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Bioorganic & Medicinal Chemistry Feb 2023Deregulation of cyclin-dependent kinase 2 (CDK2) and its activating partners, cyclins A and E, is associated with the pathogenesis of a myriad of human cancers and with...
Deregulation of cyclin-dependent kinase 2 (CDK2) and its activating partners, cyclins A and E, is associated with the pathogenesis of a myriad of human cancers and with resistance to anticancer drugs including CDK4/6 inhibitors. Thus, CDK2 has become an attractive target for the development of new anticancer therapies and for the amelioration of the resistance to CDK4/6 inhibitors. Bioisosteric replacement of the thiazole moiety of CDKI-73, a clinically trialled CDK inhibitor, by a pyrazole group afforded 9 and 19 that displayed potent CDK2-cyclin E inhibition (K = 0.023 and 0.001 μM, respectively) with submicromolar antiproliferative activity against a panel of cancer cell lines (GI = 0.025-0.780 μM). Mechanistic studies on 19 with HCT-116 colorectal cancer cells revealed that the compound reduced the phosphorylation of retinoblastoma at Ser807/811, arrested the cells at the G2/M phase, and induced apoptosis. These results highlight the potential of the 2-anilino-4-(1-methyl-1H-pyrazol-4-yl)pyrimidine series in developing potent and selective CDK2 inhibitors to combat cancer.
Topics: Humans; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinases; Antineoplastic Agents; Neoplasms; Pyrimidines; Pyrazoles
PubMed: 36706608
DOI: 10.1016/j.bmc.2023.117158 -
Archiv Der Pharmazie Feb 2020Hsp90, as a key molecular chaperone, plays an important role in modulating the activity of many cell signaling proteins and is an attractive target for anticancer...
Hsp90, as a key molecular chaperone, plays an important role in modulating the activity of many cell signaling proteins and is an attractive target for anticancer therapeutics. Herein, we report the discovery of N-pyridoyl-Δ -pyrazoline analogs as novel Hsp90 inhibitors by integrated approaches of drug design, organic synthesis, cell biology, and qualitative proteomic analysis. Novel chemical compounds were designed and optimized in the adenosine triphosphate-binding site of Hsp90; lead optimized compounds were found to have significant interactions with Asp93 and other amino acids crucial for Hsp90 inhibition. The designed compounds were synthesized by a two-step procedure; different aromatic aldehydes were reacted with various acetophenones to form substituted 1,3-diphenyl-prop-2-enones (Ic-Io), which upon reaction with isonicotinic acid hydrazide in the presence of glacial acetic acid form N-pyridoyl-Δ -pyrazoline compounds (PY1-PY13). Compounds PY3, PY2, and PY1 were identified as potential leads amongst the series, with promising anticancer activity against human breast cancer and melanoma cells, and the ability to inhibit Hsp90 similar to radicicol by drug-affinity responsive target stability proteomic analysis in a whole-cell assay.
Topics: Antineoplastic Agents; Cell Proliferation; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; HSP90 Heat-Shock Proteins; Humans; Models, Molecular; Molecular Structure; Pyrazoles; Small Molecule Libraries; Structure-Activity Relationship; Tumor Cells, Cultured
PubMed: 31808979
DOI: 10.1002/ardp.201900192 -
Bioorganic Chemistry Mar 2023Tertiary phosphine oxides, phosphine sulfides, and phosphine selenides containing pyridine, imidazole, and pyrazole groups have been synthesized via the reaction of...
Tertiary phosphine oxides, phosphine sulfides, and phosphine selenides containing pyridine, imidazole, and pyrazole groups have been synthesized via the reaction of elemental phosphorus or secondary phosphine oxides with functional pyridines, imidazoles, and pyrazoles. Alkyl tris(2-pyridylethyl)phosphonium iodide and bromide are also obtained by quaternization of the corresponding phosphine. Antimicrobial activity of the synthesized compounds, including nitrogen-containing heterocycles, phosphorus, selenium, and sulfur, with respect to Enterococcus durans, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa microorganisms is evaluated. It is found that phosphine chalcogenides bearing imidazole (14, 19), pyrazole (13), and pyridine fragments (5, 9) and phosphonium salts (11, 12) can be considered as new promising antibacterial agents. For some synthesized compounds, LC is determined. Phosphine oxide with methylpyrazole fragments (13) and phosphonium salts (11, 12) show strong profile of antimicrobial activity, and cytotoxic effect of phosphonium bromide having a long chain radical (12) is by order of magnitude higher than that of cisplatin. We believe that the results obtained may contribute to the development of highly effective agents for the treatment and prevention of bacterial infections and cancers.
Topics: Cytostatic Agents; Phosphorus; Bromides; Salts; Anti-Infective Agents; Anti-Bacterial Agents; Pyrazoles; Pyridines; Imidazoles; Oxides; Microbial Sensitivity Tests
PubMed: 36702003
DOI: 10.1016/j.bioorg.2023.106363 -
European Journal of Pharmaceutical... Jan 2022The development of new COX-2 inhibitors with analgesic and anti-inflammatory efficacy as well as minimal gastrointestinal, renal and cardiovascular toxicity, is of vital...
The development of new COX-2 inhibitors with analgesic and anti-inflammatory efficacy as well as minimal gastrointestinal, renal and cardiovascular toxicity, is of vital importance to patients suffering from chronic course pain and inflammatory conditions. This study aims at evaluating the therapeutic activity and adverse drug reactions associated with the use of the newly synthesized pyrazole derivative, compound AD732, E-4-[3-(4-methylphenyl)-5-hydroxyliminomethyl-1H-pyrazol-1-yl]benzenesulfonamide, as compared to indomethacin and celecoxib as standard agents. Anti-inflammatory activity was assessed using carrageenan-induced rat paw edema and cotton pellet granuloma tests; formalin-induced hyperalgesia and hot plate tests were done to study analgesic activity. In vitro tests to determine COX-1/COX-2 selectivity and assessment of renal and gastric toxicity upon acute exposure to AD732 were also conducted. Compound AD732 exhibited promising results; higher anti-inflammatory and analgesic effects compared to standard agents, coupled with the absence of ulcerogenic effects and minimal detrimental effects on renal function. Additionally, compound AD732 was a less potent inhibitor of COX-2 in vitro than celecoxib, which may indicate lower potential cardiovascular toxicity. It may be concluded that compound AD732 appears to be a safer and more effective molecule with promising potential for the management of pain and inflammation.
Topics: Analgesics; Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Edema; Pyrazoles; Rats; Rats, Wistar
PubMed: 34818572
DOI: 10.1016/j.ejps.2021.106080 -
Journal of Biomolecular Structure &... 2022A new pyrazole-tethered thiazolidine-2,4-dione derivative () has been synthesized by the Knoevenagel condensation of 3-(4-nitrophenyl)-1-phenyl-1-pyrazole-4-carbaldehyde...
A new pyrazole-tethered thiazolidine-2,4-dione derivative () has been synthesized by the Knoevenagel condensation of 3-(4-nitrophenyl)-1-phenyl-1-pyrazole-4-carbaldehyde () and 3-(2,4-dioxothiazolidin-3-yl)propanenitrile (). The structure of the final compound was confirmed by standard spectroscopic techniques including IR spectroscopy, H-NMR spectroscopy, and ESI-MS mass spectrometry. Molecular features including frontier molecular orbital (HOMO-LUMO) energies, reactivity descriptors and molecular electrostatic potential (ESP) of the title molecule were determined using density functional theory (DFT) calculation. The cytotoxicity of both the intermediate () and final () compounds were investigated against cancerous (SW-480 and MCF-7) and normal (HEK-293) cell lines by MTT assay. Compound () displayed higher activity than () with higher sensitivity against breast cancer cell line and lesser toxicity. The experimental data were further complemented by docking and absorption, distribution, metabolism, and excretion (ADME) studies.Communicated by Ramaswamy H. Sarma.
Topics: Humans; Molecular Docking Simulation; HEK293 Cells; Pyrazoles; Chemical Phenomena
PubMed: 34551668
DOI: 10.1080/07391102.2021.1981451 -
Journal of Agricultural and Food... Jun 20224-Hydroxyphenylpyruvate dioxygenase (HPPD) is an important target for the development of new herbicides. HPPD inhibitors can hinder photosynthesis and induce weed death...
4-Hydroxyphenylpyruvate dioxygenase (HPPD) is an important target for the development of new herbicides. HPPD inhibitors can hinder photosynthesis and induce weed death with bleaching symptoms. To explore the novel skeleton of HPPD inhibitors, a series of novel pyrazole amide derivatives were synthesized and evaluated for their inhibitory effects on HPPD (HPPD) and herbicidal activities. Some compounds had excellent inhibitory activities against HPPD. Among them, compound displayed top-rank inhibitory activity against HPPD with an IC value of 0.04 μM, which was obviously superior to that of topramezone (IC value of 0.11 μM). Furthermore, compounds and had 100% herbicidal activities in Petri dish assays against and at 100 μg/mL. In particular, compound not only possessed strong HPPD inhibitory activity but also exhibited significant preemergence herbicidal activity. However, compound was completely harmless to soybean, cotton, and wheat. In addition, the molecular docking and microscale thermophoresis measurement experiment verified that compounds can bind well with HPPD π-π interactions. The present work provides a new approach for the rational design of more effective HPPD inhibitors, and pyrazole amides could be used as useful substructures for the development of new HPPD inhibitors and preemergence herbicidal agents.
Topics: 4-Hydroxyphenylpyruvate Dioxygenase; Amides; Arabidopsis; Enzyme Inhibitors; Herbicides; Molecular Docking Simulation; Molecular Structure; Pyrazoles; Structure-Activity Relationship
PubMed: 35687877
DOI: 10.1021/acs.jafc.2c02123 -
Archiv Der Pharmazie May 2023The α-glucosidase is a validated target to develop drugs for treating type 2 diabetes mellitus. The existing α-glucosidase inhibitors have certain shortcomings related... (Review)
Review
The α-glucosidase is a validated target to develop drugs for treating type 2 diabetes mellitus. The existing α-glucosidase inhibitors have certain shortcomings related to side effects and route of synthesis. Accordingly, it is inevitable to develop new chemical templates as α-glucosidase inhibitors. Pyrazole derivatives have a special place in medicinal chemistry because of various biological activities. Recently, pyrazole-based heterocyclic compounds have emerged as a promising scaffold to develop α-glucosidase inhibitors. This study focuses on the recently reported pyrazole-based α-glucosidase inhibitors, including their biological activity (in vivo, in vitro, and in silico), structure-activity relationship, and ways of synthesis. The literature revealed the development of several promising pyrazole-based α-glucosidase inhibitors and new synthetic routes for their preparation. The encouraging α-glucosidase inhibitory results of the pyrazole-based heterocyclic compounds make them an attractive target for further research. The authors also foresee the arrival of the pyrazole-based α-glucosidase inhibitors in clinical practice.
Topics: Humans; Structure-Activity Relationship; Molecular Structure; Glycoside Hydrolase Inhibitors; alpha-Glucosidases; Diabetes Mellitus, Type 2; Pyrazoles; Molecular Docking Simulation
PubMed: 36617511
DOI: 10.1002/ardp.202200421 -
International Journal of Molecular... Mar 2023Multi-drug resistant bacterial strains (MDR) have become an increasing challenge to our health system, resulting in multiple classical antibiotics being clinically...
Multi-drug resistant bacterial strains (MDR) have become an increasing challenge to our health system, resulting in multiple classical antibiotics being clinically inactive today. As the de-novo development of effective antibiotics is a very costly and time-consuming process, alternative strategies such as the screening of natural and synthetic compound libraries is a simple approach towards finding new lead compounds. We thus report on the antimicrobial evaluation of a small collection of fourteen drug-like compounds featuring indazoles, pyrazoles and pyrazolines as key heterocyclic moieties whose synthesis was achieved in continuous flow mode. It was found that several compounds possessed significant antibacterial potency against clinical and MDR strains of the and genera, with the lead compound () reaching MIC values of 4 µg/mL on those species. In addition, time killing experiments performed on compound on MDR strains highlight its activity as bacteriostatic. Additional evaluations regarding the physiochemical and pharmacokinetic properties of the most active compounds are reported and showcased, promising drug-likeness, which warrants further explorations of the newly identified antimicrobial lead compound.
Topics: Pyrazoles; Indazoles; Structure-Activity Relationship; Anti-Infective Agents; Anti-Bacterial Agents; Microbial Sensitivity Tests
PubMed: 36982392
DOI: 10.3390/ijms24065319 -
Molecules (Basel, Switzerland) Dec 2022Pyrazole, an important pharmacophore and a privileged scaffold of immense significance, is a five-membered heterocyclic moiety with an extensive therapeutic profile,... (Review)
Review
Pyrazole, an important pharmacophore and a privileged scaffold of immense significance, is a five-membered heterocyclic moiety with an extensive therapeutic profile, viz., anti-inflammatory, anti-microbial, anti-anxiety, anticancer, analgesic, antipyretic, etc. Due to the expansion of pyrazolecent red pharmacological molecules at a quicker pace, there is an urgent need to put emphasis on recent literature with hitherto available information to recognize the status of this scaffold for pharmaceutical research. The reported potential pyrazole-containing compounds are highlighted in the manuscript for the treatment of cancer and inflammation, and the results are mentioned in % inhibition of inflammation, % growth inhibition, IC, etc. Pyrazole is an important heterocyclic moiety with a strong pharmacological profile, which may act as an important pharmacophore for the drug discovery process. In the struggle to cultivate suitable anti-inflammatory and anticancer agents, chemists have now focused on pyrazole biomolecules. This review conceals the recent expansion of pyrazole biomolecules as anti-inflammatory and anticancer agents with an aim to provide better correlation among different research going around the world.
Topics: Humans; Anti-Inflammatory Agents; Drug Design; Pyrazoles; Antineoplastic Agents; Inflammation; Structure-Activity Relationship; Neoplasms
PubMed: 36557840
DOI: 10.3390/molecules27248708 -
Bioorganic & Medicinal Chemistry Nov 2023Staphylococcus aureus is a highly adaptable opportunistic pathogen that can form biofilms and generate persister cells, leading to life-threatening infections that are...
Staphylococcus aureus is a highly adaptable opportunistic pathogen that can form biofilms and generate persister cells, leading to life-threatening infections that are difficult to treat with antibiotics alone. Therefore, there is a need for an effective S. aureus biofilm inhibitor to combat this public health threat. In this study, a small library of indolenine-substituted pyrazoles and pyrimido[1,2-b]indazole derivatives were synthesised, of which the hit compound exhibited promising antibiofilm activities against methicillin-susceptible S. aureus (MSSA ATCC 29213) and methicillin-resistant S. aureus (MRSA ATCC 33591) at concentrations significantly lower than the planktonic growth inhibition. The hit compound could prevent biofilm formation and eradicate mature biofilms of MSSA and MRSA, with a minimum biofilm inhibitory concentration (MBIC) value as low as 1.56 µg/mL and a minimum biofilm eradication concentration (MBEC) value as low as 6.25 µg/mL. The minimum inhibitory concentration (MIC) values of the hit compound against MSSA and MRSA were 50 µg/mL and 25 µg/mL, respectively, while the minimum bactericidal concentration (MBC) values against MSSA and MRSA were > 100 µg/mL. Preliminary structure-activity relationship analysis reveals that the fused benzene ring and COOH group of the hit compound are crucial for the antibiofilm activity. Additionally, the compound was not cytotoxic to human alveolar A549 cells, thus highlighting its potential as a suitable candidate for further development as a S. aureus biofilm inhibitor.
Topics: Humans; Staphylococcus aureus; Methicillin-Resistant Staphylococcus aureus; Indazoles; Anti-Bacterial Agents; Biofilms; Staphylococcal Infections; Pyrazoles; Microbial Sensitivity Tests
PubMed: 37812886
DOI: 10.1016/j.bmc.2023.117485