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Molecular Diversity Oct 2022A new series of 13 pyrazole-derivative compounds with potential antifungal activity were synthetized with good yields. The series have the...
A new series of 13 pyrazole-derivative compounds with potential antifungal activity were synthetized with good yields. The series have the (E)-2-((1-(R)-3,5-dimethyl-1H-pyrazol-4-yl)diazenyl)phenol general structure and were characterized by means of X-ray diffraction, UV-Vis, FTIR, H-NMR, C-NMR, and two-dimensional NMR experiments. This experimental characterization was complemented by DFT simulations. A deep insight regarding molecular reactivity was accomplished employing a conceptual DFT approach. In this sense, dual descriptors were calculated at HF and DFT level of theory and GGV spin-density Fukui functions. The main reactive region within the molecules was mapped through isosurface and condensed representations. Finally, chemical descriptors that have previously shown to be close related to biological activity were compared within the series. Thus, higher values of chemical potential ω and electrophilicity χ obtained for compounds 10, 9, 8, 6 and 7, in this order, suggest that these molecules are the better candidates as biological agents.
Topics: Antifungal Agents; Biological Factors; Models, Molecular; Phenols; Pyrazoles
PubMed: 34724138
DOI: 10.1007/s11030-021-10342-z -
Molecular Diversity Nov 2013A simple and practical four-step protocol for the parallel synthesis of 7-heteroaryl-pyrazolo[1,5-[Formula: see text]]pyrimidine-3-carboxamides was developed. The...
A simple and practical four-step protocol for the parallel synthesis of 7-heteroaryl-pyrazolo[1,5-[Formula: see text]]pyrimidine-3-carboxamides was developed. The synthesis starts with transformation of commercially available 2-acetylpyridine and acetylpyrazine with [Formula: see text] [Formula: see text]-dimethylformamide dimethylacetal into the corresponding [Formula: see text]-3-(dimethylamino)-1-(heteroaryl)prop-2-en-1-ones followed by cyclisation with methyl 5-amino-1[Formula: see text]-pyrazole-4-carboxylate to give methyl 7-heteroarylpyrazolo[1,5-[Formula: see text]]pyrimidine-3-carboxylates. Hydrolysis of the ester group and subsequent amidation of the so formed carboxylic acids with 12 primary and secondary aliphatic amines furnished a library of 24 title compounds in good overall yields and purity.
Topics: Combinatorial Chemistry Techniques; Cyclization; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Pyrazoles; Pyrimidines
PubMed: 23975596
DOI: 10.1007/s11030-013-9469-3 -
Bioorganic & Medicinal Chemistry Letters Dec 2011A series of 1-aryl-4-(4,5-dihydro-1H-imidazol-2-yl)-1H-pyrazoles (4a-g) and 5-amino-1-aryl-4-(4,5-dihydro-1H-imidazol-2-yl)-1H-pyrazoles (5a-g) were synthesized and...
A series of 1-aryl-4-(4,5-dihydro-1H-imidazol-2-yl)-1H-pyrazoles (4a-g) and 5-amino-1-aryl-4-(4,5-dihydro-1H-imidazol-2-yl)-1H-pyrazoles (5a-g) were synthesized and evaluated in vitro against three Leishmania species: L. amazonensis, L. braziliensis and L. infantum (L. chagasi syn.). The cytotoxicity was assessed. Among the derivatives examined, six compounds emerged as the most active on promastigotes forms of L. amazonensis with IC(50) values ranging from 15 to 60 μM. The reference drug pentamidine presented IC(50)=10 μM. However, these new compounds were less cytotoxic than pentamidine. Based on these results, the more promising derivative 5d was tested further in vivo. This compound showed inhibition of the progression of cutaneous lesions in CBA mice infected with L. amazonensis relative to an untreated control.
Topics: Animals; Antiprotozoal Agents; Imidazoles; Leishmania; Leishmaniasis; Mice; Pyrazoles; Structure-Activity Relationship
PubMed: 22055204
DOI: 10.1016/j.bmcl.2011.09.134 -
Molecular Diversity Feb 2021A simple approach for the synthesis of spiroacenaphthylene-pyranopyrazole derivatives was achieved via the reaction between acenaphthoquinone, pyrazolones, and activated...
A simple approach for the synthesis of spiroacenaphthylene-pyranopyrazole derivatives was achieved via the reaction between acenaphthoquinone, pyrazolones, and activated methylene compounds (malononitrile derivatives) in water as a green solvent without using any catalyst in order to avoid the use of transition metal. This method has the advantages of mild reaction condition, short reaction time, easy workup, excellent yields, and avoidance of environmentally hazardous solvents.
Topics: Acenaphthenes; Catalysis; Pyrazoles; Solvents; Spiro Compounds; Water
PubMed: 31997049
DOI: 10.1007/s11030-019-10030-z -
Biomolecules Dec 2022The combination of two compounds with known antimicrobial activity may, in some cases, be an effective way to limit the resistance to antibiotics of specific pathogens....
The combination of two compounds with known antimicrobial activity may, in some cases, be an effective way to limit the resistance to antibiotics of specific pathogens. Molecules carrying pyrazole moiety are well known for their bioactive properties and have wide applicability in the medical and pharmaceutical field. Surfactants have, among other useful properties, the ability to affect the growth of microorganisms. The paper reports on the effect of the combination of two pyrazole derivatives, (1H-pyrazol-1-yl) methanol 1-hydroxymethylpyrazole (SAM1) and 1,1'methandiylbis (1H-pyrazol) (AM1), with sorbitan monolaurate (polysorbate 21, Tween 21, T21) on the growth of Gram-positive and Gram-negative bacteria. The results demonstrated a different ability of this combination to inhibit and . T21 intensified the inhibitory activity of the pyrazoles to a greater extent in the Gram-negative bacteria compared to the Gram-positive ones, a fact confirmed by time-kill experiments. The experimental data showed that the association of T21 with the pyrazoles led to the increased release of intracellular material and a more intense uptake of crystal violet, which indicates that the potentiation of the antibacterial effect was based on the modification of the normal permeability of bacterial cells. T21 acted as a modulating factor and increased the permeability of the membrane, allowing the accelerated penetration of the pyrazoles inside the bacterial cells. This fact is important in controlling the global increase in microbial resistance to antibiotics and antimicrobials and finding viable solutions to overcome the antibiotic crisis. The paper highlights the possibility of using non-toxic surfactant molecules in antimicrobial combinations with practical applications. This could widen the range of adjuvants in applications which would be useful in the control of resistant microorganisms.
Topics: Anti-Bacterial Agents; Polysorbates; Gram-Negative Bacteria; Gram-Positive Bacteria; Anti-Infective Agents; Pyrazoles; Surface-Active Agents; Microbial Sensitivity Tests
PubMed: 36551246
DOI: 10.3390/biom12121819 -
Journal of Medicinal Chemistry May 2024-myristoyltransferase (NMT) is a promising antimalarial drug target. Despite biochemical similarities between and human NMTs, our recent research demonstrated that high...
-myristoyltransferase (NMT) is a promising antimalarial drug target. Despite biochemical similarities between and human NMTs, our recent research demonstrated that high selectivity is achievable. Herein, we report NMT-inhibiting compounds aimed at identifying novel mechanisms of selectivity. Various functional groups are appended to a pyrazole moiety in the inhibitor to target a pocket formed beneath the peptide binding cleft. The inhibitor core group polarity, lipophilicity, and size are also varied to probe the water structure near a channel. Selectivity index values range from 0.8 to 125.3. Cocrystal structures of two selective compounds, determined at 1.97 and 2.43 Å, show that extensions bind the targeted pocket but with different stabilities. A bulky naphthalene moiety introduced into the core binds next to instead of displacing protein-bound waters, causing a shift in the inhibitor position and expanding the binding site. Our structure-activity data provide a conceptual foundation for guiding future inhibitor optimizations.
Topics: Pyrazoles; Plasmodium vivax; Acyltransferases; Structure-Activity Relationship; Antimalarials; Enzyme Inhibitors; Crystallography, X-Ray; Humans; Models, Molecular; Binding Sites
PubMed: 38680035
DOI: 10.1021/acs.jmedchem.4c00168 -
Future Medicinal Chemistry Aug 2019Everyday studies prove the increasing need for newer and safer agents to control cellular inflammatory response, an underlying cause for the pathophysiology of many...
Everyday studies prove the increasing need for newer and safer agents to control cellular inflammatory response, an underlying cause for the pathophysiology of many other clinical cases. Two newly designed sets of schiff and chlacone substituted pyrazoles were synthesized and evaluated for their anti-inflammatory activities. Most potent representatives were chosen for investigation of ulcerogenic and molecular docking properties The synthesized compounds showed considerable edema inhibition percentage range if compared with celecoxib (13-93% and 58-93%, respectively) at different time intervals. Compound showed the best screening results if compared with celecoxib (inhibition % = 93.62 and 93.51% at 5 h, COX-1/COX-2 selectivity index SI = 215.44 and 308.16 and ulcer index = 7.25 and 8, respectively).
Topics: Animals; Anti-Inflammatory Agents; Binding Sites; Catalytic Domain; Celecoxib; Cyclooxygenase 1; Cyclooxygenase 2; Edema; Hydrogen Bonding; Male; Molecular Docking Simulation; Pyrazoles; Rats; Rats, Wistar; Structure-Activity Relationship
PubMed: 31517535
DOI: 10.4155/fmc-2018-0548 -
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 -
Molecular Diversity Feb 2021A library of pyrazole-thiazolidinone conjugates was synthesized using a molecular hybridization approach through a Vilsmeier-Haack reaction. The compounds were tested...
A library of pyrazole-thiazolidinone conjugates was synthesized using a molecular hybridization approach through a Vilsmeier-Haack reaction. The compounds were tested for anti-microbial activity against two Gram-positive bacteria (Staphylococcus aureus and methicillin-resistant Staphylococcus aureus) and four Gram-negative bacteria (Escherichia coli, Salmonella typhimurium, Klebsiella pneumonia and Pseudomonas aeruginosa). Among the compounds tested, 3-((2,4-dichlorophenyl)-1-(2,4-dinitrophenyl)-1H-pyrazol-yl)methylene)hydrazinecarbothioamide (3a) and 2-((3-(2-chlorophenyl)-1-(2,4 dinitrophenyl)-1H-pyrazol-4-yl)methyleneamino)thiazolidin-4-one (4b) emerged as the most potent anti-microbial compounds with minimum bactericidal concentrations of < 0.2 µM against MRSA and S. aureus. Structure-activity relationship analysis further revealed that the presence of 2,4-dichloro moiety surprisingly influenced the activity of the compounds. Molecular docking studies of the compounds into the crystal structure of topoisomerase II and topoisomerase IV suggest that compounds 3a and 4b preferably interact with the targets through hydrogen bonding.
Topics: Anti-Bacterial Agents; Gram-Negative Bacteria; Gram-Positive Bacteria; Hydrazines; Microbial Sensitivity Tests; Molecular Docking Simulation; Pyrazoles; Structure-Activity Relationship; Thioamides; Thiosemicarbazones
PubMed: 32086698
DOI: 10.1007/s11030-020-10046-w -
Journal of Medicinal Chemistry Jul 2015Following our discovery of human dihydroorotate dehydrogenase (DHODH) inhibition by 2-(3-alkoxy-1H-pyrazol-1-yl)pyrimidine derivatives as well as...
Following our discovery of human dihydroorotate dehydrogenase (DHODH) inhibition by 2-(3-alkoxy-1H-pyrazol-1-yl)pyrimidine derivatives as well as 2-(4-benzyl-3-ethoxy-5-methyl-1H-pyrazol-1-yl)-5-methylpyridine, we describe here the syntheses and evaluation of an array of azine-bearing analogues. As in our previous report, the structure-activity study of this series of human DHODH inhibitors was based on a phenotypic assay measuring measles virus replication. Among other inhibitors, this round of syntheses and biological evaluation iteration led to the highly active 5-cyclopropyl-2-(4-(2,6-difluorophenoxy)-3-isopropoxy-5-methyl-1H-pyrazol-1-yl)-3-fluoropyridine. Inhibition of DHODH by this compound was confirmed in an array of in vitro assays, including enzymatic tests and cell-based assays for viral replication and cellular growth. This molecule was found to be more active than the known inhibitors of DHODH, brequinar and teriflunomide, thus opening perspectives for its use as a tool or for the design of an original series of immunosuppressive agent. Moreover, because other series of inhibitors of human DHODH have been found to also affect Plasmodium falciparum DHODH, all the compounds were assayed for their effect on P. falciparum growth. However, the modest in vitro inhibition solely observed for two compounds did not correlate with their inhibition of P. falciparum DHODH.
Topics: Antiviral Agents; Dihydroorotate Dehydrogenase; Drug Design; Enzyme Inhibitors; HEK293 Cells; Humans; Inhibitory Concentration 50; Measles virus; Oxidoreductases Acting on CH-CH Group Donors; Plasmodium falciparum; Pyrazoles; Virus Replication
PubMed: 26079043
DOI: 10.1021/acs.jmedchem.5b00606