- Cyclooxygenase-2 inhibitors. 1,5-diarylpyrrol-3-acetic esters with enhanced inhibitory activity toward cyclooxygenase-2 and improved cyclooxygenase-2/ cyclooxygenase-1 selectivity
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The important role of cyclooxygenase-2 (COX-2) in the pathogenesis of inflammation and side effect limitations of current COX-2 inhibitor drugs illustrates a need for the design of new compounds based on alternative structural templates. We previously reported a set of substituted 1,5-diarylpyrrole derivatives, along with their inhibitory activity toward COX enzymes. Several compounds proved to be highly selective COX-2 inhibitors and their affinity data were rationalized through docking simulations. In this paper, we describe the synthesis of new 1,5-diarylpyrrole derivatives that were assayed for their in vitro inhibitory effects toward COX isozymes. Among them, the ethyl-2-methyl-5-[4-(methylsulfonyl)phenyl]-1-[3-fluorophenyl]-1H-pyrrol-3- acetate (1d), which was the most potent and COX-2 selective compound, also showed a very interesting in vivo anti-inflammatory and analgesic activity, laying the foundations for developing new lead compounds that could be effective agents in the armamentarium for the management of inflammation and pain.
- Biava, Mariangela,Porretta, Giulio Cesare,Poce, Giovanna,Supino, Sibilla,Forli, Stefano,Rovini, Michele,Cappelli, Andrea,Manetti, Fabrizio,Botta, Maurizio,Sautebin, Lidia,Rossi, Antonietta,Pergola, Carlo,Ghelardini, Carla,Vivoli, Elisa,Makovec, Francesco,Anzellotti, Paola,Patrignani, Paola,Anzini, Maurizio
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Read Online
- Formation of 1,4-diketones via bis-acylation of the conjugated carbon-carbon double bonds in acrylates, acrylamides, methyl vinyl ketone and styrenes with aroyl chlorides promoted by samarium metal in DMF
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Promoted by samarium in DMF, aroyl chlorides react readily with conjugated carbon-carbon double bonds in acrylates, acrylamides, methyl vinyl ketone and styrenes in a bis-acylation manner. These reactions proceed smoothly under mild conditions without the need of pretreating or activating the metallic samarium, affording the corresponding 1,4-diketones in good to excellent yields.
- Liu, Yongjun,Zhang, Yongmin
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Read Online
- A fluorescent target-guided Paal-Knorr reaction
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It has become increasingly apparent that high-diversity chemical reactions play a significant role in the discovery of bioactive small molecules. Here, we describe an expanse of this paradigm, combining a ‘target-guided synthesis’ concept with Paal-Knorr chemistry applied to the preparation of fluorescent ligands for human prostaglandin-endoperoxide synthase (COX-2).
- Kornienko, Alexander,La Clair, James J.,Maslivetc, Vladimir,Wagh, Sachin B.
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p. 37035 - 37039
(2020/10/19)
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- Copper-Catalyzed Decarboxylative Oxyalkylation of Alkynyl Carboxylic Acids: Synthesis of ?-Diketones and ?-Ketonitriles
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A novel copper-catalyzed decarboxylative oxyalkylation of alkynyl carboxylic acids with ketones and alkylnitriles via direct C(sp3)-H bond functionalization to construct new C-C bonds and C-O double bonds was developed. This transformation is featured by wide functional group compatibility and the use of readily available reagents, thus affording a general approach to ?-diketones and ?-ketonitriles. A possible mechanism is proposed.
- Li, Yi,Shang, Jia-Qi,Wang, Xiang-Xiang,Xia, Wen-Jin,Yang, Tao,Xin, Yangchun,Li, Ya-Min
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supporting information
p. 2227 - 2230
(2019/03/26)
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- Nonclassical Mechanism in the Cyclodehydration of Diols Catalyzed by a Bifunctional Iridium Complex
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1,4- and 1,5-diols undergo cyclodehydration upon treatment with cationic N-heterocyclic carbene (NHC)–IrIII complexes to give tetrahydrofurans and tetrahydropyrans, respectively. The mechanism was investigated, and a metal-hydride-driven pathway was proposed for all substrates, except for very electron-rich ones. This contrasts with the well-established classical pathways that involve nucleophilic substitution.
- González Miera, Greco,Bermejo López, Aitor,Martínez-Castro, Elisa,Norrby, Per-Ola,Martín-Matute, Belén
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supporting information
p. 2631 - 2636
(2019/02/01)
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- Switching on the activity of 1,5-diaryl-pyrrole derivatives against drug-resistant ESKAPE bacteria: Structure-activity relationships and mode of action studies
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Antibiotic resistance represents a major threat worldwide. Gram-positive and Gram-negative opportunistic pathogens are becoming resistant to all known drugs mainly because of the overuse and misuse of these medications and the lack of new antibiotic development by the pharmaceutical industry. There is an urgent need to discover structurally innovative antibacterial agents for which no pre-existing resistance is known. This work describes the identification, synthesis and biological evaluation of a novel series of 1,5-diphenylpyrrole compounds active against a panel of ESKAPE bacteria. The new compounds show high activity against both wild type and drug-resistant Gram + ve and Gram-ve pathogens at concentrations similar or lower than levofloxacin. Microbiology studies revealed that the plausible target of the pyrrole derivatives is the bacterial DNA gyrase, with the pyrrole derivatives displaying similar inhibitory activity to levofloxacin against the wild type enzyme and retaining activity against the fluoroquinolone-resistant enzyme.
- Masci, Domiziana,Hind, Charlotte,Islam, Mohammad K.,Toscani, Anita,Clifford, Melanie,Coluccia, Antonio,Conforti, Irene,Touitou, Meir,Memdouh, Siham,Wei, Xumin,La Regina, Giuseppe,Silvestri, Romano,Sutton, J. Mark,Castagnolo, Daniele
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p. 500 - 514
(2019/06/18)
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- Copper/Manganese Cocatalyzed Oxidative Coupling of Vinylarenes with Ketones
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A novel copper/manganese cocatalyzed direct oxidative coupling of terminal vinylarenes with ketones via C(sp3)-H bond functionalization following C-C bond formation has been developed using tert-butyl hydroperoxide as the radical initiator. Various ketones underwent a free-radical addition of terminal vinylarenes to give the corresponding 1,4-dicarbonyl products with excellent regioselectivity and efficiency through one step. A possible reaction mechanism has been proposed.
- Lan, Xing-Wang,Wang, Nai-Xing,Zhang, Wei,Wen, Jia-Long,Bai, Cui-Bing,Xing, Yalan,Li, Yi-He
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supporting information
p. 4460 - 4463
(2015/09/28)
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- A regio- and stereoselective ω-transaminase/monoamine oxidase cascade for the synthesis of chiral 2,5-disubstituted pyrrolidines
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Biocatalytic approaches to the synthesis of optically pure chiral amines, starting from simple achiral building blocks, are highly desirable because such motifs are present in a wide variety of important natural products and pharmaceutical compounds. Herein, a novel one-pot ω-transaminase (TA)/monoamine oxidase (MAO-N) cascade process for the synthesis of chiral 2,5-disubstituted pyrrolidines is reported. The reactions proceeded with excellent enantio- and diastereoselectivity (>94 % ee; >98 % de) and can be performed on a preparative scale. This methodology exploits the complementary regio- and stereoselectivity displayed by both enzymes, which ensures that the stereogenic center established by the transaminase is not affected by the monoamine oxidase, and highlights the potential of this multienzyme cascade for the efficient synthesis of chiral building blocks. Mirror mirror on the wall: A ω-transaminase (ω-TA)/monoamine oxidase (MAO-N) cascade process for the asymmetric synthesis of chiral 2,5-disubstituted pyrrolidines is reported. The methodology exploits the complementary regio- and stereoselectivity displayed by both enzymes, which ensures that the stereogenic center established by the TA reaction is not affected by the MAO-N catalyzed step. Copyright
- O'Reilly, Elaine,Iglesias, Cesar,Ghislieri, Diego,Hopwood, Jennifer,Galman, James L.,Lloyd, Richard C.,Turner, Nicholas J.
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supporting information
p. 2447 - 2450
(2014/03/21)
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- Synthesis and study of benzothiazole conjugates in the control of cell proliferation by modulating Ras/MEK/ERK-dependent pathway in MCF-7 cells
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By applying a methodology, a series of benzothiazole-pyrrole based conjugates (4a-r) were synthesized and evaluated for their antiproliferative activity. Compounds such as 4a, 4c, 4e, 4g-j, 4m, 4n, 4o and 4r exhibited significant cytotoxic effect in the MCF-7 cell line. Cell cycle effects were examined for these conjugates at 2 μM as well as 4 μM concentrations and FACS analysis show an increase of G2/M phase cells with concomitant decrease of G1 phase cells thereby indicating G2/M cell cycle arrest by them. Interestingly 4o and 4r are effective in causing apoptosis in MCF-7 cells. Moreover, 4o showed down regulation of oncogenic expression of Ras and its downstream effector molecules such as MEK1, ERK1/2, p38 MAPK and VEGF. The apoptotic aspect of this conjugate is further evidenced by increased expression of caspase-9 in MCF-7 cells. Hence these small molecules have the potential to control both the cell proliferation as well as the invasion process in the highly malignant breast cancers.
- Kamal, Ahmed,Faazil, Shaikh,Ramaiah, M. Janaki,Ashraf, Md.,Balakrishna,Pushpavalli,Patel, Nibedita,Pal-Bhadra, Manika
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supporting information
p. 5733 - 5739
(2013/10/01)
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- Polarity reversal induced by electrochemically generated thiazol-2-ylidenes: The Stetter reaction
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The inversion of the normal reactivity (umpolung) of aldehydes has been induced via N-heterocyclic carbenes (NHCs) thiazol-2-ylidenes 2a or 3a, generated by simple electrolyses of solutions containing thiazolium salt 2 or 3. Accordingly, 1,4-dicarbonyl compounds have been obtained, in mild conditions and in moderate to very high yields, via 1,4-addition of the Breslow intermediates to the suitable Michael acceptor. The procedure has been performed in classical organic solvents (VOCs) as well as in room temperature ionic liquids (RTILs). The different reactivity of aliphatic aldehydes vs the one of aromatic and heteroaromatic aldehydes has been emphasized.
- Orsini, Monica,Chiarotto, Isabella,Sotgiu, Giovanni,Inesi, Achille
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experimental part
p. 3511 - 3517
(2010/07/09)
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- Identification of a novel pyrrole derivative endowed with antimycobacterial activity and protection index comparable to that of the current antitubercular drugs streptomycin and rifampin
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A hit optimization procedure based on isosteric and bioisosteric replacement of decorating groups at both the N1 and the C5 phenyl rings of 1,5-diarylpyrroles led to identification of 4-((1-(4-fluorophenyl)-2-methyl-5- (4-(methylthio)phenyl)-1H-pyrrol-3-yl)methyl)thiomorpholine that is characterized by a very high activity toward both Mycobacterium tuberculosis 103471 and H37Rv strains (MIC values of 0.125 μg/mL), and a safe profile in terms of cytotoxicity (CC50 of >128 μg/mL) and protection index (>1000). Antitubercular activity and protection index of the new compound are comparable to those found for the current antitubercular drugs streptomycin and rifampin.
- Biava, Mariangela,Porretta, Giulio Cesare,Poce, Giovanna,Battilocchio, Claudio,Alfonso, Salvatore,Logu, Alessandro De,Serra, Nadia,Manetti, Fabrizio,Botta, Maurizio
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experimental part
p. 8076 - 8084
(2011/01/13)
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- Synthesis of furans, pyrroles and pyridazines by a ruthenium-catalysed isomerisation of alkynediols and in situ cyclisation
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Alkyne-1,4-diols are readily available substrates which are isomerised to 1,4-diketones using Ru(PPh3)3(CO)H2/xantphos as a catalyst. In situ cyclisation into furans, pyrroles and pyridazines has been achieved under suitable conditions.
- Pridmore, Simon J.,Slatford, Paul A.,Taylor, James E.,Whittlesey, Michael K.,Williams, Jonathan M.J.
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supporting information; experimental part
p. 8981 - 8986
(2009/12/27)
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- Highly selective synthesis of 1-phenylpentane-1, 4-diones, and (E)-5-hydroxy-5-phenylpent-3-en-2-ones catalyzed by organophosphorus compounds
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1-Phenylpentane-1, 4-diones, and (E)- 5-hydroxy-5-phenylpent-3-en-2-ones were synthesized via organophosphine-catalyzed addition reaction of but-3-en-2-one with aldehydes. The features of the present protocols include high selectivity, operational simplicity, atom economy, and mild reaction conditions without transition metals.
- Zhang, Qing,Qiao, Yan-Fei,Huang, Min,Liang, Hong-Dong,Zhou, Ru-Jin
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experimental part
p. 425 - 430
(2010/07/16)
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- PYRROLE DERIVATIVES AND THEIR METHODS OF USE
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The invention relates to a series of substituted pyrrole derivatives, compositions comprising the same, and methods of treating conditions and disorders using such compounds and compositions.
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Page/Page column 68-69; 76-77
(2008/06/13)
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- 1,5-Diphenylpyrrole derivatives as antimycobacterial agents. Probing the influence on antimycobacterial activity of lipophilic substituents at the phenyl rings
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Synthesis and biological evaluation of new derivatives of 1,5-bis(4-chlorophenyl)-2-methyl-3-(4-methylpiperazin-1-yl)methyl-1H-pyrrole (BM 212, 16) are reported. Variously substituted phenyl rings with different substitution pattern and lipophilicity were
- Biava, Mariangela,Porretta, Giulio Cesare,Poce, Giovanna,De Logu, Alessandro,Saddi, Manuela,Meleddu, Rita,Manetti, Fabrizio,De Rossi, Edda,Botta, Maurizio
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supporting information; experimental part
p. 3644 - 3648
(2009/04/07)
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- 2,5-Disubstituted furans from 1,4-alkynediols
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1,4-Alkynediols serve as readily available starting materials for isomerisation to 1,4-diketones, which can be converted in situ into the corresponding furans by acid-catalysed dehydration. A range of 2,5-disubstituted furans was prepared using the ruthenium-based catalyst Ru(PPh3)3(CO)H2 with Xantphos at 1 mol % loading.
- Pridmore, Simon J.,Slatford, Paul A.,Williams, Jonathan M.J.
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p. 5111 - 5114
(2008/02/09)
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- Ruthenium-catalysed conversion of 1,4-alkynediols into pyrroles
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Various 1,2,5-substituted pyrroles have been synthesised from 1,4-alkynediols using a ruthenium catalysed isomerisation to give the corresponding 1,4-dicarbonyl compounds, which undergo in situ cyclisation to pyrroles in the presence of amine.
- Pridmore, Simon J.,Slatford, Paul A.,Daniel, Aurélie,Whittlesey, Michael K.,Williams, Jonathan M.J.
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p. 5115 - 5120
(2008/02/09)
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- 1,4-Carbonylative addition of arylboronic acids to methyl vinyl ketone: a new synthetic tool for rapid furan and pyrrole synthesis
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The rhodium catalysed 1,4-carbonylative addition of arylboronic acids to methyl vinyl ketone under carbon monoxide pressure was studied. High yields of 1,4-diketones were obtained using a catalytic system formed from Rh(COD)2BF4 (COD=1,5-cyclooctadiene) and triphenylphosphine even at very low catalyst loading (0.02 mol %). A short synthetic procedure combining this carbonylation reaction with a subsequent cyclisation step affords pyrroles or furans.
- Chochois, Hélène,Sauthier, Mathieu,Maerten, Eddy,Castanet, Yves,Mortreux, André
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p. 11740 - 11746
(2007/10/03)
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- Antimycobacterial agents. Novel diarylpyrrole derivatives of BM212 endowed with high activity toward Mycobacterium tuberculosis and low cytotoxicity
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On the basis of suggestions derived either from a pharmacophoric model for antitubercular agents or from a structure-activity relationship analysis of many pyrroles previously described by us, we report here the design and synthesis of new analogues of 1,
- Biava, Mariangela,Porretta, Giulio Cesare,Poce, Giovanna,Supino, Sibilla,Deidda, Delia,Pompei, Raffaello,Molicotti, Paola,Manetti, Fabrizio,Botta, Maurizio
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p. 4946 - 4952
(2007/10/03)
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- DERIVATIVES OF 1-{ [1,5-BIS(4-CHLOROPHENYL)-2-METHYL-1H-PYRROL-3-YL] METHYL}-4- METHYLPIPERAZINE, SYNTHESIS PROCESS AND USES THEREOF
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The present invention concerns pyrrole compounds, derivatives of 1-{[1,5-bis(4- chlorophenyl)-2-methyl-lH-pyrrol-3-yl]methyl}-4-methylpiperazine (BM212). The invention concerns the use of the described compounds as antitubercular agents having high activi
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Page/Page column 15
(2008/06/13)
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- New synthesis of 1,4-diketones via rhodium-catalysed 1,4 carbonylative addition of arylboronic acids to α,β-unsaturated ketones
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The reaction of various arylboronic acids with α,β-unsaturated ketones under CO pressure and in the presence of rhodium catalyst yields 1,4-diketones.
- Sauthier, Mathieu,Castanet, Yves,Mortreux, Andre
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p. 1520 - 1521
(2007/10/03)
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- Stetter reaction in room temperature ionic liquids and application to the synthesis of haloperidol
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Imidazolium-type room temperature ionic liquids (RTILs) have been used for the Stetter reaction, affording the desired 1,4-dicarbonyl compounds in good yields. Thiazolium salts and Et3N are efficient catalysts for this reaction performed in ionic liquid. The possibility to recycle and reuse the solvent has been demonstrated, although it was not possible to recycle the thiazolium catalyst. This method was used in the total synthesis of haloperidol.
- Anjaiah, Siddam,Chandrasekhar, Srivari,Gree, Rene
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p. 1329 - 1334
(2007/10/03)
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- 1,2-Diarylpyrroles as potent and selective inhibitors of cyclooxygenase- 2
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Series of 1,2-diarylpyrroles has been synthesized and found to contain very potent and selective inhibitors of the human cyclooxygenase-2 (COX-2) enzyme. The paper describes short and practical syntheses of the target molecules utilizing the Paal-Knorr reaction. Electrophilic substitution on 1 proceeds in a regioselective fashion, and the method was used to generate a number of tetrasubstituted pyrroles. Detailed SAR on the series has been studied by modifications of the aryl rings and the substituents in the pyrrole ring. Diarylpyrrole 1 is a very potent (COX-2, IC50 = 60 nm) and selective (COX-1/COX-2 = > 1700) inhibitor whereas the isomeric 2 is completely inactive against COX-2. Modifications of the substituents on the fluorophenyl ring in 1 yields very potent inhibitors of COX-2 (IC50 = 40- 80 nm) with excellent selectivity(1200 to >2500) vs COX-1, Analog 20 containing a sulfonamide group is an excellent inhibitor of COX-2 with an IC50 of 14 nm. Tetrasubstituted pyrroles containing groups such as COCF3, SO2CF3, or CH2OAr at position 3 in the pyrrole ring give excellent inhibitors (COX-2, IC50 = 30-120 nm). In vivo testing in the carrageenan- induced paw edema model in the rat establishes that the 1,2-diarylpyrroles are orally active antiinflammatory agents. Compound 3 is the most potent inhibitor of edema with an ED50 of 4.7 mpk.
- Khanna, Ish K.,Weier, Richard M.,Yu, Yi,Collins, Paul W.,Miyashiro, Julie M.,Koboldt, Carol M.,Veenhuizen, Amy W.,Currie, Jerry L.,Seibert, Karen,Isakson, Peter C.
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p. 1619 - 1633
(2007/10/03)
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- Facile Synthesis of 1,4-Diketones via Palladium Complex Catalyzed Isomerization of Alkynediols
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Alkynediols isomerized under the catalysis of Pd(dba)3*CHCl3 + 2n-Bu3P in acetonitrile at 80 deg C to give 1,4-diketones in high yields.This experimentally simple and economically synthetic method is illustrated with examples including substituents such as alkyl, alkenyl, and aryl groups.The order of reactivity of the substituents in this reaction is aryl >/= alkenyl > alkyl.Alkenyl-substituted alkynediols chemoselectively isomerized to the corresponding α,β-unsaturated 1,4-diketones.The usefulness of this novel method is examplified by the synthesis of dihydrojasmone.
- Lu, Xiyan,Ji, Jianguo,Ma, Dawei,Shen, Wei
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p. 5774 - 5778
(2007/10/02)
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- Inhibitors of Cholesterol Biosynthesis. 1. trans-6-(2-Pyrrol-1-ylethyl)-4-hydroxypyran-2-ones, a Novel Series of HMG-CoA Reductase Inhibitors. 1. Effects of Structural Modifications at the 2- and 5-Positions of the Pyrrole Nucleus
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A novel series of trans-6-(2-pyrrol-1-ylethyl)-4-hydroxypyran-2-ones and their dihydroxy acid derivatives were prepared and evaluated for their ability to inhibit the enzyme HMG-CoA reductase in vitro.A systematic study of substitution at the 2- and 5-positions of the pyrrole ring revealed that optimum potency was realized with the 2-(4-fluorophenyl)-5-isopropyl derivative 8x (Table III), which possessed 30percent of the in vitro activity of the potent fungal metabolite compactin (I).A molecular modeling analysis led to the description of a pharmacophore model characterized by (A) length limits of 5.9 and 3.3 Angstroem for the 2- and 5-substituents, respectively, as well as an overall width limit of 10.6 Angstroem across the pyrrole ring from the 2- to the 5-substituent and (B) an orientation of the ethyl(ene) bridge to the 4-hydroxypyran-2-one ring nearly perpendicular to the planes of the parent pyrrole, hexahydronaphthalene, and phenyl rings of the structures examined (Figure 3, θ = 80-110 deg).Attempts to more closely mimic compactin's polar isobutyric ester side chain with the synthesis of 2-phenylpyrroles containing polar phenyl substituents resulted in analogues (Table III, 8m-p) with equal or slightly reduced potencies when compared to the 2-pyrroles, supporting the hypothesis that inhibitory potency is relatively insensitive to side-chain polarity or charge distribution in this area.
- Roth, B. D.,Ortwine, D. F.,Hoefle, M. L.,Stratton, C. D.,Sliskovic, D. R.,et al.
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