No abstract

A fast and efficient protocol for the formation of amides from low nucleophilic amines and esters in flow is described. Products were obtained in good to excellent yields and with the advantage of simultaneous mixing of all reagents at once, avoiding steps for intermediate formation. The protocol is also suitable to be combined with ester synthesis, resulting in the preparation of amides in-line from haloarenes.

Ta rget-guided synthesis (TGS) has emerged as a promising strategy in drug discovery.A lthough reported examples of TGS generally involve two-component reactions, there is as trong case for developing target-guided versions of three-componentr eactions (3CRs) because of their potential to deliver highly diversified druglike molecules. To this end, the Groebke-Blackburn-BienaymØ reaction was selected as am odel 3CR. We recently reported as eries of druglike urokinase inhibitors, and these serve as reference compounds in the present study. Due to the limited number of literaturer eports on target-guided 3CRs, multiple experimentalp arameters were optimized here. Most challenging was the formationofimine intermediates under near-physiological conditions. This aspectw as addressed by exploring chemicali mine stabilizations trategies. Notably,i mines are also crucial intermediates of other 3CRs. Such systematic studies are strongly required for furtherd evelopmento ft he TGS domain but are largely absent in the literature.H ence, this work is intended as ar eference for future multicomponent-based TGS studies. Figure 2. Schematic representation of three-component TGS for enzyme inhibitordiscovery. Scheme1.The classicalGroebke-Blackburn-BienaymØ (GBB) reaction.

The first continuous flow carbonylation reaction using aryl formates as CO precursor is reported. The reaction is practical, scalable and high yielding. The use of a flow protocol safely allows expanding the scope to activated chlorides, nitrogen heterocycles and to the selective introduction of an ester group in dihalo-derivatives. Further selective reduction of the ester formed to an aldehyde in flow is also described.

A novel reaction cascade for converting benzodiazepinediones into oxazoloquinolinones using carboxylic acid anhydrides in the presence of base has been developed using flow methods. Products are obtained in yields up to 98%.

Tricyclic scaffolds structurally related to the well‐known benzodiazepine class of drugs show diverse biological activities strikingly different from those of their benzodiazepine counterparts. Interested by this scaffold‐hopping perspective, we previously developed a continuous‐flow method for the conversion of benzodiazepinediones into oxazoloquinolinones. Attempted extension of this synthetic route to the corresponding oxazolonaphthyridinone scaffolds met with limited success, however. This encouraged us to develop a different approach to pyridine‐based tricyclic motifs. In line with our interest in scaffold hopping, in this paper we describe a general, convergent [3+3] cyclocondensation approach to [1,3]oxazolo[4,5‐c]‐1‐naphthyridin‐4(5H)‐ones. The key synthetic steps in this approach are: (1) the construction of an amide linkage connecting two peripheral heterocycles; and (2) a palladium‐catalysed intramolecular C–H arylation to complete the tricyclic scaffold.

Polygodial is a “hot” peppery-tasting sesquiterpenoid that was first described for its anti-feedant activity against African armyworms. Using the haploid deletion mutant library of Saccharomyces cerevisiae, a genome-wide mutant screen was performed to shed more light on polygodial’s antifungal mechanism of action. We identified 66 deletion strains that were hypersensitive and 47 that were highly resistant to polygodial treatment. Among the hypersensitive strains, an enrichment was found for genes required for vacuolar acidification, amino acid biosynthesis, nucleosome mobilization, the transcription mediator complex, autophagy and vesicular trafficking, while the resistant strains were enriched for genes encoding cytoskeleton-binding proteins, ribosomal proteins, mitochondrial matrix proteins, components of the heme activator protein (HAP) complex, and known regulators of the target of rapamycin complex 1 (TORC1) signaling. WE confirm that polygodial triggers a dose-dependent vacuolar alkalinization and that it increases Ca2+ influx and inhibits glucose-induced Ca2+ signaling. Moreover, we provide evidence suggesting that TORC1 signaling and its protective agent ubiquitin play a central role in polygodial resistance, suggesting that they can be targeted by polygodial either directly or via altered Ca2+ homeostasis.

The structure of an oxazolonaphthyridinone derivative unexpectedly formed during the synthesis of pyridodiazepinediones is reported.