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Current Topics in Medicinal Chemistry 2023Pyrazole is considered an important active scaffold that possesses various types of pharmacological activities. The overwhelming literature reported earlier reflects the... (Review)
Review
Pyrazole is considered an important active scaffold that possesses various types of pharmacological activities. The overwhelming literature reported earlier reflects the immense biological potential of pyrazole derivatives. The presence of this moiety in various FDA-approved drugs, including celecoxib (anti-inflammatory), apixaban (anticoagulant), rimonabant (anti-obesity), difenamizole (analgesic), and sildenafil (for erectile dysfunction), has proved its pharmacological potential. Owing to its diversity in the biological field, this nucleus has attracted the attention of many researchers to study its skeleton chemically and biologically. This review highlights the literature supporting the research of the past 10 years related to the structures of pyrazole derivatives with their corresponding biological activities. The findings of this review may open new avenues for an upcoming scientific breakthrough.
Topics: Humans; Chemistry, Pharmaceutical; Anti-Inflammatory Agents; Analgesics; Pyrazoles; Obesity; Structure-Activity Relationship
PubMed: 37455456
DOI: 10.2174/1568026623666230714161726 -
Molecules (Basel, Switzerland) Jul 2019A series of disubstituted 1-pyrazoles with methyl (), amino (), and nitro () groups, as well as ester () or amide () groups in positions 3 and 5 was synthesized, and...
A series of disubstituted 1-pyrazoles with methyl (), amino (), and nitro () groups, as well as ester () or amide () groups in positions 3 and 5 was synthesized, and annular tautomerism was investigated using X-ray, theoretical calculations, NMR, and FT-IR methods. The X-ray experiment in the crystal state showed for the compounds with methyl (, ) and amino () groups the tautomer with ester or amide groups at position 3 (tautomer 3), but for those with a nitro group (, ), tautomer 5. Similar results were obtained in solution by NMR NOE experiments in CDCl, DMSO-, and CDOD solvents. However, tautomer equilibrium was observed for in DMSO. The FT-IR spectra in chloroform and acetonitrile showed equilibria, which can be ascribed to conformational changes of the cis/trans arrangement of the ester/amide group and pyrazole ring. Theoretical analysis using the M06-2X/6-311++G(d,p) method (in vacuo, chloroform, acetonitrile, and water) and measurement of aromaticity (NICS) showed dependence on internal hydrogen bonds, the influence of the environment, and the effect of the substituent. These factors, pyrazole aromaticity and intra- and inter-molecular interactions, seem to have a considerable influence on the choice of tautomer.
Topics: Amides; Crystallography, X-Ray; Esters; Hydrogen Bonding; Models, Molecular; Models, Theoretical; Molecular Conformation; Molecular Structure; Pyrazoles; Spectrum Analysis
PubMed: 31330976
DOI: 10.3390/molecules24142632 -
Current Medicinal Chemistry 2023Among the aromatic heterocycle rings, pyrazole -a five-membered ring with two adjacent nitrogen atoms in its structure has been postulated as a potent candidate in the... (Review)
Review
Among the aromatic heterocycle rings, pyrazole -a five-membered ring with two adjacent nitrogen atoms in its structure has been postulated as a potent candidate in the pharmacological context. This moiety is an interesting therapeutic target covering a broad spectrum of biological activities due to its presence in many natural substances. Hence, the potential of the pyrazole derivatives as antitumor agents has been explored in many investigations, showing promising results in some cases. In this sense, breast cancer, which is already the leading cause of cancer mortality in women in some countries, has been the topic selected for this review, which covers a range of different research from the earliest studies published in 2003 to the most recent ones in 2021.
Topics: Humans; Female; Breast Neoplasms; Pyrazoles; Antineoplastic Agents; Structure-Activity Relationship
PubMed: 36043746
DOI: 10.2174/0929867329666220829091830 -
European Journal of Medicinal Chemistry Nov 2022Mutations in the Leucine Rich Repeat Protein Kinase 2 gene (LRRK2) are genetic predispositions for Parkinson's Disease, of which the G2019S (GS) missense mutation is the...
Mutations in the Leucine Rich Repeat Protein Kinase 2 gene (LRRK2) are genetic predispositions for Parkinson's Disease, of which the G2019S (GS) missense mutation is the most common. GS-LRRK2 has a hyperactive kinase, and although numerous drug discovery programs have targeted the LRRK2 kinase, few have reached clinical trials. We recently reported on the discovery of a novel LRRK2 kinase inhibitor chemotype, 1H-pyrazole biaryl sulfonamides. Although both potent and selective GS-LRRK2 inhibitors, 1H-pyrazole biaryl sulfonamides are incapable of crossing the blood-brain barrier. Retaining the core 1H-pyrazole and focusing our efforts on a phenylsulfonamide bioisosteric replacement, we report the discovery and preliminary development of azaspirocyclic 1H-3,4,5-trisubstituted pyrazoles as potent and selective (>2000-fold) GS-LRRK2 kinase inhibitors capable of entering rodent brain. The compounds disclosed here present an excellent starting point for the development of more brain penetrant compounds.
Topics: Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Mutation; Parkinson Disease; Protein Kinase Inhibitors; Pyrazoles; Sulfonamides
PubMed: 36049274
DOI: 10.1016/j.ejmech.2022.114693 -
European Journal of Medicinal Chemistry Feb 2021Methicillin-resistant Staphylococcus aureus (MRSA) is becoming lethal to humanity due to easy transmission and difficult-to-treat skin and flimsy diseases. The most... (Review)
Review
Methicillin-resistant Staphylococcus aureus (MRSA) is becoming lethal to humanity due to easy transmission and difficult-to-treat skin and flimsy diseases. The most threatening aspect is the rapid resistance development of MRSA to any approved antibiotics, including vancomycin. The development of new, efficient, and nontoxic drug candidate to fight against MRSA isolates is the need of the hour. The intriguing molecular structure and versatile bioactive pyrazole core attracting to development required novel antibiotics. This review presents the decade developments of pyrazole-containing derivatives with a broad antibacterial movement against diverged bacterial strains. In specific, we correlated the efficacy of structurally diversified pyrazole analogs against MRSA and discussed different angles of structure-activity relationship (SAR). The current survey highlights pyrazole hybrids' present scenario on MRSA studies, covering articles published from 2011 to 2020. This collective information may become an excellent platform to plan and develop new pyrazole-based small MRSA growth inhibitors with minimal side effects.
Topics: Anti-Bacterial Agents; Dose-Response Relationship, Drug; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Molecular Structure; Pyrazoles; Structure-Activity Relationship
PubMed: 33395624
DOI: 10.1016/j.ejmech.2020.113134 -
Archiv Der Pharmazie Aug 2023Four series of novel pyrazole derivatives (compounds 17a-m, 18a-m, 19a-g, and 20a-g) were synthesized, and their antibacterial and antifungal activities were evaluated....
Four series of novel pyrazole derivatives (compounds 17a-m, 18a-m, 19a-g, and 20a-g) were synthesized, and their antibacterial and antifungal activities were evaluated. Most of the target compounds (17a-m, 18k-m, and 19b-g) showed strong antifungal activity and high selectivity relative to both Gram-positive and Gram-negative bacteria. Among them, compounds 17l (minimum inhibitory concentration [MIC] = 0.25 µg/mL) and 17m (MIC = 0.25 µg/mL) showed the strongest antifungal activity, being 2- and 4-fold more active than the positive controls gatifloxacin and fluconazole, respectively. In particular, compound 17l showed little cytotoxicity against human LO2 cells and did not exhibit hemolysis at ultrahigh concentrations, as did the positive control compounds gatifloxacin and fluconazole. These results indicate that these compounds are valuable for further development as antifungal agents.
Topics: Humans; Anti-Bacterial Agents; Antifungal Agents; Gatifloxacin; Thiadiazoles; Fluconazole; Structure-Activity Relationship; Gram-Negative Bacteria; Gram-Positive Bacteria; Microbial Sensitivity Tests; Pyrazoles
PubMed: 37328442
DOI: 10.1002/ardp.202300110 -
European Journal of Medicinal Chemistry Jan 2021The FGFR family is characterized by four receptors (FGFR 1-4), binding to 18 ligands called fibroblast growth factors (FGFs). Aberrant activation of FGFs and their FGFRs... (Review)
Review
The FGFR family is characterized by four receptors (FGFR 1-4), binding to 18 ligands called fibroblast growth factors (FGFs). Aberrant activation of FGFs and their FGFRs has been implicated in a broad spectrum of human tumors. We employed the scaffolds hybridization approach, scaffold-hopping concept to synthesize a series of novel pyrazole-benzimidazole derivatives 56 (a-x). Compound 56q (CPL304110) was identified as a selective and potent pan-FGFR inhibitor for FGFR1, -2, -3 with ICs of 0.75 nM, 0.50 nM, 3.05 nM respectively, whereas IC of 87.90 nM for FGFR4. Due to its favorable pharmacokinetic profile, low toxicity and potent anti-tumor activity in vivo, compound 56q is currently under evaluation in phase I clinical trial for the treatment of bladder, gastric and squamous cell lung cancers (01FGFR2018; NCT04149691).
Topics: Antineoplastic Agents; Benzimidazoles; Cell Proliferation; Drug Discovery; Humans; Protein Kinase Inhibitors; Pyrazoles; Receptor, Fibroblast Growth Factor, Type 1; Receptor, Fibroblast Growth Factor, Type 2; Receptor, Fibroblast Growth Factor, Type 3
PubMed: 33199155
DOI: 10.1016/j.ejmech.2020.112990 -
Molecules (Basel, Switzerland) Sep 2022A small library of highly functionalized phenylaminopyrazoles, bearing different substituents at position 1, 3, and 4 of the pyrazole ring, was prepared by the one-pot...
A small library of highly functionalized phenylaminopyrazoles, bearing different substituents at position 1, 3, and 4 of the pyrazole ring, was prepared by the one-pot condensation of active methylene reagents, phenylisothiocyanate, and substituted hydrazine (namely, methyl- and benzyl-hydrazine). The identified reaction conditions proved to be versatile and efficient. Furthermore, the evaluation of alternative stepwise protocols affected the chemo- and regio-selectivity outcome of the one-pot procedure. The chemical identities of two -methyl pyrazole isomers, selected as prototypes of the whole series, were unambiguously identified by means of NMR and mass spectrometry studies. Additionally, semiempirical calculations provided a structural rationale for the different chromatographic behavior of the two isomers. The prepared tetra-substituted phenylaminopyrazoles were tested in cell-based assays on a panel of cancer and normal cell lines. The tested compounds did not show any cytotoxic effect on the selected cell lines, thus supporting their pharmaceutical potentials.
Topics: Antineoplastic Agents; Drug Design; Hydrazines; Molecular Structure; Pharmaceutical Preparations; Pyrazoles; Structure-Activity Relationship
PubMed: 36144549
DOI: 10.3390/molecules27185814 -
International Journal of Molecular... May 2024In a screen of over 200 novel pyrazole compounds, ethyl 1-(2-hydroxypentyl)-5-(3-(3-(trifluoromethyl) phenyl)ureido)-1-pyrazole-4-carboxylate (named GeGe-3) has emerged...
In a screen of over 200 novel pyrazole compounds, ethyl 1-(2-hydroxypentyl)-5-(3-(3-(trifluoromethyl) phenyl)ureido)-1-pyrazole-4-carboxylate (named GeGe-3) has emerged as a potential anticancer compound. GeGe-3 displays potent anti-angiogenic properties through the presumptive targeting of the protein kinase DMPK1 and the Ca2-binding protein calreticulin. We further explored the anticancer potential of GeGe-3 on a range of established cancer cell lines, including PC3 (prostate adenocarcinoma), SKMEL-28 (cutaneous melanoma), SKOV-3 (ovarian adenocarcinoma), Hep-G2 (hepatocellular carcinoma), MDA-MB231, SKBR3, MCF7 (breast adenocarcinoma), A549 (lung carcinoma), and HeLa (cervix epithelioid carcinoma). At concentrations in the range of 10 μM, GeGe-3 significantly restricted cell proliferation and metabolism. GeGe-3 also reduced PC3 cell migration in a standard wound closure and trans-well assay. Together, these results confirm the anticancer potential of GeGe-3 and underline the need for more detailed pre-clinical investigations into its molecular targets and mechanisms of action.
Topics: Humans; Pyrazoles; Antineoplastic Agents; Cell Proliferation; Cell Movement; Cell Line, Tumor; Urea
PubMed: 38791418
DOI: 10.3390/ijms25105380 -
Journal of Agricultural and Food... Nov 2022Succinate dehydrogenase (SDH) inhibitor is one of the research hotspots for the development of fungicides. Herein, we describe the design and synthesis of...
Succinate dehydrogenase (SDH) inhibitor is one of the research hotspots for the development of fungicides. Herein, we describe the design and synthesis of -methoxy-(biphenyl-ethyl)-pyrazole-carboxamide derivatives with enhanced fungicidal activity by employing fragment combination strategy. The SDH enzymatic activity was evaluated for 24 title compounds, and compound was identified as the highest activity against porcine SDH with an IC value of 0.014 μM, 205-fold greater than that of fluxapyroxad. Furthermore, the greenhouse experiments showed that compound exhibited potent fungicidal activity against wheat powdery mildew with an EC value of 0.633 mg/L, higher activity than fluxapyroxad and benzovindiflupyr. The computational results showed that the fluorine atom substituted on the pyrazole ring formed an extra dipolar-dipolar interaction with C_S42 and then increased the van der Waals interaction between the compound and SDH. The structural and mechanistic insights obtained from the present work will provide a valuable clue to developing novel SDH inhibitors.
Topics: Swine; Animals; Succinate Dehydrogenase; Structure-Activity Relationship; Fungicides, Industrial; Pyrazoles; Molecular Docking Simulation; Enzyme Inhibitors
PubMed: 36321207
DOI: 10.1021/acs.jafc.2c04770