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ChemMedChem Sep 2021Pyrazole-thiazole core-containing compound KP-40 and 20 novel derivatives were designed and synthesized through traditional SAR analysis. These molecules displayed...
Pyrazole-thiazole core-containing compound KP-40 and 20 novel derivatives were designed and synthesized through traditional SAR analysis. These molecules displayed adjunctive activity with meropenem against Gram-negative bacteria evidenced by a range of fractional inhibitory concentration (FIC=0.5-0.25) and minimum adjunctive concentration (MAC=128-32 μM) values. Of this series of molecules, four compounds displayed notable adjunctive potential, with FIC and MAC values of 0.25 and 32 μM, respectively. Moreover, the solubility of these compounds was improved to an acceptable range. Further analysis using our "in house" permeation and efflux multi parameter optimization (PEMPO) algorithm revealed key physicochemical properties that may be critical for the development of active Gram-negative antibacterials. Taking PEMPO scores into consideration prior to executing synthesis of analogs may be a simple, yet rapid and effective strategy that can be used in conjunction with traditional SAR approaches to aid in the design of potent Gram-negative antibacterials.
Topics: Anti-Bacterial Agents; Carbapenem-Resistant Enterobacteriaceae; Dose-Response Relationship, Drug; Meropenem; Microbial Sensitivity Tests; Molecular Structure; Pyrazoles; Structure-Activity Relationship; Thiazoles
PubMed: 34096189
DOI: 10.1002/cmdc.202100321 -
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) Nov 2019Due to a significant and prolific activity in the field of design and synthesis of new energetic molecules, it becomes increasingly difficult to introduce new...
Due to a significant and prolific activity in the field of design and synthesis of new energetic molecules, it becomes increasingly difficult to introduce new explosophore structures with attractive properties. In this work, we synthesized a trans-bimane-based energetic material-3,7-diamino-2,6-dinitro-1,5-pyrazolo-[1,2-a]pyrazole-1,5-dione (4), the structure of which was comprehensively analyzed by a variety of advanced spectroscopic methods and by X-ray crystallo-graphy (with density of 1.845 g·cm at 173 K). Although obtained crystals of 4 contained solvent molecules in their structure, state-of-the-art density functional theory (DFT) computational techniques allowed us to predict that solvent-free crystals of this explosive would preserve a similar tightly packed planar layered molecular arrangement, with the same number of molecules of 4 per unit cell, but with a smaller unit cell volume and therefore higher energy density. Explosive 4 was found to be heat resistant, with an onset decomposition temperature of 328.8 °C, and was calculated to exhibit velocity of detonation in a range of 6.88-7.14 km·s and detonation pressure in the range of 19.14-22.04 GPa, using for comparison both HASEM and the EXPLO 5 software. Our results indicate that the -bimane explosophore could be a viable platform for the development of new thermostable energetic materials.
Topics: Bridged Bicyclo Compounds, Heterocyclic; Explosive Agents; Hot Temperature; Pyrazoles; Software; Solvents; Thermodynamics
PubMed: 31779257
DOI: 10.3390/molecules24234324 -
Journal of Inorganic Biochemistry Aug 2024A new pyrazole based thiosemicarbazone ligand, 5-methyl-3-formylpyrazole-N(4)-isopropylthiosemicarbazone, (HMPNHPr) (compound I), and its cobalt(III) and nickel(II)...
Anticancer, antimicrobial and photocatalytic activities of a new pyrazole containing thiosemicarbazone ligand and its Co(III) and Ni(II) complexes: Synthesis, spectroscopic characterization and X-ray crystallography.
A new pyrazole based thiosemicarbazone ligand, 5-methyl-3-formylpyrazole-N(4)-isopropylthiosemicarbazone, (HMPNHPr) (compound I), and its cobalt(III) and nickel(II) complexes, [Co(MPNHPr)]Cl (compound II) and [Ni(HMPNHPr)]Br (compound III), respectively, have been synthesized and characterized through various physico-chemical and spectroscopic studies. Both the reported Co(III) and Ni(II) complexes are cationic in nature and behave as 1:1 and 1:2 electrolytes in MeOH, respectively. Electronic spectral features of the complexes have classified them as distorted octahedral ones. IR spectral data (4000-450 cm) have suggested a monoprotic tridentate (NNS) function of compound I coordinating to the Co(III) ion via the pyrazolyl (tertiary) ring nitrogen, azomethine nitrogen and thiolato sulphur atom; while for compound III, compound I has been found to act as neutral NNS tridentate one, coordinating to Ni(II) via the pyrazolyl iminic nitrogen, azomethine nitrogen and thioketo sulphur. Structural features of all the compounds are confirmed by the single crystal X-ray data. All the compounds reported here have been found to exhibit significant photocatalytic activity towards degradation of Methylene Blue (MB) under UV radiation. Anticancer activity of all the three compounds against cancer cell lines (HeLa and A549) and a normal cell line (HEK293) have been investigated. Compound II has been found to be more efficient against the human cervical cancer cell (HeLa) and the lung cancer cell (A549) than compounds I and III. The ligand and both the complexes display potential activities against both gram-positive (Bacillus subtilis MTCC 7193) and gram-negative bacteria (E. coli MTCC 1610).
Topics: Thiosemicarbazones; Nickel; Cobalt; Pyrazoles; Antineoplastic Agents; Humans; Coordination Complexes; Crystallography, X-Ray; Ligands; Cell Line, Tumor; Catalysis; Anti-Bacterial Agents; Microbial Sensitivity Tests
PubMed: 38714060
DOI: 10.1016/j.jinorgbio.2024.112577 -
Mini Reviews in Medicinal Chemistry 2022The search for new anticancer agents is considered a dynamic field of medicinal chemistry. In recent years, the synthesis of compounds with anticancer potential has... (Review)
Review
The search for new anticancer agents is considered a dynamic field of medicinal chemistry. In recent years, the synthesis of compounds with anticancer potential has increased and a large number of structurally varied compounds displaying potent anticancer activities have been published. Pyrazole is an important biologically active scaffold that possesses nearly all types of biological activities. The aim of this review is to collate literature work reported by researchers to provide an overview on in vivo and in vitro anticancer activities of pyrazole based derivatives among the diverse biological activities displayed by them and also to present recent efforts made on this heterocyclic moiety regarding anticancer activities. This review has been driven by the increasing number of publications on this issue, which have been reported in the literature since the end of the 20 century (from 1995-to date).
Topics: Antineoplastic Agents; Chemistry, Pharmaceutical; Pyrazoles; Structure-Activity Relationship
PubMed: 33823764
DOI: 10.2174/1389557521666210325115218 -
Bioorganic & Medicinal Chemistry Letters Mar 2024To discover mode-selective TRPV1 antagonists as thermoneutral drug candidates, the previous potent antagonist benzopyridone 2 was optimized based on the pharmacophore A-...
To discover mode-selective TRPV1 antagonists as thermoneutral drug candidates, the previous potent antagonist benzopyridone 2 was optimized based on the pharmacophore A- and C-regions. The structure activity relationship was investigated systematically by modifying the A-region by incorporating a polar side chain on the pyridone and then by changing the C-region with a variety of substituted pyridine and pyrazole moieties. The 3-t-butyl and 3-(1-methylcyclopropyl) pyrazole C-region analogs provided high potency as well as mode-selectivity. Among them, 51 and 54 displayed potent and capsaicin-selective antagonism with IC = 2.85 and 3.27 nM to capsaicin activation and 28.5 and 31.5 % inhibition at 3 µM concentration toward proton activation, respectively. The molecular modeling study of 51 with our homology model indicated that the hydroxyethyl side chain in the A-region interacted with Arg557 and Glu570, the urea B-region engaged in hydrogen bonding with Tyr511 and Thr550, respectively, and the pyrazole C-region made two hydrophobic interactions with the receptor. Optimization of antagonist 2, which has full antagonism for activators of all modes, lead to mode-selective antagonists 51 and 54. These observations will provide insight into the future development of clinical TRPV1 antagonists without target-based side effects.
Topics: Urea; Capsaicin; Structure-Activity Relationship; Models, Molecular; Pyrazoles; TRPV Cation Channels
PubMed: 38355061
DOI: 10.1016/j.bmcl.2024.129656 -
Molecules (Basel, Switzerland) Aug 2023On the basis of the three-component synthetic methodology developed by us, a total of twenty-six pyrazole compounds bearing aryl OCF were designed and synthesized. Their...
On the basis of the three-component synthetic methodology developed by us, a total of twenty-six pyrazole compounds bearing aryl OCF were designed and synthesized. Their chemical structures were characterized by H and C nuclear magnetic resonance and high-resolution mass spectrometry. These compounds were evaluated systematically for antifungal activities in vitro against six plant pathogenic fungi by the mycelium growth rate method. Most of the compounds showed some activity against each of the fungi at 100 μg/mL. Compounds and exhibited higher activity against all the tested fungi, and displayed the highest activity against with an EC value of 0.0530 μM, which was comparable with commercial pyraclostrobin. Structure-activity relationship analysis showed that, with respect to the R substituent, the straight chain or cycloalkyl ring moiety was a key structural moiety for the activity, and the R substituent on the pyrazole ring could have significant effects on the activity. Simple and readily available pyrazoles with potent antifungal activity were obtained, which are ready for further elaboration to serve as a pharmacophore in new potential antifungal agents.
Topics: Antifungal Agents; Pyrazoles; Mass Spectrometry; Mycelium
PubMed: 37687108
DOI: 10.3390/molecules28176279 -
Archiv Der Pharmazie Aug 20145-Amino-1-p-tolyl-1H-pyrazole-4-carbonitrile (1) was used for the preparation of some novel pyrazoles and pyrazolo[3,4-d]pyrimidines 2-10. Moreover, the cytotoxicity and...
5-Amino-1-p-tolyl-1H-pyrazole-4-carbonitrile (1) was used for the preparation of some novel pyrazoles and pyrazolo[3,4-d]pyrimidines 2-10. Moreover, the cytotoxicity and in vitro anticancer activities of the prepared compounds were also assessed against the MCF-7 breast cancer, HepG2 liver cancer, and A549 lung carcinoma cell lines, along with investigation of the effect of the synthesized compounds on the expression of urokinase plasminogen activator (uPA). The tested compounds exhibited remarkable cytotoxic activity against MCF-7 and HepG2 cells. Among the tested compounds, 2 and 9 revealed promising anticancer activity compared to the activity of the commonly used anticancer drug, doxorubicin, by inhibiting the expression of uPA.
Topics: Antineoplastic Agents; Cell Culture Techniques; Cell Survival; Hep G2 Cells; Humans; Inhibitory Concentration 50; MCF-7 Cells; Molecular Structure; Pyrazoles; Pyrimidines; Urokinase-Type Plasminogen Activator
PubMed: 24801813
DOI: 10.1002/ardp.201400064 -
Canadian Journal of Physiology and... Jul 2020Pyrazoles represent a significant class of heterocyclic compounds that exhibit pharmacological properties. The present study aimed to investigate the antioxidant...
Pyrazoles represent a significant class of heterocyclic compounds that exhibit pharmacological properties. The present study aimed to investigate the antioxidant potential of pyrazol derivative compounds in brain of mice in vitro and the effect of pyrazol derivative compounds in the oxidative damage and toxicity parameters in mouse brain and plasma of mice. The compounds tested were 3,5-dimethyl-1-phenyl-4-(phenylselanyl)-1-pyrazol (), 3,5-dimethyl-4-(phenylselanyl)-1-pyrazole (), 4-((4-methoxyphenyl)selanyl)-3,5-dimethyl-1-phenyl-1-pyrazole (), 4-((4-chlorophenyl)selanyl)-3,5-dimethyl-1-phenyl-1-pyrazole (), 3,5-dimethyl-1-phenyl-4-(phenylthio)-1-pyrazole (), 3,5-dimethyl-4-(phenylthio)-1-pyrazole (), 4-((4-methoxyphenyl)thio)-3,5-dimethyl-1-phenyl-1-pyrazole (), 4-((4-chlorophenyl)thio)-3,5-dimethyl-1-phenyl-1-pyrazole (), and 3,5-dimethyl-1-phenyl-1-pyrazole (). In vitro, 4-(arylcalcogenyl)-1-pyrazoles, at low molecular range, reduced lipid peroxidation and reactive species in mouse brain homogenates. The compounds also presented ferric-reducing ability as well nitric oxide-scavenging activity. Especially compounds , , and presented efficiency to 1,1-diphenyl-2-picryl-hydrazyl-scavenging activity. Compounds and presented 2,20 -azino-bis(3-ethylbenzthiazoline-6-sulfonic acid)-scavenging activity. In vivo assays demonstrated that compounds , , and (300 mg/kg, intragastric, a single administration) did not cause alteration in the of δ-aminolevulinic acid dehydratase activity, an enzyme that exhibits high sensibility to prooxidants situations, in the brain, liver, and kidney of mice. Compound reduced per se the lipid peroxidation in liver and brain of mice. Toxicological assays demonstrate that compounds , , and did not present toxicity in the aspartate aminotransferase, alanine aminotransferase, urea, and creatinine levels in the plasma. In conclusion, the results demonstrated the antioxidant action of pyrazol derivative compounds in in vitro assays. Furthermore, the results showed low toxicity of compounds in in vivo assays.
Topics: Administration, Oral; Animals; Cerebral Cortex; Drug Evaluation, Preclinical; Free Radical Scavengers; Kidney; Lipid Peroxidation; Liver; Male; Mice; Models, Animal; Pyrazoles; Reactive Oxygen Species; Selenium; Sulfur; Toxicity Tests, Acute
PubMed: 32597688
DOI: 10.1139/cjpp-2019-0356 -
Organic & Biomolecular Chemistry Sep 2019Rapamycin-induced dimerization of FKBP and FRB has been utilized as a tool for co-localizing two proteins of interest in numerous applications. Due to the tight binding...
Rapamycin-induced dimerization of FKBP and FRB has been utilized as a tool for co-localizing two proteins of interest in numerous applications. Due to the tight binding interaction of rapamycin with FKBP and FRB, the ternary complex formation is essentially irreversible. Since biological processes occur in a highly dynamic fashion with cycles of protein association and dissociation to generate a cellular response, it is useful to have chemical tools that function in a similar manner. We have developed arylazopyrazole-modified rapamycin analogs which undergo a configurational change upon light exposure and we observed enhanced ternary complex formation for the cis-isomer over the trans-isomer for one of the analogs.
Topics: Azo Compounds; HEK293 Cells; Humans; Light; Molecular Structure; Pyrazoles; Sirolimus; Stereoisomerism
PubMed: 31469140
DOI: 10.1039/c9ob01719d