- Pyrazole and Triazole Derivatives as Mycobacterium tuberculosis UDP-Galactopyranose Inhibitors
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UDP-galactopyranose mutase (UGM) is an essential enzyme involved in the bacterial cell wall synthesis, and is not present in mammalian cells. Thus, UGM from Mycobacterium tuberculosis (Mtb) represents a novel and attractive drug target for developing antituberculosis agents. A pyrazole-based compound, MS208, was previously identified as a mixed inhibitor of MtbUGM which targets an allosteric site. To understand more about the structure activity relationship around the MS208 scaffold as a MtbUGM inhibitor, thirteen pyrazoles and triazole analogues were synthesized and tested against both MtbUGM and Mycobacterium tuberculosis in vitro. While the introduced structural modifications to MS208 did not improve the antituberculosis activity, most of the compounds showed MtbUGM inhibitory activity. Interestingly, the pyrazole derivative DA10 showed a competitive model for MtbUGM inhibition with improved Ki value of 51 ± 4 μM. However, the same compound did not inhibit the growth of Mycobacterium tuberculosis.
- Ahmed, Dalia M.,Chen, Jeffrey M.,Sanders, David A. R.
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- 4-Substituted quinoline derivatives and preparation methods and applications thereof
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The present invention provides a 4-substituted quinoline derivative and preparation method and application thereof, in particular, the present invention relates to a compound shown in formula (I), a method for preparing a compound shown in formula (I), an
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Paragraph 0166-0169
(2022/01/12)
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- Design, synthesis and evaluation of dihydrotriazine derivatives-bearing 5-aryloxypyrazole moieties as antibacterial agents
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Abstract: In the present investigation, a series of dihydrotriazine derivatives-bearing 5-aryloxypyrazole moieties were synthesized and their structures were confirmed by different spectral tools. The biological evaluation in vitro revealed that some of the target compounds exerted good antibacterial and antifungal activity in comparison with the reference drugs. Among these novel hybrids, compound 10d showed the most potent activity with minimum inhibitory concentration values (MIC) of 0.5?μg/mL against S. aureus 4220, MRSA 3506 and E. coli 1924 strain. The cytotoxic activity of the compounds 6d, 6m, 10d and 10g was assessed in MCF-7 and HeLa cells. Growth kinetics study showed significant inhibition of bacterial growth when treated with different conc. of 10d. In vitro enzyme study implied that compound 10d exerted its antibacterial activity through DHFR inhibition. Moreover, significant inhibition of biofilm formation was observed in bacterial cells treated with MIC conc. of 10d as visualized by SEM micrographs. Graphic abstract: Twenty-nine target compounds were designed, synthesized and evaluated in terms of their antibacterial and antifungal activities.[Figure not available: see fulltext.].
- Zhang, Tian-Yi,Li, Chun-Shi,Cui, Ming-Yue,Bai, Xue-Qian,Chen, Jiang-Hui,Song, Ze-Wen,Feng, Bo,Liu, Xue-Kun
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p. 861 - 876
(2020/04/09)
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- New hydrazone derivatives of pyrazole-4-carboxaldehydes exhibited anti-inflammatory properties
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Background: Several series of hydrazone derivatives of pyrazole-4-carboxaldehydes (4-11) were designed and synthesized to screen their inflammatory activity. Methods: The products were characterized by1H NMR,13C NMR and HRMS. In vitro LPS-induced TNF-α model and in vivo xylene-induced ear-edema model were used to evaluate their anti-inflammatory activity. Results and Conclusion: Bioassays indicated that most of the compounds markedly inhibited the expression of TNF-α at the concentration of 10 μg/mL. Compounds 7b and 11c, two of the most potent compounds, exhibited TNF-α inhibitory ability in a dose-dependent manner with IC50 values of 5.56 and 3.69 μM, respectively. In vivo, intraperitoneal administration with 7b and 11c markedly inhibited the ear edema at the doses of 20 and 50 mg/kg. Compound 11c, inhibited edema by 49.59 % at the dose of 20 mg/kg, was comparable to the reference drug dexamethasone at the same dose (with an inhibition of 50.49 %). To understand the binding pattern, molecular docking of representa-tive 7b and 11c was performed, which demonstrated that both compounds have a forceful binding with the TNF-α, and that the phenyl and hydrazide moieties of them play a significant role in binding with the target site.
- Chen, Qiuyan,Deng, Xianqing,He, Shihui,Li, Sifan,Liang, Yuqiu,Liu, Bing,Song, Mingxia,Yu, Shengwang
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p. 501 - 510
(2020/04/17)
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- “On-water” one-pot four-component synthesis of novel 1H-furo[2,3-c]pyrazole-4-amine derivatives
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A catalyst-free, simple and green protocol has been accomplished for the synthesis of novel 1H-furo[2,3-c]pyrazole-4-amines in a one-pot four-component domino reaction involving hydrazines, ethyl acetoacetate, aromatic amines and phenylglyoxal monohydrate in water. The protocol presented herein describes in situ generated pyrazolone as intermediate reactants with phenylglyoxal monohydrate in a Knoevenagel condensation followed by a Michael addition of amine, intramolecular cyclization, dehydration and the resulting to the title compound. It was observed that in this protocol bis(pyrazole-5-ols) are formed with amines bearing strong electron withdrawing groups under similar reaction conditions instead of the expected products. The reaction merits the use of water as solvent, no additive catalyst, easy workup, easy purification of products by non-chromatography and provides high yield of products with good purity.
- Noruzian, Fatemeh,Olyaei, Abolfazl,Hajinasiri, Rahimeh
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p. 4383 - 4394
(2019/05/01)
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- Guanidine hydrochloride catalyzed efficient one-pot pseudo five-component synthesis of 4,4′-(arylmethylene)bis(1H-pyrazol-5-ols) in water
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The present methodology describes an efficient, environmentally friendly and simple protocol for the synthesis of some 4,4′-(arylmethylene)bis(1H-pyrazol-5-ol) derivatives through a one-pot pseudo-five-component reaction of hydrazine hydrate/phenyl hydrazine, ethyl acetoacetate, and various aromatic aldehydes catalyzed by guanidine hydrochloride. This condensation reaction was performed by tandem Knoevenagel–Michael reaction in water under refluxing conditions giving the title compounds in 82–92% yields. Atom economy, simple operation, easy work-up, using inexpensive organocatalyst, high yields in short times, clean transformation, and environmentally benign are some of the important features of this new protocol.
- Noruzian, Fatemeh,Olyaei, Abolfazl,Hajinasiri, Rahimeh,Sadeghpour, Mahdieh
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supporting information
p. 2717 - 2724
(2019/08/08)
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- Synthesis of Pyrazolofuropyrazine via One-Pot S N Ar Reaction and Intramolecular Direct C-H Arylation
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Fused-ring systems containing heterocycles are attractive templates for drug discovery. Biologically active 6-5-5+6 fused-ring systems that possess heterocycles are available, but these require a relatively large number of synthetic steps for preparation. Therefore, pyrazolofuropyrazine was designed as a 6-5-5+6 ring system template that incorporates ready accessibility for drug discovery. Pyrazolofuropyrazines were successfully constructed in only a few steps via one-pot S N Ar reaction/intramolecular C-H direct arylation. As a drug candidate, pyrazolofuropyrazine has earned a favorable LogP, although significant biological activity has yet to be established; the ready accessibility of pyrazolofuropyrazine template, however, offers an opportunity for the rapid development of promising new drug candidates.
- Fuse, Shinichiro,Inaba, Megumi,Sato, Shinichi,Joshi, Manjusha,Nakamura, Hiroyuki
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p. 1493 - 1498
(2018/01/17)
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- Structure-activity relationships in a new class of non-substrate-like covalent inhibitors of the bacterial glycosyltransferase LgtC
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Lipooligosaccharide (LOS) structures in the outer core of Gram-negative mucosal pathogens such as Neisseria meningitidis and Haemophilus influenzae contain characteristic glycoepitopes that contribute significantly to bacterial virulence. An important example is the digalactoside epitope generated by the retaining α-1,4-galactosyltransferase LgtC. These digalactosides camouflage the pathogen from the host immune system and increase its serum resistance. Small molecular inhibitors of LgtC are therefore sought after as chemical tools to study bacterial virulence, and as potential candidates for anti-virulence drug discovery. We have recently discovered a new class of non-substrate-like inhibitors of LgtC. The new inhibitors act via a covalent mode of action, targeting a non-catalytic cysteine residue in the LgtC active site. Here, we describe, for the first time, structure-activity relationships for this new class of glycosyltransferase inhibitors. We have carried out a detailed analysis of the inhibition kinetics to establish the relative contribution of the non-covalent binding and the covalent inactivation steps for overall inhibitory activity. Selected inhibitors were also evaluated against a serum-resistant strain of Haemophilus influenzae, but did not enhance the killing effect of human serum.
- Xu, Yong,Cuccui, Jon,Denman, Carmen,Maharjan, Tripty,Wren, Brendan W.,Wagner, Gerd K.
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p. 2973 - 2983
(2018/03/29)
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- Three-component reaction for an efficient synthesis of 5-hydroxy-1-phenyl-1H-pyrazoles containing a stable phosphorus ylide moiety
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A concise synthesis of new polysubstituted pyrazoles containing a phosphorane is achieved from readily available organic compounds. This C–H bond functionalization is an efficient means of selectively substituting 4-position of pyrazole to produce a five-membered aromatic ring with a chain containing ylide moiety. This protocol requires no additional catalyst and can be used for other pyrazoles including different substituents.
- Ghonchepour, Ehsan,Islami, Mohammad Reza,Mostafavi, Hamid,Tikdari, Ahmad Momeni
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p. 459 - 463
(2018/03/01)
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- Design, Synthesis, DFT study and antifungal activity of pyrazolecarboxamide derivatives
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A series of novel pyrazole amide derivatives were designed and synthesized by multi-step reactions from phenylhydrazine and ethyl 3-oxobutanoate as starting materials, and their structures were characterized by NMR, MS and elemental analysis. The antifungal activity of the title compounds was determined. The results indicated that some of title compounds exhibited moderate antifungal activity. Furthermore, DFT calculations were used to study the structure-activity relationships (SAR).
- Mu, Jin-Xia,Shi, Yan-Xia,Yang, Ming-Yan,Sun, Zhao-Hui,Liu, Xing-Hai,Li, Bao-Ju,Sun, Na-Bo
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- Pyrazole amides compound, preparation method therefor and application thereof
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The present invention discloses a pyrazole amides compound. The structural formula of the compound is as shown in the description, wherein R is optionally substituted with one or more substituents of C1-C6 alkyl, alkoxy, halogen, nitro, and trifluoromethyl. The present invention also discloses a preparation method for the pyrazole amides compound. The pyrazole amides compound can be used for antibacterium, in particular for prevention and control of tomato late blight, tomato damping-off, corynespora cassiicola, botrytis cinerea, and cucumber sheath blight. The pyrazole amides compound can also be used for weeding, in particular for prevention and control of barnyard grass and rape.
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Paragraph 0011; 0037; 0038
(2016/10/10)
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- Regiocontrolled synthesis of 3- and 5-aminopyrazoles, pyrazolo[3,4-d] pyrimidines, pyrazolo[3,4-b]pyridines and pyrazolo[3,4-b]quinolinones as MAPK inhibitors
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Microwave irradiation of a hydrazine and 3-methoxyacrylonitrile, ethoxymethylenemalononitrile or ethyl acetoacetate provides rapid access to 3- or 5-substituted pyrazoles in excellent yield and with total regiocontrol in a process that can be switched from one regioisomer to the other by choice of conditions. Subsequent reaction, either by microwave-assisted hydrolysis and cyclocondensation with formamide, Hantzsch-type three-component reaction with an aldehyde and ketone, or by cyclocondensation with 2-nitrobenzaldehyde, provides the pyrazolo[3,4-d]pyrimidine, pyrazolo[3,4-b]pyridine or pyrazolo[3,4-b] quinolin-4-one framework, respectively, of inhibitors of mitogen-activated protein kinases.
- Bagley, Mark C.,Baashen, Mohammed,Paddock, Victoria L.,Kipling, David,Davis, Terence
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p. 8429 - 8438
(2013/09/02)
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- Synthesis and antibacterial evaluation of rhodanine-based 5-aryloxy pyrazoles against selected methicillin resistant and quinolone-resistant Staphylococcus aureus (MRSA and QRSA)
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With an intention to synergize the anti-bacterial activity of 5-aryloxy pyrazole and rhodanine derivatives, eight series of hybrid compounds have been synthesized and evaluated for their antibacterial activity. The majority of the synthesized compounds showed good inhibitory activity against selected methicillin resistant and quinolone-resistant Staphylococcus aureus (MRSA, QRSA) with minimum inhibitory concentration (MIC) values in the range of 1-32 μg/mL. The cytotoxicity test suggests that these compounds exhibited in vitro antibacterial activity at non-cytotoxic concentrations. These studies therefore suggest that rhodanine-based 5-aryloxy pyrazoles are interesting scaffolds for the development of novel Gram-positive antibacterial agents.
- Song, Ming-Xia,Zheng, Chang-Ji,Deng, Xian-Qing,Sun, Liang-Peng,Wu, Yan,Hong, Lan,Li, Ying-Jing,Liu, Yi,Wei, Zhi-Yu,Jin, Ming-Jun,Piao, Hu-Ri
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p. 376 - 385
(2013/03/28)
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- A one-pot three-component reactions for the synthesis of fully substituted spiro indeno[1,2-b]quinoxaline derivatives
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An efficient and simple approach of the synthesis of some spiro indeno[1,2-b]quinoxalines via a one-pot three-component reaction of 11H-indeno[1,2-b]quinoxalin-11-one, pyrazolone, and malononitrile in the presence of Na2CO3 at 70 C is reported. This reaction has shown to have high atom economy.
- Soleimani, Ebrahim,Hariri, Mina,Saei, Parisa
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p. 773 - 777
(2013/09/02)
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- Synthesis and biological evaluation of 5-aryloxypyrazole derivatives bearing a rhodanine-3-aromatic acid as potential antimicrobial agents
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Three novel series of 5-aryloxypyrazole derivatives have been synthesized and tested for their antibacterial activity. The majority of the synthesized compounds showed potent inhibitory activity against Gram-positive bacteria Staphylococcus aureus 4220, especially against the strains of multidrug-resistant clinical isolates (MRSA3167/3506 and QRSA3505/3519). Among which compounds IIIb, IIIg and IIIm showed the most potent levels of activity (MIC = 1 μg/mL) against the multidrug-resistant strains. And cytotoxic activity assay showed that the compounds tested did not affect cell viability on the Human cervical (HeLa) cells at their MICs. The current study therefore suggests that 5-aryloxypyrazoles bearing a rhodanine-3-aromatic acid moiety are promising scaffolds for the development of novel Gram-positive antibacterial agents.
- Zheng, Chang-Ji,Song, Ming-Xia,Sun, Liang-Peng,Wu, Yan,Hong, Lan,Piao, Hu-Ri
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p. 7024 - 7028
(2013/01/15)
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- Facile, fast and safe process development of nitration and bromination reactions using continuous flow reactors
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Chemists working in a pilot plant often face safety issues during scale-up operations. With the help of emerging microfluidic applications and microdevices, running hazardous, highly exothermic or potentially unstable reactions can be easily transposed into a safe continuous flow mode. This paper describes how a potentially hazardous pyrazole nitration and the bromination of a variety of electron-rich heteroaromatic substrates were efficiently performed using a cheap and easily available system for bench chemists. Advantages of the continuous flow mode in organic synthetic chemistry will be exemplified by the large-scale production of raw materials under safe, green and reproducible conditions.
- Pelleter, Jacques,Renaud, Fabrice
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experimental part
p. 698 - 705
(2010/04/22)
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- Cyclic and acyclic products from the reactions between methyl 3-oxo-butanoate and aryl-hydrazines
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The mol-ecules of methyl 3-(2-nitro-phenyl-hydrazono)-butan-oate, C11H13N3O4, (I), and methyl 3-(2,4-dinitro-phenyl-hydrazono)butanoate, C11H12N4O6, (II), both prepared from methyl 3-oxobutanoate and the corresponding nitro-phenyl-hydrazine, exhibit polarized mol-ecular electronic structures; in each of (I) and (II), the mol-ecules are linked into chains by a single C - H...O hydrogen bond. The mol-ecules of 5-hydroxy-3-methyl-1-phenyl-1H- pyrazole, C10H10N2O, (III), prepared by the reaction of methyl 3-oxobutanoate and phenyl-hydrazine, are linked into chains by a single O - H...N hydrogen bond. The reaction between methyl 3-oxobutanoate and 3-nitro-phenyl-hydrazine yields 5-hydr-oxy-3-methyl-1-(3-nitro-phen-yl)-1H-pyrazole, (IV), which when crystallized from acetone yields 4-isopropyl-idene-3-methyl-1-(3-nitro-phen-yl)- 1H-pyrazol-5(4H)-one, C13H13N3O3, (V). International Union of Crystallography 2007.
- Wardell, James L.,Skakle, Janet M. S.,Low, John N.,Glidewell, Christopher
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p. o462-o467
(2008/09/16)
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- Synthesis and SAR of 1,9-dihydro-9-hydroxypyrazolo[3,4-b]quinolin-4-ones as novel, selective c-Jun N-terminal kinase inhibitors
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A novel class of 1,9-dihydro-9-hydroxypyrazolo[3,4-b]quinolin-4-ones as c-Jun-N-terminal kinase (JNK) inhibitors is described. These compounds were synthesized via the condensation of 2-nitrobenzaldehydes and hydroxypyrazoles. The structure-activity relationships (SAR) and kinase selectivity profile of the inhibitors are also discussed. Compound 16 was identified as a potent JNK inhibitor with good cellular potency.
- Liu, Mei,Xin, Zhili,Clampit, Jill E.,Wang, Sanyi,Gum, Rebecca J.,Haasch, Deanna L.,Trevillyan, James M.,Abad-Zapatero, Cele,Fry, Elizabeth H.,Sham, Hing L.,Liu, Gang
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p. 2590 - 2594
(2007/10/03)
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- C-C bond cleavage studies in bipyrazoles: A convenient synthesis of pyrazolo-5-ols
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The treatment of 4-acetoacetyl derivative (3) of the pyrazoles with hydrazines in ethanol/HCl furnished a variety of bipyrazoles (4). However, when the reaction was performed in sodium acetate/acetic acid/ethanol, different hydrazines gave different products. Under these conditions an unexpected C-C bond cleavage was observed thus affording a convenient route for the formation of pyrazolo-5-ols (5 and 6).
- Singh, Shiv P.,Naithani, Rajesh,Aggarwal, Ranjana,Prakash, Om
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p. 611 - 619
(2007/10/03)
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- Synthesis of new heterocycles containing pyrazole
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New heterocyclic systems derived from pyrazole associating different nuclei such as pyrimidobenzimidazole, pyrimidopyrimidine, thiazolopyrimidine and pyrazolylpyridone have been synthesized by the treatment of some bisnucleophiles with acetoacetylpyrazole resulting from dehydroacetic acid.
- Djerrari,Fifani,Ahabchane,Essassi,Garrigues,Pierrot
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p. 2558 - 2562
(2007/10/03)
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- Synthesis and crystal structure of 2-[1-phenyl-3-methyl-5-oxo-pyrazol-4-ylidene]-4-methyl-1,5-benzodiazepine
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A novel pyrazolopyrane 5, obtained from phenylhydrazone 4, in boiling acetic acid reacts with o-phenylenediamine to give new 1,5-benzodiazepine 6.
- Djerrari,Essassi,Fifani,Garrigues,Pierrot
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p. 2820 - 2827
(2007/10/03)
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- The Solid-State Michael Addition of 3-Methyl-1-phenyl-5-pyrazolone
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A novel solid-state Michael addition between pyrazolone 1 and 4-arylidenepyrazolones 2 at ambient temperature produced Michael adducts, 4,4′-arylidenebis(3-methyl-1-phenyl-5-pyrazolones) 3. Pyrazolones 3 formed salts 4 with Cu2+ in solution, indicating the enolic structure of the pyrazolone rings. The reactivity of 2 with 1 is discussed in terms of the electronic and steric effects of the substituent on the arylidene group of compounds 2. Pyrazolone 1 also underwent the solid state Michael addition reaction with maleimide at 100° to give the adducts 7, 8 and 9.
- Li, Xiao-Liu,Wang, Yong-Mei,Tian, Bing,Matsuura, Teruo,Meng, Ji-Ben
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p. 129 - 134
(2007/10/03)
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- REACTIONS OF COPPER(II) POLYFLUORINATED β-DIKETONATES AND β-KETOESTERATES WITH HYDRAZINES
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It has been shown that pyrazoles (hydroxypyrazoles) are formed upon reaction of fluorine-containing copper β-diketonates (β-ketoesterates) with hydrazines and their hydrochlorides.A preparative method has been developed for the synthesis of fluorinated pyrazoles and hydroxypyrazoles via treatment of fluorine-containing β-diketonate and β-ketoesterate copper compounds with hydrazines.The molecular structure of 1-phenyl-3-octafluorobutyl-5-hydroxypyrazole has been established based on x-ray structural analysis.
- Kondrat'ev, P. N.,Skryabina, Z. E.,Saloutin, V. I.,Pashkevich, K. I.,Klyuev, N. A.,Aleksandrov, G. G.
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p. 561 - 565
(2007/10/02)
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- 1H-N.M.R., 13C-N.M.R., and I.R.-Investigations Concerning Tautomerism of 15N-Labeled 3-Methyl-1-phenyl-Δ2-pyrazolin-5-one
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The behaviour of the 15N-mono and dilabeled compound in dependence on temperature and solvent polarity is described.Chemical shifts, nJ(15N-13C) coupling constants (n = 1 - 3) have been determined.In the cases of 2,2,2-trifluoroethanole and hexafluoroisopropanole the Δ4-pyrazolin-3-one is stabilized and detected by 3J(15N-2-H-4) = 3 Hz, 1J(13C-3-15N-2) = 11,0 Hz and δ(13C-5).In HMPT the 5-hydroxypyrazole form predominates and is characterized by 3J(15N-1-H-4) = 5,1 Hz and δ (13C-5).Coupling constants 3J(15N-2-H-4) and J(13C-3-15N-2) could not be observed in this solvent.In accordance with 1H- and 13C-n.m.r.-parameters i.r. measurements in dependence on temperature lead to the conclusion that in DMSO and THF for instance all three tautomers are present and variation of temperature does not change the equilibrium between the tautomers.A good relationship between the content of the CH2, OH and NH forms and the Donor Numbers (DN) and Acceptor Numbers (AN) by Gutmann has been found.
- Freyer, Wolfgang,Koeppel, Hubert,Radeglia, Reiner,Malewski, Guenter
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p. 238 - 250
(2007/10/02)
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