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Molecules (Basel, Switzerland) Jul 2022Pyrazole and its derivatives are considered a privileged -heterocycle with immense therapeutic potential. Over the last few decades, the pot, atom, and step economy... (Review)
Review
Pyrazole and its derivatives are considered a privileged -heterocycle with immense therapeutic potential. Over the last few decades, the pot, atom, and step economy (PASE) synthesis of pyrazole derivatives by multicomponent reactions (MCRs) has gained increasing popularity in pharmaceutical and medicinal chemistry. The present review summarizes the recent developments of multicomponent reactions for the synthesis of biologically active molecules containing the pyrazole moiety. Particularly, it covers the articles published from 2015 to date related to antibacterial, anticancer, antifungal, antioxidant, α-glucosidase and α-amylase inhibitory, anti-inflammatory, antimycobacterial, antimalarial, and miscellaneous activities of pyrazole derivatives obtained exclusively via an MCR. The reported analytical and activity data, plausible synthetic mechanisms, and molecular docking simulations are organized in concise tables, schemes, and figures to facilitate comparison and underscore the key points of this review. We hope that this review will be helpful in the quest for developing more biologically active molecules and marketed drugs containing the pyrazole moiety.
Topics: Anti-Bacterial Agents; Antifungal Agents; Chemistry, Pharmaceutical; Molecular Docking Simulation; Pyrazoles; alpha-Glucosidases
PubMed: 35897899
DOI: 10.3390/molecules27154723 -
European Journal of Medicinal Chemistry Jul 2021A collection of potent antimicrobials consisting of novel 1,3-bis-benzoic acid and trifluoromethyl phenyl derived pyrazoles has been synthesized and tested for...
A collection of potent antimicrobials consisting of novel 1,3-bis-benzoic acid and trifluoromethyl phenyl derived pyrazoles has been synthesized and tested for antibacterial activity. The majority of trifluoromethyl phenyl derivatives are highly potent growth inhibitors of Gram-positive bacteria and showed low toxicity to human cultured cells. In particular, two compounds (59 and 74) were selected for additional studies. These compounds are highly effective against Staphylococcus aureus as shown by a low minimum inhibitory concentration (MIC), a bactericidal effect in time-kill assays, moderate inhibition of biofilm formation as well as biofilm destruction, and a bactericidal effect against stationary phase cells representing non-growing persister cells. Multistep resistance assays showed a very low tendency for S. aureus and Enterococcus faecalis to develop resistance through mutation. Additionally, in vivo mouse model studies showed no harmful effects at doses up to 50 mg/kg using 14 blood plasma organ toxicity markers or TUNEL assay in liver and kidney. Investigations into the mode of action by performing macromolecular synthesis inhibition studies showed a broad range of inhibitory effects, suggesting targets that have a global effect on bacterial cell function.
Topics: Aniline Compounds; Anti-Bacterial Agents; Biofilms; Cell Line; Cell Survival; Drug Resistance, Bacterial; Enterococcus faecalis; Gram-Positive Bacteria; Humans; Liver; Microbial Sensitivity Tests; Pyrazoles; Staphylococcus aureus; Structure-Activity Relationship
PubMed: 33845234
DOI: 10.1016/j.ejmech.2021.113402 -
Molecules (Basel, Switzerland) Jan 2022Pyrazole has been recognized as a pharmacologically important privileged scaffold whose derivatives produce almost all types of pharmacological activities and have... (Review)
Review
Pyrazole has been recognized as a pharmacologically important privileged scaffold whose derivatives produce almost all types of pharmacological activities and have attracted much attention in the last decades. Of the various pyrazole derivatives reported as potential therapeutic agents, this article focuses on pyrazole-based kinase inhibitors. Pyrazole-possessing kinase inhibitors play a crucial role in various disease areas, especially in many cancer types such as lymphoma, breast cancer, melanoma, cervical cancer, and others in addition to inflammation and neurodegenerative disorders. In this article, we reviewed the structural and biological characteristics of the pyrazole derivatives recently reported as kinase inhibitors and classified them according to their target kinases in a chronological order. We reviewed the reports including pyrazole derivatives as kinase inhibitors published during the past decade (2011-2020).
Topics: Anti-Inflammatory Agents; Antineoplastic Agents; Apoptosis; Biomarkers, Tumor; Drug Development; Enzyme Inhibitors; History, 21st Century; Humans; Immune Checkpoint Inhibitors; Models, Molecular; Protein Kinase Inhibitors; Pyrazoles; Signal Transduction; Structure-Activity Relationship
PubMed: 35011562
DOI: 10.3390/molecules27010330 -
Future Medicinal Chemistry Feb 2022Methicillin-resistant , vancomycin-resistant enterococci and cause serious antibiotic-resistant infections. Finding new antibiotics to treat these infections is...
Methicillin-resistant , vancomycin-resistant enterococci and cause serious antibiotic-resistant infections. Finding new antibiotics to treat these infections is imperative for combating this worldwide menace. In this study, the authors designed and synthesized potent antimicrobial agents using 4-trifluoromethylphenyl-substituted pyrazole derivatives. In addition to their potency against planktonic bacteria, potent compounds effectively eradicated and biofilms. Human cells tolerated these compounds with good selectivity factors. Furthermore, the authors provide evidence for the mode of action of compounds based on time-kill kinetics, flow cytometry analysis of propidium iodide-treated bacteria and oxygen uptake studies. This study demonstrated 20 novel compounds with potent antibacterial activity that are tolerated by human cell lines.
Topics: Acinetobacter baumannii; Anti-Infective Agents; Biofilms; Cell Survival; Enterococcus; HEK293 Cells; Humans; Microbial Sensitivity Tests; Pyrazoles; Staphylococcus; Staphylococcus aureus; Structure-Activity Relationship
PubMed: 34877890
DOI: 10.4155/fmc-2021-0140 -
Methods (San Diego, Calif.) Jun 2023Small molecules that bind to oligomeric protein species such as membrane proteins and fibrils are of clinical interest for development of therapeutics and diagnostics....
Small molecules that bind to oligomeric protein species such as membrane proteins and fibrils are of clinical interest for development of therapeutics and diagnostics. Definition of the binding site at atomic resolution via NMR is often challenging due to low binding stoichiometry of the small molecule. For fibrils and aggregation intermediates grown in the presence of lipids, we report atomic-resolution contacts to the small molecule at sub nm distance via solid-state NMR using dynamic nuclear polarization (DNP) and orthogonally labelled samples of the protein and the small molecule. We apply this approach to α-synuclein (αS) aggregates in complex with the small molecule anle138b, which is a clinical drug candidate for disease modifying therapy. The small central pyrazole moiety of anle138b is detected in close proximity to the protein backbone and differences in the contacts between fibrils and early intermediates are observed. For intermediate species, the 100 K condition for DNP helps to preserve the aggregation state, while for both fibrils and oligomers, the DNP enhancement is essential to obtain sufficient sensitivity.
Topics: alpha-Synuclein; Pyrazoles; Benzodioxoles; Magnetic Resonance Spectroscopy; Protein Aggregates
PubMed: 37037308
DOI: 10.1016/j.ymeth.2023.04.002 -
Database : the Journal of Biological... Sep 2023The present article describes the building of a small-molecule web server, CBPDdb, employing R-shiny. For the generation of the web server, three compounds were chosen,...
The present article describes the building of a small-molecule web server, CBPDdb, employing R-shiny. For the generation of the web server, three compounds were chosen, namely coumarin, benzothiazole and pyrazole, and their derivatives were curated from the literature. The two-dimensional (2D) structures were drawn using ChemDraw, and the .sdf file was created employing Discovery Studio Visualizer v2017. These compounds were read on the R-shiny app using ChemmineR, and the dataframe consisting of a total of 1146 compounds was generated and manipulated employing the dplyr package. The web server is provided with JSME 2D sketcher. The descriptors of the compounds are obtained using propOB with a filter. The users can download the filtered data in the .csv and .sdf formats, and the entire dataset of a compound can be downloaded in .sdf format. This web server facilitates the researchers to screen plausible inhibitors for different diseases. Additionally, the method used in building the web server can be adapted for developing other small-molecule databases (web servers) in RStudio. Database URL: https://srampogu.shinyapps.io/CBPDdb_Revised/.
Topics: Benzothiazoles; Coumarins; Databases, Factual; Pyrazoles
PubMed: 37702993
DOI: 10.1093/database/baad062 -
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 -
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 -
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 -
The Journal of Organic Chemistry Dec 2019A facile synthetic route toward either 3- or 5-fluoroalkyl-substituted isoxazoles or pyrazoles containing an additional functionalization site was developed and applied...
A facile synthetic route toward either 3- or 5-fluoroalkyl-substituted isoxazoles or pyrazoles containing an additional functionalization site was developed and applied on a multigram scale. The elaborated approach extends the scope of fluoroalkyl substituents for introduction into the heterocyclic moiety, and uses convenient transformations of the side chain for incorporation of fluoroalkyl-substituted azoles into the structures of biologically active molecules. The utility of the obtained building blocks for isosteric replacement of alkyl-substituted isoxazole and pyrazole was shown by the synthesis of fluorinated Isocarboxazid and Mepiprazole analogues.
Topics: Chemistry Techniques, Synthetic; Isoxazoles; Ketones; Molecular Structure; Pyrazoles; Stereoisomerism
PubMed: 31661620
DOI: 10.1021/acs.joc.9b02258