we screened a library of 3500 + compounds in a cell-based assay for enhanced Aβ42/Aβ43 production. Nine pyrazole insecticides were found to induce a β- and γ-secretase-dependent, 3-10-fold increase in the production of extracellular Aβ42 in various cell lines and neurons differentiated from induced pluripotent stem cells derived from healthy and FAD patients. Immunoprecipitation/mass spectrometry analyses showed increased production of Aβs cleaved at positions 42/43, and reduced production of peptides cleaved at positions 38 and shorter. Strongly supporting a direct effect on γ-secretase activity, pyrazoles shifted the cleavage pattern of another γ-secretase substrate, alcadeinα, and shifted the cleavage of AβPP by highly purified γ-secretase toward Aβ42/Aβ43. Focusing on fipronil, we showed that some of its metabolites, in particular the persistent fipronil sulfone, also favor the production of Aβ42/Aβ43 in both cell-based and cell-free systems. Fipronil administered orally to mice and rats is known to be metabolized rapidly, mostly to fipronil sulfone, which stably accumulates in adipose tissue and brain. In conclusion, several widely used pyrazole insecticides enhance the production of toxic, aggregation prone Aβ42/Aβ43 peptides, suggesting the possible existence of environmental "Alzheimerogens" which may contribute to the initiation and propagation of the amyloidogenic process in sporadic AD.
Topics: Adipose Tissue; Alzheimer Disease; Amyloid Precursor Protein Secretases; Amyloid beta-Peptides; Animals; Brain; Environmental Exposure; HEK293 Cells; Humans; Induced Pluripotent Stem Cells; Insecticides; Mice; Neurons; Peptide Fragments; Proteome; Pyrazoles; Rats
PubMed: 29504531
DOI: 10.3233/JAD-170875 -
Asian Pacific Journal of Cancer... Jul 2021Triple-negative breast cancer accounts for approximately 15-20% of all breast carcinomas and is associated with earlier age of onset, aggressive clinical course, and...
BACKGROUND
Triple-negative breast cancer accounts for approximately 15-20% of all breast carcinomas and is associated with earlier age of onset, aggressive clinical course, and dismal prognosis. A series of 1,3-diaryl-5-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1 H-Pyrazole and 1,3-diaryl-5- (3,4,5-trimethoxyphenyl)- 1 H-Pyrazole were evaluated for their anticancer activity against MDA-MB-468, human triple negative breast cancer cell line.
METHODS
The cytotoxic effects of Pyrazole derivatives on the growth of MDA-MB-468 and AGO1522 were determined using MTT assay. Annexin-V-FITC and PI staining were performed to detect apoptosis and cell cycle distribution using Flow cytometry. The level of Reactive oxygen species (ROS) formation and caspase 3 activity were determined accordingly.
RESULTS
Pyrazole derivatives induced a dose and time-dependent cell toxicity in MDA-MB-468 compared with untreated cells. The results showed that 3-(4-methoxyphenyl)-1-(p-tolyl)-5-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-Pyrazole (3f) was the most active compound with IC50 values 14.97 μM and 6.45 μM compared with Paclitaxel with IC50 values 49.90 μM and 25.19 μM, after 24 and 48 hours, respectively. Upon treatment with 14.97 μM of 3f after 24 h, the compound induced cell cycle arrest in S phase. 3f provoked apoptosis was accompanied by the elevated level of ROS and increased caspase 3 activity in MDA-MB-468 cells compared with untreated cells.
CONCLUSION
The overall results of the present study provided evidence for the cytotoxicity of compound 3f against MDA-MB-468 cells in comparison to reference standard, Paclitaxel. It proves that compound 3f can trigger apoptosis through ROS production and caspase 3 activation. These bring supportive data for future investigations that will lead to their use in cancer therapy.
.Topics: Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Humans; Paclitaxel; Pyrazoles; Reactive Oxygen Species; Triple Negative Breast Neoplasms
PubMed: 34319030
DOI: 10.31557/APJCP.2021.22.7.2079 -
Molecules (Basel, Switzerland) May 2024Chronic inflammation contributes to a number of diseases. Therefore, control of the inflammatory response is an important therapeutic goal. To identify novel...
Chronic inflammation contributes to a number of diseases. Therefore, control of the inflammatory response is an important therapeutic goal. To identify novel anti-inflammatory compounds, we synthesized and screened a library of 80 pyrazolo[1,5-]quinazoline compounds and related derivatives. Screening of these compounds for their ability to inhibit lipopolysaccharide (LPS)-induced nuclear factor κB (NF-κB) transcriptional activity in human THP-1Blue monocytic cells identified 13 compounds with anti-inflammatory activity (IC < 50 µM) in a cell-based test system, with two of the most potent being compounds (5-[(4-sulfamoylbenzyl)oxy]pyrazolo[1,5-]quinazoline-3-carboxamide) and (5-[(4-(methylsulfinyl)benzyloxy]pyrazolo[1,5-]quinazoline-3-carboxamide). Pharmacophore mapping of potential targets predicted that and may be ligands for three mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase 2 (ERK2), p38α, and -Jun -terminal kinase 3 (JNK3). Indeed, molecular modeling supported that these compounds could effectively bind to ERK2, p38α, and JNK3, with the highest complementarity to JNK3. The key residues of JNK3 important for this binding were identified. Moreover, compounds and exhibited micromolar binding affinities for JNK1, JNK2, and JNK3. Thus, our results demonstrate the potential for developing lead anti-inflammatory drugs based on the pyrazolo[1,5-]quinazoline and related scaffolds that are targeted toward MAPKs.
Topics: Humans; Quinazolines; Anti-Inflammatory Agents; NF-kappa B; Lipopolysaccharides; Molecular Docking Simulation; Pyrazoles; Structure-Activity Relationship; THP-1 Cells
PubMed: 38893295
DOI: 10.3390/molecules29112421 -
British Journal of Cancer Jan 2020Cancer metabolism has undergone a resurgence in the last decade, 70 years after Warburg described aerobic glycolysis as a feature of cancer cells. A wide range of...
Cancer metabolism has undergone a resurgence in the last decade, 70 years after Warburg described aerobic glycolysis as a feature of cancer cells. A wide range of techniques have elucidated the complexity and heterogeneity in preclinical models and clinical studies. What emerges are the large differences between tissues, tumour types and intratumour heterogeneity. However, synergies with inhibition of metabolic pathways have been found for many drugs and therapeutic approaches, and a critical role of window studies and translational trial design is key to success.
Topics: Animals; Azetidines; Biomarkers, Tumor; Clinical Trials as Topic; Drug Therapy, Combination; Fatty Acid Synthase, Type I; Fatty Acids; Glycolysis; Humans; Mice; Molecular Targeted Therapy; Neoplasms; Nitriles; Pyrazoles; Signal Transduction
PubMed: 31819198
DOI: 10.1038/s41416-019-0666-4 -
Molecules (Basel, Switzerland) Jul 2023The altered activation or overexpression of protein kinases (PKs) is a major subject of research in oncology and their inhibition using small molecules, protein kinases... (Review)
Review
The altered activation or overexpression of protein kinases (PKs) is a major subject of research in oncology and their inhibition using small molecules, protein kinases inhibitors (PKI) is the best available option for the cure of cancer. The pyrazole ring is extensively employed in the field of medicinal chemistry and drug development strategies, playing a vital role as a fundamental framework in the structure of various PKIs. This scaffold holds major importance and is considered a privileged structure based on its synthetic accessibility, drug-like properties, and its versatile bioisosteric replacement function. It has proven to play a key role in many PKI, such as the inhibitors of Akt, Aurora kinases, MAPK, B-raf, JAK, Bcr-Abl, c-Met, PDGFR, FGFRT, and RET. Of the 74 small molecule PKI approved by the US FDA, 8 contain a pyrazole ring: Avapritinib, Asciminib, Crizotinib, Encorafenib, Erdafitinib, Pralsetinib, Pirtobrutinib, and Ruxolitinib. The focus of this review is on the importance of the unfused pyrazole ring within the clinically tested PKI and on the additional required elements of their chemical structures. Related important pyrazole fused scaffolds like indazole, pyrrolo[1,2-b]pyrazole, pyrazolo[4,3-b]pyridine, pyrazolo[1,5-a]pyrimidine, or pyrazolo[3,4-d]pyrimidine are beyond the subject of this work.
Topics: Pyrazoles; Protein Kinase Inhibitors; Antineoplastic Agents; Drug Design; Structure-Activity Relationship; Humans; Animals
PubMed: 37513232
DOI: 10.3390/molecules28145359 -
Cellular & Molecular Biology Letters Dec 2021Esterase D (ESD) is a nonspecific esterase that detoxifies formaldehyde. Many reports have stated that ESD activity is associated with a variety of physiological and...
BACKGROUND
Esterase D (ESD) is a nonspecific esterase that detoxifies formaldehyde. Many reports have stated that ESD activity is associated with a variety of physiological and pathological processes. However, the detailed signaling pathway of ESD remains poorly understood.
METHODS
Considering the advantages of the small chemical molecule, our recent work demonstrated that 4-chloro-2-(5-phenyl-1-(pyridin-2-yl)-4,5-dihydro-1H-pyrazol-3-yl) phenol (FPD5) activates ESD, and will be a good tool for studying ESD further. Firstly, we determined the interaction between ESD and FK506 binding protein 25 (FKBP25) by yeast two-hybrid assay and co-immunoprecipitation (CO-IP) and analyzed the phosphorylation levels of mTORC1, P70S6K and 4EBP1 by western blot. Furthermore, we used the sulforhodamine B (SRB) and chick chorioallantoic membrane (CAM) assay to analyze cell viability in vitro and in vivo after treatment with ESD activator FPD5.
RESULTS
We screened FKBP25 as a candidate protein to interact with ESD by yeast two-hybrid assay. Then we verified the interaction between ESD and endogenous FKBP25 or ectopically expressed GFP-FKBP25 by CO-IP. Moreover, the N-terminus (1-90 aa) domain of FKBP25 served as the crucial element for their interaction. More importantly, ESD reduced the K48-linked poly-ubiquitin chains of FKBP25 and thus stabilized cytoplasmic FKBP25. ESD also promoted FKBP25 to bind more mTORC1, suppressing the activity of mTORC1. In addition, ESD suppressed tumor cell growth in vitro and in vivo through autophagy.
CONCLUSIONS
These findings provide novel evidence for elucidating the molecular mechanism of ESD and ubiquitination of FKBP25 to regulate autophagy and cancer cell growth. The ESD/FKBP25/mTORC1 signaling pathway is involved in inhibiting tumor cell growth via regulating autophagy.
Topics: Animals; Autophagy; Cell Cycle; Cell Line; Cell Line, Tumor; Chickens; HEK293 Cells; HeLa Cells; Humans; Mechanistic Target of Rapamycin Complex 1; Phosphorylation; Pyrazoles; Signal Transduction; Tacrolimus; Tacrolimus Binding Proteins; Thiolester Hydrolases; Ubiquitination
PubMed: 34875997
DOI: 10.1186/s11658-021-00297-2