- Synthesis of 2-heptyl-1-hydroxy-4(1H)-quinolone - Unexpected rearrangement of 4-(alkoxycarbonyloxy)quinoline N-oxides to 1-(alkoxycarbonyloxy)-4(1H)- quinolones
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2-Heptyl-4(1H)-quinolone was converted in two steps into the 4-ethoxycarbonyloxy-, 4-(tert-butoxycarbonyloxy)-, and 4- (dimethylaminocarbonyloxy)quinoline N-oxides. While the former two rearranged to the corresponding 1-(alkoxycarbonyloxy)-4(1H)-quinolones at room temperature, the latter was stable, even at 140°C in refluxing xylenes. Basic hydrolysis of these compounds furnished 2-heptyl-1-hydroxy-4(1H)-quinolone. Georg Thieme Verlag Stuttgart.
- Woschek, Anna,Mahout, Marek,Mereiter, Kurt,Hammerschmidt, Friedrich
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- Discovery of antagonists of PqsR, a key player in 2-alkyl-4-quinolone- dependent quorum sensing in Pseudomonas aeruginosa
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The pqs quorum sensing communication system of Pseudomonas aeruginosa controls virulence factor production and is involved in biofilm formation, therefore playing an important role for pathogenicity. In order to attenuate P. aeruginosa pathogenicity, we followed a ligand-based drug design approach and synthesized a series of compounds targeting PqsR, the receptor of the pqs system. In vitro evaluation using a reporter gene assay in Escherichia coli led to the discovery of the first competitive PqsR antagonists, which are highly potent (Kd,app of compound 20: 7 nM). These antagonists are able to reduce the production of the virulence factor pyocyanin in P. aeruginosa. Our finding offers insights into the ligand-receptor interaction of PqsR and provides a promising starting point for further drug design.
- Lu, Cenbin,Kirsch, Benjamin,Zimmer, Christina,De Jong, Johannes C.,Henn, Claudia,Maurer, Christine K.,Muesken, Mathias,Haeussler, Susanne,Steinbach, Anke,Hartmann, Rolf W.
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- QUINOLONE COMPOUNDS AND PROCESS FOR PREPARATION THEREOF
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The present invention relates to quinolones of formula (I) and process for its preparation by amine insertion into aryl-ynones thereof. [Formula I] The invention further relates to the process to obtain the natural products such as: graveoline, graveolinine, pseudane IV, pseudane VII, pseudane VIII and pseudane XII. The invention also describes the process for the total synthesis of waltherione F in concise approach from the quinolone synthesized. [Formula II]
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Paragraph 00047-00048
(2022/03/21)
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- Access to 2-Alkyl/Aryl-4-(1 H)-Quinolones via Orthogonal "nH3" Insertion into o-Haloaryl Ynones: Total Synthesis of Bioactive Pseudanes, Graveoline, Graveolinine, and Waltherione F
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An efficient one-pot synthesis of 4-(1H)-quinolones through an orthogonal engagement of diverse o-haloaryl ynones with ammonia in the presence of Cu(I), involving tandem Michael addition and ArCsp2-N coupling, is presented. The substrate scope of this convenient protocol, wherein ammonium carbonate acts as both an in situ ammonia source and a base toward diverse 2-substituted 4-(1H)-quinolones, has been mapped and its efficacy validated through concise total synthesis of bioactive natural products pseudanes (IV, VII, VIII, and XII), graveoline, graveolinine, and waltherione F.
- Mehta, Goverdhan,Nerella, Sharanya,Pabbaraja, Srihari,Singh, Shweta
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- Synthesis and biological activity of methylated derivatives of the Pseudomonas metabolites HHQ, HQNO and PQS
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Selectively methylated analogues of naturally occurring 2-heptyl-4(1H)-quinolones, which are alkaloids common within the Rutaceae family and moreover are associated with quorum sensing and virulence of the human pathogen Pseudomonas aeruginosa, have been prepared. While the synthesis by direct methylation was successful for 3-unsubstituted 2-heptyl-4(1H)-quinolones, methylated derivatives of the Pseudomonas quinolone signal (PQS) were synthesized from 3-iodinated quinolones by methylation and iodine–metal exchange/oxidation. The two N- and O-methylated derivatives of the PQS showed strong quorum sensing activity comparable to that of PQS itself. Staphylococcus aureus, another pathogenic bacterium often co-occurring with P. aeruginosa especially in the lung of cystic fibrosis patients, was inhibited in planktonic growth and cellular respiration by the 4-O-methylated derivatives of HQNO and HHQ, respectively.
- Thierbach, Sven,Wienhold, Max,Fetzner, Susanne,Hennecke, Ulrich
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p. 187 - 193
(2019/01/30)
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- COMPOUND FOR USE AGAINST PATHOGENIC NEISSERIA AND HAEMOPHILUS SPECIES AND MORAXELLA CATARRHALIS
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The present invention relates to a compound, which can be used in the prevention and treatment of infections with pathogenic Neisseria species, in particular N. gonorrhoeae and N. meningitidis (the gonococcus and the meningococcus, respectively), and other pathogenic bacteria (e.g. Haemophilus species or Moraxella catarrhalis ), and which can be used for disinfecting a substrate from said bacteria. Moreover, the present invention relates to a corresponding pharmaceutical composition comprising said compound.
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- Gold-catalyzed cyclization of 1-(2′-Azidoaryl) propynols: Synthesis of polysubstituted 4-quinolones
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An unprecedented gold-catalyzed procedure for the synthesis of polysubstituted 4-quinolones from 1-(2′-Azidoaryl) propynols is described. The reaction undergoes an intramolecular nucleophilic attack of the azide group to the Au-Activated triple bonds in a 6-endo-dig manner and subsequent gold-Assisted expulsion of N2 to furnish an α-imino gold carbene intermediate, which triggers a 1,2-carbon migration and finally is converted to 2,3-disubstituted 4-quinolone.
- Wu, Xiang,Zheng, Lang-Lang,Zhao, Li-Ping,Zhu, Cheng-Feng,Li, You-Gui
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supporting information
p. 14769 - 14772
(2019/12/24)
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- PqsL uses reduced flavin to produce 2-hydroxylaminobenzoylacetate, a preferred PqsBC substrate in alkyl quinolone biosynthesis in Pseudomonas aeruginosa
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Alkyl hydroxyquinoline N-oxides (AQNOs) are antibiotic compounds produced by the opportunistic bacterial pathogen Pseudomonas aeruginosa. They are products of the alkyl quinolone (AQ) biosynthetic pathway, which also generates the quorum-sensing molecules 2-heptyl-4(1H)-quinolone (HHQ) and 2-heptyl-3-hydroxy-4(1H)-quinolone (PQS). Although the enzymatic synthesis of HHQ and PQS had been elucidated, the route by which AQNOs are synthesized remained elusive. Here, we report on PqsL, the key enzyme for AQNO production, which structurally resembles class A flavoprotein monooxygenases such as p-hydroxybenzoate 3-hydroxylase (pHBH) and 3-hydroxybenzoate 6-hydroxylase. However, we found that unlike related enzymes, PqsL hydroxylates a primary aromatic amine group, and it does not use NAD(P)H as cosubstrate, but unexpectedly required reduced flavin as electron donor. We also observed that PqsL is active toward 2-aminobenzoylacetate (2-ABA), the central intermediate of the AQ pathway, and forms the unstable compound 2-hydroxylaminobenzoylacetate, which was preferred over 2-ABA as substrate of the downstream enzyme PqsBC. In vitro reconstitution of the PqsL/PqsBC reaction was feasible by using the FAD reductase HpaC, and we noted that the AQ:AQNO ratio is increased in an hpaC-deletion mutant of P. aeruginosa PAO1 compared with the ratio in the WT strain. A structural comparison with pHBH, the model enzyme of class A flavoprotein monooxygenases, revealed that structural features associated with NAD(P)H binding are missing in PqsL. Our study completes the AQNO biosynthetic pathway in P. aeruginosa, indicating that PqsL produces the unstable product 2-hydroxylaminobenzoylacetate from 2-ABA and depends on free reduced flavin as electron donor instead of NAD(P)H.
- Drees, Steffen Lorenz,Ernst, Simon,Belviso, Benny Danilo,Jagmann, Nina,Hennecke, Ulrich,Fetzner, Susanne
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p. 9345 - 9357
(2018/07/05)
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- Quinolones modulate ghrelin receptor signaling: Potential for a novel small molecule scaffold in the treatment of cachexia
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Cachexia is a metabolic wasting disorder characterized by progressive weight loss, muscle atrophy, fatigue, weakness, and appetite loss. Cachexia is associated with almost all major chronic illnesses including cancer, heart failure, obstructive pulmonary disease, and kidney disease and significantly impedes treatment outcome and therapy tolerance, reducing physical function and increasing mortality. Current cachexia treatments are limited and new pharmacological strategies are needed. Agonists for the growth hormone secretagogue (GHS-R1a), or ghrelin receptor, prospectively regulate the central regulation of appetite and growth hormone secretion, and therefore have tremendous potential as cachexia therapeutics. Non-peptide GHS-R1a agonists are of particular interest, especially given the high gastrointestinal degradation of peptide-based structures, including that of the endogenous ligand, ghrelin, which has a half-life of only 30 min. However, few compounds have been reported in the literature as non-peptide GHS-R1a agonists. In this paper, we investigate the in vitro potential of quinolone compounds to modulate the GHS-R1a in both transfected human cells and mouse hypothalamic cells. These chemically synthesized compounds demonstrate a promising potential as GHS-R1a agonists, shown by an increased intracellular calcium influx. Further studies are now warranted to substantiate and exploit the potential of these novel quinolone-based compounds as orexigenic therapeutics in conditions of cachexia and other metabolic and eating disorders.
- Torres-Fuentes, Cristina,Pastor-Cavada, Elena,Cano, Rafael,Kandil, Dalia,Shanahan, Rachel,Juan, Rocio,Shaban, Hamdy,McGlacken, Gerard P.,Schellekens, Harri?t
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- COMPOUNDS FOR USE AS AN ANTI-BACTERIAL OR ANTI-FUNGAL AGENT AND AS A ZINC SENSOR
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The present invention relates to a compound, which can be used as an anti-bacterial and/or an anti-fungal agent as well as a zinc sensor. Moreover, the present invention relates to a pharmaceutical composition comprising said compound and methods for treating bacterial or fungal infections in mammals.
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- The requirements at the C-3 position of alkylquinolones for signalling in Pseudomonas aeruginosa
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The 'perfect storm' of increasing bacterial antibiotic resistance and a decline in the discovery of new antibiotics, has made it necessary to search for new and innovative strategies to treat bacterial infections. Interruption of bacterial cell-to-cell communication signalling (Quorum Sensing), thus neutralizing virulence in pathogenic bacteria, is a growing area. 2-Alkyl-4-quinolones, HHQ and PQS, play a key role in the quorum sensing circuitry of P. aeruginosa. We report a new set of isosteres of 2-heptyl-6-nitroquinolin-4-one, with alterations at C-3, and evaluate the key structural requirements for agonistic and antagonistic activity in Pseudomonas aeruginosa.
- Shanahan, Rachel,Reen, F. Jerry,Cano, Rafael,O'Gara, Fergal,McGlacken, Gerard P.
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supporting information
p. 306 - 310
(2017/01/13)
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- An Unsaturated Quinolone N-Oxide of Pseudomonas aeruginosa Modulates Growth and Virulence of Staphylococcus aureus
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The pathogen Pseudomonas aeruginosa produces over 50 different quinolones, 16 of which belong to the class of 2-alkyl-4-quinolone N-oxides (AQNOs) with various chain lengths and degrees of saturation. We present the first synthesis of a previously proposed unsaturated compound that is confirmed to be present in culture extracts of P. aeruginosa, and its structure is shown to be trans-Δ1-2-(non-1-enyl)-4-quinolone N-oxide. This compound is the most active agent against S. aureus, including MRSA strains, by more than one order of magnitude whereas its cis isomer is inactive. At lower concentrations, the compound induces small-colony variants of S. aureus, reduces the virulence by inhibiting hemolysis, and inhibits nitrate reductase activity under anaerobic conditions. These studies suggest that this unsaturated AQNO is one of the major agents that are used by P. aeruginosa to modulate competing bacterial species.
- Szamosvári, Dávid,B?ttcher, Thomas
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p. 7271 - 7275
(2017/06/13)
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- Synthetic quinolone signal analogues inhibiting the virulence factor elastase of Pseudomonas aeruginosa
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We explore the chemical space of Pseudomonas quinolone signal analogs as privileged structures and report the discovery of a thioquinolone as a potent inhibitor of the important virulence factor elastase of the human pathogen Pseudomonas aeruginosa. We provide evidence that the derivative binds to the active site zinc of elastase and additionally acts as a fluorescent zinc sensor.
- Szamosvári, Dávid,Reichle, Valentin F.,Jureschi, Monica,B?ttcher, Thomas
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p. 13440 - 13443
(2016/11/19)
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- Synthesis of Unnatural 2-Substituted Quinolones and 1,3-Diketones by a Member of Type III Polyketide Synthases from Huperzia serrata
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A curcuminoids, benzalacetone-, and quinolone-producing type III polyketide synthase (HsPKS3) from Huperzia serrata uniquely catalyzes the formation of unnatural 2-substituted quinolones and 1,3-diketones via head-to-head condensation of two completely different substrates. The broad range of substrate tolerance of HsPKS3 facilitates accessing structurally diverse 2-substituted quinolones and 1,3-diketones.
- Wang, Juan,Wang, Xiao-Hui,Liu, Xiao,Li, Jun,Shi, Xiao-Ping,Song, Yue-Lin,Zeng, Ke-Wu,Zhang, Le,Tu, Peng-Fei,Shi, She-Po
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supporting information
p. 3550 - 3553
(2016/08/16)
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- Optimization of anti-virulence PqsR antagonists regarding aqueous solubility and biological properties resulting in new insights in structure-activity relationships
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Increasing antibiotic resistance urgently requires novel therapeutic options to combat bacterial infections. The anti-virulence therapy selectively intervening with pathogenicity without affecting bacterial viability is such a strategy to overcome resistance. We consider the virulence regulator PqsR as an attractive target in the human pathogen Pseudomonas aeruginosa, and recently discovered the first PqsR antagonists, which, however, suffered from poor aqueous solubility. In this work, the antagonists were structurally modified to become more soluble, and their structure-activity as well as structure-property relationships were studied. A novel promising compound with improved solubility and enhanced anti-virulence activity was discovered (IC50: 3.8 μM, pyocyanin). Our findings emphasize the crucial role of substituents at the 3-position and the carbonyl group at the 4-position for ligand-receptor interactions, and illuminate the way for further optimization of PqsR antagonists as anti-virulence agents.
- Lu, Cenbin,Kirsch, Benjamin,Maurer, Christine K.,De Jong, Johannes C.,Braunshausen, Andrea,Steinbach, Anke,Hartmann, Rolf W.
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p. 173 - 183
(2014/05/06)
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- Structure-function analysis of the C-3 position in analogues of microbial behavioural modulators HHQ and PQS
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2-Heptyl-3-hydroxy-4-quinolone (PQS) and its precursor 2-heptyl-4-quinolone (HHQ) are key signalling molecules of the important nosocomial pathogen Pseudomonas aeruginosa. We have recently reported an interkingdom dimension to these molecules, influencing key virulence traits in a broad spectrum of microbial species and in the human pathogenic yeast Candida albicans. For the first time, targeted chemical derivatisation of the C-3 position was undertaken to investigate the structural and molecular properties underpinning the biological activity of these compounds in P. aeruginosa, and using Bacillus subtilis as a suitable model system for investigating modulation of interspecies behaviour.
- Reen, F. Jerry,Clarke, Sarah L.,Legendre, Claire,McSweeney, Christina M.,Eccles, Kevin S.,Lawrence, Simon E.,O'Gara, Fergal,McGlacken, Gerard P.
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supporting information
p. 8903 - 8910
(2013/01/15)
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- Synthesis of 3-halo-analogues of HHQ, subsequent cross-coupling and first crystal structure of Pseudomonas quinolone signal (PQS)
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2-Aryl- and 2-alkyl-quinolin-4-ones and their N-substituted derivatives have several important biological functions such as the Pseudomonas quinolone signal (PQS) molecule participation in quorum sensing. Herein, we report the synthesis of its biological precursor, 2-heptyl-4-hydroxy-quinoline (HHQ) and possible isosteres of PQS; the C-3 Cl, Br and I analogues. N-Methylation of the iodide was also feasible and the usefulness of this compound showcased in Pd-catalysed cross-coupling reactions, thus allowing access to a diverse set of biologically important molecules. The first crystal structure of PQS is also included.
- McGlacken, Gerard P.,McSweeney, Christina M.,O'Brien, Timothy,Lawrence, Simon E.,Elcoate, Curtis J.,Reen, F. Jerry,O'Gara, Fergal
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scheme or table
p. 5919 - 5921
(2010/11/18)
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- Substituted-4-quinolones
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Substituted-4-quinolones of the formula (I): wherein R1 is a straight or branched chain, saturated or ethylenically-unsaturated aliphatic hydrocarbyl group containing 1 to 18 carbon atoms which may optionally be substituted by one or more substituent groups selected from halo, 1-6C alkoxy, carboxy, 1-6C alkoxycarbonyl and NR6R7, wherein each of R6 and R7 is independently selected from H and 1-6C alkyl or R6 and R7 together with the N atom to which they are attached form a saturated heterocyclic group selected from piperidino, piperazino and morpholino. R2 is a group selected from H, —OH, halo, —CHO, —CO2H and CONHR8 wherein R8 is H or a 1-6C alkyl; each of R3, R4 and R1 is independently selected form H, —CH3, —OCH3 and halo; or a non-toxic pharmaceutically-acceptable salt thereof, have use in the manufacture of a medicament for the treatment of a disease of a living animal body, including a human, which disease is responsive to the activity of an immunosuppressant. The preferred compound of the formula 1 is 2-n-heptyl-3-hydroxy-4(1H)-quinolone.
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