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CNS & Neurological Disorders Drug... 2022As a source of therapeutic agents, heterocyclic nitrogen-containing compounds and their derivatives are still interesting and essential. Pyrazole, a five-member... (Review)
Review
As a source of therapeutic agents, heterocyclic nitrogen-containing compounds and their derivatives are still interesting and essential. Pyrazole, a five-member heteroaromatic ring with two nitrogen atoms, has a major impact in chemical industries as well as pharmaceutical industries. Due to its wide range of biological activities against various diseases, it has been identified as a biologically important heterocyclic scaffold. The treatment of neurological disorders has always been a difficult task in both the past and present. Therefore, identifying therapeutically effective molecules for neurological conditions remains an open challenge in biomedical research and development. For developing novel entities as neuroprotective agents, recently, pyrazole scaffold has attracted medicinal chemists worldwide. The major focus of research in this area is discovering novel molecules as neuroprotective agents with minimal adverse effects and better effectiveness in improving the neurological condition. This review mainly covers recent developments in the neuropharmacological role of pyrazole incorporated compounds, including their structural-activity relationship (SAR), which also further includes IC values (in mM as well as in μM), recent patents, and a brief history as neuroprotective agents.
Topics: Antineoplastic Agents; Neuroprotective Agents; Nitrogen; Pyrazoles; Structure-Activity Relationship
PubMed: 34080970
DOI: 10.2174/1871527320666210602152308 -
Journal of Agricultural and Food... Mar 2023As one of the essential herbicide targets, 4-hydroxyphenylpyruvate dioxygenase (HPPD) has recently been typically used to produce potent new herbicides. In continuation...
As one of the essential herbicide targets, 4-hydroxyphenylpyruvate dioxygenase (HPPD) has recently been typically used to produce potent new herbicides. In continuation with the previous work, several pyrazole derivatives comprising a benzoyl scaffold were designed and synthesized, and their inhibitory effects on hydroxyphenylpyruvate dioxygenase (AtHPPD) and herbicidal activities were comprehensively evaluated in this study. Compound showed top-rank inhibitory activity to AtHPPD with an half-maximal inhibitory concentration (IC) value of 0.05 μM, which was superior to topramezone (1.33 μM) and mesotrione (1.76 μM). Compound exhibited superior preemergence inhibitory activity against , with stem and root inhibition rates of 44.3 and 69.6%, respectively, compared to topramezone (16.0 and 53.0%) and mesotrione (12.8 and 41.7%). Compounds , , , and showed excellent postemergence herbicidal activities at a dosage of 150 g ai/ha, along with distinct bleaching symptoms and higher crop safety than topramezone and mesotrione, and they all were safe for maize, cotton, and wheat with injury rates of 0 or 10%. In addition, the molecular docking analysis also revealed that these compounds formed hydrophobic π-π interactions with Phe360 and Phe403 to AtHPPD. This study suggests that pyrazole derivatives containing a benzoyl scaffold could be used as new HPPD inhibitors to develop pre- and postemergence herbicides and be applied to additional crop fields.
Topics: 4-Hydroxyphenylpyruvate Dioxygenase; Molecular Docking Simulation; Pyrazoles; Arabidopsis; Herbicides
PubMed: 36848139
DOI: 10.1021/acs.jafc.2c07551 -
Archiv Der Pharmazie Nov 2023Herein, we report the design and synthesis of two series of pyrazole-tethered sulfamoyl phenyl acetamides and pyrazole-tethered sulfamoyl phenyl benzamides. The...
Herein, we report the design and synthesis of two series of pyrazole-tethered sulfamoyl phenyl acetamides and pyrazole-tethered sulfamoyl phenyl benzamides. The synthesized compounds were investigated for inhibiting two human carbonic anhydrases, human carbonic anhydrases (hCA) I and II, and those of the bacterial pathogen Mycobacterium tuberculosis, mtCA 1-3. The results indicate that, among the synthesized compounds, pyrazoles with 4-aminobenzene sulfonamide were more selective toward hCA I and II over mtCAs, and compounds with 3-aminobenzene sulfonamide were selective toward mtCA 1-3 over hCA I, II. Compound 6g showed significant and selective inhibition toward hCA I and II, with K values of 0.0366 and 0.0310 µM, respectively. Compound 5g exhibited the best inhibition toward mtCA 2, with a K value of 0.0617 µM. Among the benzamides, compound 9b exhibited significant activity toward mtCA 2, with a K value of 0.0696 µM. Selectivity of these compounds was further supported by docking studies. When tested for antitubercular activity, many compounds showed moderate to good inhibition against the Mtb H37Rv strain, with minimum inhibitory concentration (MIC) values in the range of 4-128 µg/mL.
Topics: Humans; Carbonic Anhydrase Inhibitors; Structure-Activity Relationship; Carbonic Anhydrase II; Carbonic Anhydrases; Pyrazoles; Carbonic Anhydrase I; Sulfonamides; Benzamides; Molecular Structure
PubMed: 37691073
DOI: 10.1002/ardp.202300309 -
Molecules (Basel, Switzerland) Sep 2020The synthesis of FcC(O)CH(R)C(O)Fc (Fc = Fe(η-CH)(η-CH); R = H, ; Bu, ; CHCH(OCHCH)OMe, ), [M(κ,'-FcC(O)CHC(O)Fc)] (M = Ti, = 3, ; M = Fe, = 3, ; M = BF, = 1, ),...
The synthesis of FcC(O)CH(R)C(O)Fc (Fc = Fe(η-CH)(η-CH); R = H, ; Bu, ; CHCH(OCHCH)OMe, ), [M(κ,'-FcC(O)CHC(O)Fc)] (M = Ti, = 3, ; M = Fe, = 3, ; M = BF, = 1, ), and 1-R'-3,5-Fc-CHN (R' = H, ; Me, ; Ph, ) is discussed. The solid-state structures of , , , , , , and ([TiCl(κ,'-PhC(O)CHC(O)Ph)]) show that and exist in their β-diketo form. Compound crystallizes as a tetramer based on a hydrogen bond pattern, including one central water molecule. The electrochemical behavior of - and - was studied by cyclic and square-wave voltammetry, showing that the ferrocenyls can separately be oxidized reversibly between -50 and 750 mV (-, , -: two Fc-related events; , : six events, being partially superimposed). For complex , Ti-centered reversible redox processes appear at -985 (Ti/Ti) and -520 mV (Ti/Ti). Spectro-electrochemical UV-Vis/NIR measurements were carried out on , and , whereby only showed an IVCT (intervalence charge-transfer) band of considerable strength ( = 6250 cm, = 4725 cm, = 240 L·mol·cm), due to the rigid COB cycle, enlarging the coupling strength between the Fc groups.
Topics: Electrochemistry; Hydrogen Bonding; Ketones; Molecular Conformation; Pyrazoles; Spectrophotometry, Ultraviolet; Spectroscopy, Near-Infrared
PubMed: 33003450
DOI: 10.3390/molecules25194476 -
European Journal of Medicinal Chemistry Sep 2019Mutated adenomatous polyposis coli (APC) selectively combining with Asef has been reported to be implicated in promoting colon cancer proliferation, invasion and... (Review)
Review
Mutated adenomatous polyposis coli (APC) selectively combining with Asef has been reported to be implicated in promoting colon cancer proliferation, invasion and metastasis in several cancer biotherapy studies. However, there were universally resistance and harsh terms in disrupting APC-Asef interaction in biotherapy. Under the circumstances small-molecule inhibitors as the new APC interface could resolve the problems. In this research, a series of novel dihydropyrazole derivatives containing morpholine as high potent interaction inhibitors between APC and Asef were first synthesized after selection by means of docking simulation and virtual screening. Afterwards they were evaluated interaction inhibition of APC-Asef and pharmacological efficiency both in vitro and in vivo utilizing orthotopic transplantation model with multi-angle of view. Among them, compound 7g exhibited most excellent anti-proliferation activities against HCT116 cells with IC of 0.10 ± 0.01 μM than Regorafenib (IC = 0.16 ± 0.04 μM). The results favored our rational design intention and provides a new class of small-molecule inhibitors available for the development of colon tumor therapeutics targeting APC-Asef interaction inhibitions.
Topics: Adenomatous Polyposis Coli Protein; Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Female; Humans; Mice, Inbred BALB C; Mice, Nude; Molecular Docking Simulation; Morpholines; Neoplasm Transplantation; Protein Binding; Pyrazoles; Rho Guanine Nucleotide Exchange Factors; Structure-Activity Relationship; Thermodynamics; Xenograft Model Antitumor Assays
PubMed: 31158755
DOI: 10.1016/j.ejmech.2019.05.056 -
International Journal of Pharmaceutics Apr 2021Uncontrolled cell proliferation is a hallmark of cancer as a result of rapid and deregulated progression through the cell cycle. The inhibition of cyclin-dependent...
Uncontrolled cell proliferation is a hallmark of cancer as a result of rapid and deregulated progression through the cell cycle. The inhibition of cyclin-dependent kinases (CDKs) activities is a promising therapeutic strategy to block cell cycle of tumor cells. In this work we reported a new example of nanocomposites based on halloysite nanotubes (HNTs)/pyrazolo[3,4-d]pyrimidine derivatives (Si306 and Si113) as anticancer agents and CDK inhibitors. HNTs/Si306 and HNTs/Si113 nanocomposites were synthesized and characterized. The release kinetics were also investigated. Antitumoral activity was evaluated on three cancer cell lines (HeLa, MDA-MB-231 and HCT116) and the effects on cell cycle arrest in HCT116 cells were evaluated. Finally, molecular dynamics simulations were performed of the complexes between Si113 or Si306 and the active site of both CDK 1 and 2.
Topics: Cell Cycle Checkpoints; Cell Line, Tumor; Clay; Humans; Pyrazoles; Pyrimidines
PubMed: 33524522
DOI: 10.1016/j.ijpharm.2021.120281 -
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 -
Journal of Agricultural and Food... Sep 2022Dimpropyridaz is a pyrazole carboxamide insecticide with a novel mode of action, currently under worldwide development by BASF, providing excellent activity against...
Dimpropyridaz is a pyrazole carboxamide insecticide with a novel mode of action, currently under worldwide development by BASF, providing excellent activity against sucking pests. A series of dimpropyridaz analogues were designed to investigate the impact of bioisosteric heterocyclic replacements on the biological activity and molecular properties. Focus was given to prepare analogues where the 4-pyridazinyl moiety was replaced by 5-pyrimidinyl, 2-pyrimidinyl, 3-pyridazinyl, and 2-pyrazinyl groups. Five different synthetic routes were developed for the preparation of these analogues, delivering the target compounds in moderate to good yields. We explained some aspects of the observed structure-activity relationship by a density functional theory (DFT) calculation and DFT-derived Multiwfn and VMD program models. These findings provide first insights into the important role of the 4-pyridazinyl heterocyclic moiety in the pyrazole carboxamide insecticide chemical class and the mechanism of action of dimpropyridaz.
Topics: Insecticides; Molecular Structure; Pyrazoles; Structure-Activity Relationship
PubMed: 35412307
DOI: 10.1021/acs.jafc.2c00636 -
Scientific Reports May 2023Catalpol, a natural product mainly existed in plenty of Chinese traditional medicines, is an iridoid compound with the comprehensive effects on neuroprotective,...
Catalpol, a natural product mainly existed in plenty of Chinese traditional medicines, is an iridoid compound with the comprehensive effects on neuroprotective, anti-inflammatory, choleretic, hypoglycemic and anticancer. However, there are some disadvantages for catalpol such as a short half-life in vivo, low druggability, stingy binding efficiency to target proteins and so on. It is necessary to make structural modification and optimization which enhance its performance on disease treatments and clinic applications. Pyrazole compounds have been reported to have excellent anticancer activities. Based on the previous research foundation of our research group on iridoids and the anticancer activities of catalpol and pyrazole, a series of pyrazole modified catalpol compounds were synthesized by principle of drug combination for serving as potential cancer inhibitors. These derivatives are characterized by H NMR, C NMR and HRMS. The efficacy of anti-esophageal cancer and anti-pancreatic cancer activities were evaluated by the MTT assay on two esophageal cancer cells Eca-109 and EC-9706, and two pancreatic cancer cells PANC-1, BxPC-3 and normal pancreatic cell line HPDE6-C7, which showed that the compound 3e had strong inhibitory activity against esophageal cancer cells, this providing a theoretical basis for the discovery of catalpol-containing drugs.
Topics: Humans; Iridoid Glucosides; Neoplasms; Cell Line; Pyrazoles
PubMed: 37173367
DOI: 10.1038/s41598-023-33403-9 -
European Journal of Medicinal Chemistry Dec 2023This study aimed to design potent carbonic anhydrase inhibitors (CAIs) based on pyrazole benzenesulfonamide core. Nine series of substituted pyrazole benzenesulfonamide...
This study aimed to design potent carbonic anhydrase inhibitors (CAIs) based on pyrazole benzenesulfonamide core. Nine series of substituted pyrazole benzenesulfonamide compounds were synthesized with variable groups like sulphamoyl group as in compounds 4a-e, its bioisosteric carboxylic acid as in compounds 5a-e and 8e, ethyl carboxylate ester as in compounds 6a-e and 9a-e, which were designed as potential prodrugs, isothiazole ring as in compound 7, hydrazide derivative 10e, hydroxamic acid derivatives 11a-e and semicarbazide derivatives 12a-c,e. All the synthesized compounds were investigated for their carbonic anhydrase (CA) inhibitory activity against two human CA isoforms hCA IX and hCA XII and compared to acetazolamide (AAZ). Also, the compounds were assessed for their anticancer activity against 60 cancer cell lines according to the US NCI protocol. Compounds 4b, 5b, 5d, 5e, 6b, 9b, 9e and 11b revealed significant inhibitory activity against both isoforms hCA IX and hCA XII, while 6e, 9d, 11d and 11e showed significant inhibitory activity against hCA XII only compared to acetazolamide as a reference. This would highlight these compounds as promising anticancer drugs. Moreover, compound 6e revealed a remarkable cytostatic activity against CNS cancer cell line (SF-539; TGI = 5.58 μM), renal cancer cell line (786-0; TGI = 4.32 μM) and breast cancer cell line (HS 578 T; TGI = 5.43 μM). Accordingly, compound 6e was subjected to cell cycle analysis and apoptotic assay on the abovementioned cell lines at the specified GI (0.45, 0.89 and 1.18 μM, respectively). Also, it revealed the increment of total apoptotic cells percentage in 786-0 (53.19%), SF-539 (46.11%) and HS 578 T (43.55%) relative to the control cells (2.07, 2.64 and 2.52%, respectively). In silico prediction of BBB permeability showed that most of the calculations for compound 6e resulted as BBB (+), which is required for a compound targeting CNS. Further, the interaction of the most active compounds with the key amino acids in the active sites of hCA IX and hCA XII was highlighted by molecular docking analysis.
Topics: Humans; Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Molecular Docking Simulation; Structure-Activity Relationship; Acetazolamide; Carbonic Anhydrase IX; Protein Isoforms; Pyrazoles; Molecular Structure; Benzenesulfonamides
PubMed: 37748386
DOI: 10.1016/j.ejmech.2023.115805