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Bioorganic & Medicinal Chemistry Letters Apr 2010Utilizing a pharmacophore hypothesis, previously described gamma-secretase inhibiting HTS hits were evolved into novel tricyclic sulfonamide-pyrazoles, with high in...
Utilizing a pharmacophore hypothesis, previously described gamma-secretase inhibiting HTS hits were evolved into novel tricyclic sulfonamide-pyrazoles, with high in vitro potency, good brain penetration, low metabolic stability, and high clearance.
Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Animals; Crystallography, X-Ray; Humans; Inhibitory Concentration 50; Models, Molecular; Pyrazoles; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Sulfonamides
PubMed: 20206516
DOI: 10.1016/j.bmcl.2010.02.050 -
Molecules (Basel, Switzerland) Aug 2021Enterococci and methicillin-resistant (MRSA) are among the menacing bacterial pathogens. Novel antibiotics are urgently needed to tackle these antibiotic-resistant...
Enterococci and methicillin-resistant (MRSA) are among the menacing bacterial pathogens. Novel antibiotics are urgently needed to tackle these antibiotic-resistant bacterial infections. This article reports the design, synthesis, and antimicrobial studies of 30 novel pyrazole derivatives. Most of the synthesized compounds are potent growth inhibitors of planktonic Gram-positive bacteria with minimum inhibitory concertation (MIC) values as low as 0.25 µg/mL. Further studies led to the discovery of several lead compounds, which are bactericidal and potent against MRSA persisters. Compounds , , and are potent against biofilms with minimum biofilm eradication concentration (MBEC) values as low as 1 µg/mL.
Topics: Bacteria; Biofilms; Cell Death; Drug Resistance, Bacterial; Enterococcus faecalis; Growth Inhibitors; HEK293 Cells; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Pyrazoles
PubMed: 34443670
DOI: 10.3390/molecules26165083 -
Bioorganic & Medicinal Chemistry Letters May 2021Methicillin-resistant Staphylococcus aureus (MRSA) infections are a significant burden both clinically and economically worldwide. Increasing resistance to current...
Methicillin-resistant Staphylococcus aureus (MRSA) infections are a significant burden both clinically and economically worldwide. Increasing resistance to current antibiotics requires an urgent investigation into novel classes of antimicrobial agents. This study presents a structure-activity relationship (SAR) rationale for pyrazole linked phenylthiazole analogues as new antibacterial agents. A library of 23 novel pyrazole linked phenylthiazole compounds were synthesised, followed by screening for antimicrobial activity against five bacterial species and two fungi. The most active compound 14b has shown promising antibacterial activity against the Gram-positive methicillin-resistant Staphylococcus aureus (MRSA, ATCC 43300) strain (MIC 4 μg/mL). Furthermore, the active pyrazole linked phenylthiazole compound exhibited a better toxicity profile than standard antibiotics. In summary, these results demonstrate that a pyrazole linked phenylthiazole scaffold has potential as a lead for further investigation to afford novel antibacterial agents.
Topics: Anti-Bacterial Agents; Dose-Response Relationship, Drug; Drug Design; HEK293 Cells; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Molecular Structure; Pyrazoles; Structure-Activity Relationship; Thiazoles
PubMed: 33609657
DOI: 10.1016/j.bmcl.2021.127853 -
Current Drug Discovery Technologies 2023In the present study, a new series of 1,2,4-triazole linked to pyrazole derivatives (8a-j) of...
BACKGROUND
In the present study, a new series of 1,2,4-triazole linked to pyrazole derivatives (8a-j) of 4-(((7-amino-7H-[1,2,4]triazolo[4,3-b][1,2,4]triazol-6-yl)methyl)amino)-1,5-dimethyl- 2-phenyl-1H-pyrazol-3(2H)-one were synthesized and assessed for their antibacterial and anticancer activity.
OBJECTIVE
Encouraged by these results, these analogues 4-(((7-amino-7H-[1,2,4]triazolo[4,3- b][1,2,4]triazol-6-yl)methyl)amino)-1,5-dimethyl-2-phenyl-1H-pyrazol-3(2H)-ones 8 have been synthesized and their inhibitory potential activity against different bacterial microorganisms and cancer cell lines was discussed.
METHODS
All the synthesized final scaffolds were characterized by H NMR, C NMR, IR, mass and elemental analysis. All the synthesized 1,2,4-triazole linked to pyrazole compounds were evaluated for their antimicrobial sensitivity by using the agar dilution technique. The anticancer activity of these compounds has been assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide colorimetric assay and docking results are described by Autodock 4.2.
RESULTS
In vitro analysis suggests that compounds 8h, 8f, and 8b demonstrated excellent antibacterial activity against S. aureus, P. aeruginosa, S. epidermidis with MICs of 8, 8, 11 μg/mL respectively, while the remaining compounds showed moderate to good inhibitory potential. Some of them exhibited potent cytotoxicity against MCF-7 and P388 cancer cell lines and compounds 8c, 8f, and 8d reveal the highest potency against MCF-7 with IC values 2.8 ± 0.4, 3.1 ± 0.4, 3.5 ± 0.2 μM, respectively. Especially 8c, 8i and 8f showed better interaction patterns with amino acids Ala197 (N-N), Lys168 (N-N), Asn163 (O-N) at 3.13, 3.09, 3.00 A° as reported in DNA (Topo II) complex (1ZXM).
CONCLUSION
New findings have established the fact that fused 1,2,4-triazoles linked to pyrazole contributed great significance in the field of medicinal chemistry due to their various biological properties.
Topics: Humans; Structure-Activity Relationship; Staphylococcus aureus; Triazoles; Anti-Bacterial Agents; Neoplasms; Pyrazoles; Molecular Structure; Antineoplastic Agents
PubMed: 36437730
DOI: 10.2174/1570163820666221125121625 -
Journal of Enzyme Inhibition and... Dec 2020A novel series of pyrazole analogues including hydrazones, pyrazolo[4,3-]-pyridazines, pyrazolo[3,4-][1,2,4]triazine and pyrazolo[3,4-][1,2,3]triazoles was designed,...
A novel series of pyrazole analogues including hydrazones, pyrazolo[4,3-]-pyridazines, pyrazolo[3,4-][1,2,4]triazine and pyrazolo[3,4-][1,2,3]triazoles was designed, synthesised and screened for their antimicrobial and DHFR inhibition activity. Compounds bearing benzenesulphonamide moiety incorporated with 3-methyl-5-oxo-1-pyrazol-4(5)-ylidene) hydrazine or 6-amino-7-cyano-3-methyl-5-pyrazolo[4,3-]pyridazine revealed excellent and broad spectrum antimicrobial activity comparable to ciprofloxacin and amphotericin B as positive antibiotic and antifungal controls, respectively. Furthermore, these derivatives proved to be the most active DHFR inhibitors with IC values 0.11 ± 1.05 and 0.09 ± 0.91 µM, in comparison with methotrexate (IC = 0.14 ± 1.25 µM). The studies were done to calculate the drug-likeness and toxicity risk parameters of the newly synthesised derivatives. Additionally, the high potency of the pyrazole derivatives bearing sulphonamide against DHFR was confirmed with molecular docking and might be used as an optimum lead for further modification.
Topics: Anti-Bacterial Agents; Antifungal Agents; Aspergillus; Bacillus subtilis; Candida albicans; Dose-Response Relationship, Drug; Drug Design; Escherichia coli; Folic Acid Antagonists; Heterocyclic Compounds; Humans; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; Pseudomonas aeruginosa; Pyrazoles; Streptococcus pneumoniae; Structure-Activity Relationship; Tetrahydrofolate Dehydrogenase
PubMed: 32668994
DOI: 10.1080/14756366.2020.1791842 -
Discovery of Novel Triazole-Containing Pyrazole Ester Derivatives as Potential Antibacterial Agents.Molecules (Basel, Switzerland) Apr 2019To develop new antibacterial agents, a series of novel triazole-containing pyrazole ester derivatives were designed and synthesized and their biological activities were...
To develop new antibacterial agents, a series of novel triazole-containing pyrazole ester derivatives were designed and synthesized and their biological activities were evaluated as potential topoisomerase II inhibitors. Compound exhibited the most potent antibacterial activity with Minimum inhibitory concentration (MIC) alues of 4 µg/mL, 2 µg/mL, 4 µg/mL, and 0.5 µg/mL against , , , and , respectively. The in vivo enzyme inhibition assay displayed the most potent topoisomerase II (IC = 13.5 µg/mL) and topoisomerase IV (IC = 24.2 µg/mL) inhibitory activity. Molecular docking was performed to position compound into the topoisomerase II active site to determine the probable binding conformation. In summary, compound may serve as potential topoisomerase II inhibitor.
Topics: Anti-Bacterial Agents; DNA Gyrase; Esters; Microbial Sensitivity Tests; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Structure; Pyrazoles; Structure-Activity Relationship; Topoisomerase II Inhibitors; Triazoles
PubMed: 30987179
DOI: 10.3390/molecules24071311 -
Chemico-biological Interactions May 2019Plant cytosolic aldehyde dehydrogenases from family 2 (ALDH2s, EC 1.2.1.3) are non-specific enzymes and participate for example in the metabolism of acetaldehyde or...
Plant cytosolic aldehyde dehydrogenases from family 2 (ALDH2s, EC 1.2.1.3) are non-specific enzymes and participate for example in the metabolism of acetaldehyde or biosynthesis of phenylpropanoids. Plant aminoaldehyde dehydrogenases (AMADHs, ALDH10 family, EC 1.2.1.19) are broadly specific and play an important role in polyamine degradation or production of osmoprotectants. We have tested imidazole and pyrazole carbaldehydes and their alkyl-, allyl-, benzyl-, phenyl-, pyrimidinyl- or thienyl-derivatives as possible substrates of plant ALDH2 and ALDH10 enzymes. Imidazole represents a building block of histidine, histamine as well as certain alkaloids. It also appears in synthetic pharmaceuticals such as imidazole antifungals. Biological compounds containing pyrazole are rare (e.g. pyrazole-1-alanine and pyrazofurin antibiotics) but the ring is often found as a constituent of many synthetic drugs and pesticides. The aim was to evaluate whether aldehyde compounds based on azole heterocycles are oxidized by the enzymes, which would further support their expected role as detoxifying aldehyde scavengers. The analyzed imidazole and pyrazole carbaldehydes were only slowly converted by ALDH10s but well oxidized by cytosolic maize ALDH2 isoforms (particularly by ALDH2C1). In the latter case, the respective K values were in the range of 10-2000 μmol l; the k values appeared mostly between 0.1 and 1.0 s. The carbaldehyde group at the position 4 of imidazole was oxidized faster than that at the position 2. Such a difference was not observed for pyrazole carbaldehydes. Aldehydes with an aromatic substituent on their heterocyclic ring were oxidized faster than those with an aliphatic substituent. The most efficient of the tested substrates were comparable to benzaldehyde and p-anisaldehyde known as the best aromatic aldehyde substrates of plant cytosolic ALDH2s in vitro.
Topics: Aldehyde Dehydrogenase; Aldehydes; Imidazoles; Solanum lycopersicum; Molecular Structure; Oxidation-Reduction; Pisum sativum; Pyrazoles; Zea mays
PubMed: 30768969
DOI: 10.1016/j.cbi.2019.02.008 -
European Journal of Medicinal Chemistry Jun 2015Pyrazole is a five membered and two-nitrogen containing heterocyclic ring. These structures have been investigated in the development of novel compounds with... (Review)
Review
Pyrazole is a five membered and two-nitrogen containing heterocyclic ring. These structures have been investigated in the development of novel compounds with hypoglycemic, analgesic, anti-inflammatory, antimicrobial, anticonvulsant, antidepressant, antimycobacterial, antioxidant, antiviral, insecticidal and antitumor activities. Therefore, these compounds have been synthesized as target structures by many researchers and were evaluated for their biological activities. We hope that the bioactivity of pyrazole derivatives will be beneficial for the rational design of new generation of small molecule drugs. In this review, we report the structures of 1H-pyrazoles with their corresponding biological activities for 21st (in 2000-2014 years) century.
Topics: Animals; Drug Discovery; Humans; Pyrazoles
PubMed: 25555743
DOI: 10.1016/j.ejmech.2014.11.059 -
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 -
Molecules (Basel, Switzerland) Dec 2021Steroid sapogenin diosgenin is of significant interest due to its biological activity and synthetic application. A consecutive one-pot reaction of diosgenin, oxalyl...
Synthesis of Anti-Inflammatory Spirostene-Pyrazole Conjugates by a Consecutive Multicomponent Reaction of Diosgenin with Oxalyl Chloride, Arylalkynes and Hydrazines or Hydrazones.
Steroid sapogenin diosgenin is of significant interest due to its biological activity and synthetic application. A consecutive one-pot reaction of diosgenin, oxalyl chloride, arylacetylenes, and phenylhydrazine give rise to steroidal 1,3,5-trisubstituted pyrazoles (isolated yield 46-60%) when the Stephens-Castro reaction and heterocyclization steps were carried out by heating in benzene. When the cyclization step of alkyndione with phenylhydrazine was performed in 2-methoxyethanol at room temperature, steroidal α,β-alkynyl ()- and ()-hydrazones were isolated along with 1,3,5-trisubstituted pyrazole and the isomeric 2,3,5-trisubstituted pyrazole. The consecutive reaction of diosgenin, oxalyl chloride, phenylacetylene and benzoic acid hydrazides efficiently forms steroidal 1-benzoyl-5-hydroxy-3-phenylpyrazolines. The structure of new compounds was unambiguously corroborated by comprehensive NMR spectroscopy, mass-spectrometry, and X-ray structure analyses. Performing the heterocyclization step of ynedione with hydrazine monohydrate in 2-methoxyethanol allowed the synthesis of 5-phenyl substituted steroidal pyrazole, which was found to exhibit high anti-inflammatory activity, comparable to that of diclofenac sodium, a commercial pain reliever. It was shown by molecular docking that the new derivatives are incorporated into the binding site of the protein Keap1 Kelch-domain by their alkynylhydrazone or pyrazole substituent with the formation of more non-covalent bonds and have higher affinity than the initial spirostene core.
Topics: Animals; Anti-Inflammatory Agents; Chemistry Techniques, Synthetic; Chlorides; Combinatorial Chemistry Techniques; Diosgenin; Disease Models, Animal; Edema; Hydrazines; Hydrazones; Mice; Models, Molecular; Molecular Conformation; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Structure; Oxalates; Pyrazoles
PubMed: 35011399
DOI: 10.3390/molecules27010162