Structural modification of the Pseudomonas aeruginosa alkylquinoline cell–cell communication signal, HHQ, leads to benzofuranoquinolines with anti-virulence behaviour in ESKAPE pathogens

Microbial populations have evolved intricate networks of negotiation and communication through which they can coexist in natural and host ecosystems. The nature of these systems can be complex and they are, for the most part, poorly understood at the polymicrobial level. The Pseudomonas Quinolone Signal (PQS) and its precursor 4- hydroxy- 2-heptylquinoline (HHQ) are signal molecules produced by the important nosocomial pathogen Pseudomonas aeruginosa. They are known to modulate the behaviour of co-colonizing bacterial and fungal pathogens such as Bacillus atropheaus, Candida albicans and Aspergillus fumigatus. While the structural basis for alkyl-quinolone signalling within P. aeruginosa has been studied extensively, less is known about how structural derivatives of these molecules can influ-ence multicellular behaviour and population- level decision-making in other co-colonizing organisms. In this study, we investigated a suite of small molecules derived initially from the HHQ framework, for anti-virulence activity against ESKAPE pathogens, at the species and strain levels. Somewhat surprisingly, with appropriate substitution, loss of the alkyl chain (present in HHQ and PQS) did not result in a loss of activity, presenting a more easily accessible synthetic framework for investigation. Virulence profiling uncovered significant levels of inter-strain variation among the responses of clinical and environmental isolates to small-molecule challenge. While several lead compounds were identified in this study, further work is needed to appreciate the extent of strain- level tolerance to small-molecule anti-infectives among pathogenic organisms.National Forum for the Enhancement of Teaching and Learning in Higher Education SFI/12/IP/1315, US Cystic Fibrosis Foundation SFI/12/RC/2275, National Health and Medical Research Council (NHMRC) of Australia SFI/12/RC/2275_P2, UCC Strategic Research Fund and Science Foundation Ireland (SFI) SSPC-3 12/RC/2275_2, Synthesis and Solid State Pharmaceutical Centre (SSPC) HRB-ILP-POR-2019-004, MRCG-2018-16, Universidade do Algarve TL19UCC1481/02, OGARA1710, APP1183640 2020-5,info:eu-repo/semantics/publishedVersio

Synthesis of a diaryliodonium salt and its use in the direct arylation of andole: a two-step experiment for the organic teaching laboratory

In the past decade, C–H functionalization has been a very active topic of research in both academia and industry. When a H atom is replaced by an aryl (or heteroaryl) group, the transformation is termed “direct arylation”. This approach to the formation of key (hetero)aryl–(hetero)aryl bonds is complementary to traditional methods, such as the Suzuki–Miyaura and Stille reactions. Direct arylation/C–H functionalization is not represented in the majority of undergraduate chemistry laboratory curricula. An experiment is described here in which students carry out a multistep process, synthesizing a diaryliodonium salt and using it in the direct arylation of indole. Important organic and organometallic chemistry concepts are covered, including catalysis, traditional cross-coupling, C–H functionalization, multistep reaction processes, and regioselectivity. The experiment was successfully carried out by third- and fourth-year students in two universities over a two-year period (four times in total). Both high-yielding and low-yielding chemical steps were encountered, and a number of pedagogical approaches evolved

One-pot cross-coupling/C–H functionalization reactions: Quinoline as a substrate and ligand through N–Pd interaction

Herein, we report a one-pot process that marries mechanistically distinct, traditional cross-coupling reactions with C–H functionalization using the same precatalyst. The reactions proceed in yields of up to 95%, in air, and require no extraneous ligand. The reactions are thought to be facilitated by harnessing the substrate quinoline as an N-ligand, and evidence of the palladium–quinoline interaction is provided by 1H-15N HMBC NMR spectroscopy and X-ray crystallographic structures. Application of the methodology is demonstrated by the quick formation of fluorescent, π-extended frameworks.<br/