Synthetic approach to 2-alkyl-4-quinolones and 2-alkyl-4-quinolone-3-carboxamides based on common β-keto amide precursors

• Yordanka Mollova-Sapundzhieva,
• Plamen Angelov,
• Danail Georgiev and
• Pavel Yanev

Beilstein J. Org. Chem. 2023, 19, 1804–1810, doi:10.3762/bjoc.19.132

• extensively studied is 2-heptyl-4-quinolone (HHQ) and its oxygenated derivatives 2-heptyl-3-hydroxy-4-quionolone (PQS) and 4-hydroxy-2-heptylquinoline-N-oxide (HQNO) [27][36][37][38]. Considering the importance of 4-quinolones as potential drugs and biological probes, it is not surprising that the development

Synthesis and biological activity of methylated derivatives of the Pseudomonas metabolites HHQ, HQNO and PQS

• Sven Thierbach,
• Max Wienhold,
• Susanne Fetzner and
• Ulrich Hennecke

Beilstein J. Org. Chem. 2019, 15, 187–193, doi:10.3762/bjoc.15.18

• 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

• unsaturation and can be O- or N-methylated [1][2][3]. In the opportunistic pathogen Pseudomonas aeruginosa, AQ derivatives with heptyl or nonyl side chains are prevalent [3][7][8][9]. 2-Heptyl-3-hydroxy-4(1H)-quinolone (Pseudomonas quinolone signal, PQS) and its biosynthetic precursor 2-heptyl-4(1H)-quinolone

Synthesis and biological evaluation of 1,2-disubstituted 4-quinolone analogues of Pseudonocardia sp. natural products

• Stephen M. Geddis,
• Teodora Coroama,
• Suzanne Forrest,
• James T. Hodgkinson,
• Martin Welch and
• David R. Spring

Beilstein J. Org. Chem. 2018, 14, 2680–2688, doi:10.3762/bjoc.14.245

• analogues was observed to inhibit production of the virulence factor pyocyanin in the human pathogen Pseudomonas aeruginosa, which may be a result of their similarity to the Pseudomonas quinolone signal (PQS) quorum sensing autoinducer. This provided new insights regarding the effect of N-substitution in

• PQS analogues, which has been hitherto underexplored. Keywords: antibiotics; cross-coupling; heterocycles; quorum-sensing; structure–activity relationships; Introduction The quinolone core has long been implemented in structures possessing formidable activity in a broad range of fields, including

• -position, there is a structural resemblance to the Pseudomonas quinolone signal (PQS), and its biosynthetic precursor 2-heptyl-4(1H)-quinolone (HHQ), which are vital to the cooperative behaviour of the human pathogen Pseudomonas aeruginosa via quorum sensing (QS). This is a means by which bacteria alter

Targeting the Pseudomonas quinolone signal quorum sensing system for the discovery of novel anti-infective pathoblockers

• Christian Schütz and
• Martin Empting

Beilstein J. Org. Chem. 2018, 14, 2627–2645, doi:10.3762/bjoc.14.241

• coordinate population-wide group behaviours in the infection process like concerted secretion of virulence factors. One very important signalling network is the Pseudomonas quinolone signal (PQS) QS. With the aim to devise novel and innovative anti-infectives, inhibitors have been designed to address the

• various potential drug targets present within pqs QS. These range from enzymes within the biosynthesis cascade of the signal molecules PqsABCDE to the receptor of these autoinducers PqsR (MvfR). This review shortly introduces P. aeruginosa and its pathogenicity traits regulated by the pqs system and

• highlights the published drug discovery efforts providing insights into the compound binding modes if available. Furthermore, suitability of the individual targets for pathoblocker design is discussed. Keywords: anti-infectives; pathoblockers; PQS; Pseudomonas aeruginosa; quorum sensing; Introduction In

Pathoblockers or antivirulence drugs as a new option for the treatment of bacterial infections

• Matthew B. Calvert,
• Varsha R. Jumde and
• Alexander Titz

Beilstein J. Org. Chem. 2018, 14, 2607–2617, doi:10.3762/bjoc.14.239

• (PQS) and its biosynthetic precursors in P. aeruginosa some of which are also found in Burkholderia [71], two species that often co-infect patients for example in cystic fibrosis airways infections. By blocking QS processes, the release of virulence factors such as host degrading enzymes or chemicals

• signal molecules and mimic their structures. The PQS system of P. aeruginosa is particularly attractive and can be considered as a pathogen specific target. The biosynthesis of the PQS signal 23 involves a set of biosynthetic enzymes PqsABCDEH and its autocatalytic receptor PqsR (MvfR). Biaryl methanols

Impact of Pseudomonas aeruginosa quorum sensing signaling molecules on adhesion and inflammatory markers in endothelial cells

• Carmen Curutiu,
• Florin Iordache,
• Veronica Lazar,
• Aurelia Magdalena Pisoschi,
• Aneta Pop,
• Mariana Carmen Chifiriuc and
• Alina Maria Hoban

Beilstein J. Org. Chem. 2018, 14, 2580–2588, doi:10.3762/bjoc.14.235

• cells were stimulated with 20 µM of main P. aeruginosa QSSMs (OdDHL = N-(3-oxododecanoyl)-L-homoserine lactone, C4HSL = N-butyryl-L-homoserine lactone, PQS = 2-heptyl-3-hydroxy-4(1H)-quinolone and HHQ = 2-heptyl-4-quinolone). Adherence to endothelial cells, inert substratum and biofilm formation was

• levels were increased only by C4HSL. The inflammatory response of endothelial cells was also modulated, as observed by the modified expression of IL-1β (for C4HSL, PQS and HHQ), IL-6 (for C4HSL and HHQ), TNFα (for C4HSL and HHQ), TGFβ, and eNOS factors. Our results demonstrate that the main pseudomonadal

• infections. P. aeruginosa produce two types of quorum-sensing signaling molecules (QSSMs): N-acylhomoserine lactones (AHL) and 2-alkyl-4-quinolone (PQS) derivatives. The AHLs molecules described so far in P. aeruginosa belong at two quorum sensing (QS) systems: las and rhl systems whose autoinducer (AI

Nanoreactors for green catalysis

• M. Teresa De Martino,
• Loai K. E. A. Abdelmohsen,
• Floris P. J. T. Rutjes and
• Jan C. M. van Hest

Beilstein J. Org. Chem. 2018, 14, 716–733, doi:10.3762/bjoc.14.61

• quantitative yields were observed when aryl chloride coupling was performed with arylboronic acids. This is indeed remarkable as aryl chlorides are generally not as reactive as aryl bromides or aryl iodides. Lipshutz and Ghorai developed a micellar system called PQS to perform aldol reactions in water [25]. As

• depicted in Figure 2, PQS (4a) has an OH moiety that allows for its linkage to the organocatalyst proline 4b. Also, PQS has a lipophilic component that acts as a reaction solvent for hydrophobic dienes. The latter feature allows aldol reactions to take place efficiently in water. The aldol reaction between

• cyclohexanone and p-nitrobenzaldehyde was chosen to verify the performance of this nanoreactor. PQS-proline and the analogous mixed diester derivative of 4-hydroxyproline were prepared and tested in this process. The aldol product was achievable only by using the proline compound 4b, therefore different

Chemical probes for competitive profiling of the quorum sensing signal synthase PqsD of Pseudomonas aeruginosa

• Michaela Prothiwa,
• Dávid Szamosvári,
• Sandra Glasmacher and
• Thomas Böttcher

Beilstein J. Org. Chem. 2016, 12, 2784–2792, doi:10.3762/bjoc.12.277

• Michaela Prothiwa David Szamosvari Sandra Glasmacher Thomas Bottcher Department of Chemistry, Konstanz Research School Chemical Biology, University of Konstanz, 78457 Konstanz, Germany 10.3762/bjoc.12.277 Abstract The human pathogen Pseudomonas aeruginosa uses the pqs quorum sensing system to

• coordinate the production of its broad spectrum of virulence factors to facilitate colonization and infection of its host. Hereby, the enzyme PqsD is a virulence related quorum sensing signal synthase that catalyzes the central step in the biosynthesis of the Pseudomonas quinolone signals HHQ and PQS. We

• of covalently reacting with the active site. We demonstrated the potential of our probes in a competitive labelling platform where we screened a library of synthetic HHQ and PQS analogues with heteroatom replacements and found several inhibitors of probe binding that may represent promising scaffolds

Discovery of an inhibitor of the production of the Pseudomonas aeruginosa virulence factor pyocyanin in wild-type cells

• Bernardas Morkunas,
• Balint Gal,
• Warren R. J. D. Galloway,
• James T. Hodgkinson,
• Brett M. Ibbeson,
• Yaw Sing Tan,
• Martin Welch and
• David R. Spring

Beilstein J. Org. Chem. 2016, 12, 1428–1433, doi:10.3762/bjoc.12.137

• -oxododecanoyl)-L-homoserine lactone (OdDHL) and it’s cognate receptor LasR (Figure 1) [20][21][22]. Interlinking these two AHL signalling systems is a third signaling system utilising a quinolone signalling molecule (termed Pseudomonas quinolone signal, PQS) [20] to form an intricate hierarchical signaling

• pyocyanin biosynthesis in P. aeruginosa may be inhibitors of LasR-based quorum sensing. However, it has previously been reported that P. aeruginosa can exhibit near full virulence, including pyocyanin production, in the absence of LasR utilising solely the rhl, and pqs signalling systems [30]. Additional

• studies have demonstrated that the straight forward hierarchical QS network (with the las system at the forefront followed by the lower ranked rhl and pqs signalling system) is more elaborate and complex than this hierarchical structure [8][9][30]. Taking these studies into account it is possible that

First synthesis of 2-(benzofuran-2-yl)-6,7-methylene dioxyquinoline-3-carboxylic acid derivatives

• Wentao Gao,
• Jia Liu,
• Yun Jiang and
• Yang Li

Beilstein J. Org. Chem. 2011, 7, 210–217, doi:10.3762/bjoc.7.28

• intermediates which may be responsible for the observed antitumor activity of lignans [23][24]. The presence of the methylenedioxy moiety in some other bioactive molecules drastically alters their pharmacological properties. For example, among the tested 2-phenylquinolin-4-ones (2-PQs) with potent cytotoxicity