DPD-Inspired Discovery of Novel LsrK Kinase Inhibitors: An Opportunity To Fight Antimicrobial Resistance.

Antibiotic resistance is posing a continuous threat to global public health and represents a huge burden for society as a whole. In the past decade, the interference with bacterial quorum sensing (QS) (i.e., cell-cell communication) mechanisms has extensively been investigated as a valid therapeutic approach in the pursuit of a next generation of antimicrobials. ( S)-4,5-Dihydroxy-2,3-pentanedione, commonly known as ( S)-DPD, a small signaling molecule that modulates QS in both Gram-negative and Gram-positive bacteria, is phosphorylated by LsrK, and the resulting phospho-DPD activates QS. We designed and prepared a small library of DPD derivatives, characterized by five different scaffolds, and evaluated their LsrK inhibition in the context of QS interference. SAR studies highlighted the pyrazole moiety as an essential structural element for LsrK inhibition. Particularly, four compounds were found to be micromolar LsrK inhibitors (IC50 ranging between 100 µM and 500 µM) encouraging further exploration of novel analogues as potential new antimicrobials.

A Versatile Strategy for the Synthesis of 4,5-Dihydroxy-2,3-Pentanedione (DPD) and Related Compounds as Potential Modulators of Bacterial Quorum Sensing.

Resistance to antibiotics is an increasingly serious threat to global public health and its management translates to significant health care costs. The validation of new Gram-negative antibacterial targets as sources for potential new antibiotics remains a challenge for all the scientists working in this field. The interference with bacterial Quorum Sensing (QS) mechanisms represents a potentially interesting approach to control bacterial growth and pursue the next generation of antimicrobials. In this context, our research is focused on the discovery of novel compounds structurally related to (S)-4,5-dihydroxy-2,3-pentanedione, commonly known as (S)-DPD, a small signaling molecule able to modulate bacterial QS in both Gram-negative and Gram-positive bacteria. In this study, a practical and versatile synthesis of racemic DPD is presented. Compared to previously reported syntheses, the proposed strategy is short and robust: it requires only one purification step and avoids the use of expensive or hazardous starting materials as well as the use of specific equipment. It is therefore well suited to the synthesis of derivatives for pharmaceutical research, as demonstrated by four series of novel DPD-related compounds described herein.

Chemo- and Stereoselective Transition-Metal-Free Amination of Amides with Azides.

The synthesis of α-amino carbonyl/carboxyl compounds is a contemporary challenge in organic synthesis. Herein, we present a stereoselective α-amination of amides employing simple azides that proceeds under mild conditions with release of nitrogen gas. The amide is used as the limiting reagent, and through simple variation of the azide pattern, various differently substituted aminated products can be obtained. The reaction is fully chemoselective for amides even in the presence of esters or ketones and lends itself to preparation of optically enriched products.

Divergent ynamide reactivity in the presence of azides - an experimental and computational study.

An unusually divergent reactivity of ynamides in the presence of azides is reported. This new keteniminium-based methodology, which only requires triflic acid as promoter, facilitates access to ß-enaminoamides and biologically important oxazolidine-2,4-diones in a highly selective, divergent manner that is fully controllable by the present azide. A mechanistic rationale for these divergent reaction pathways is delineated and supported by extensive density functional theory analyses, as well as selected mechanistic experiments.

Chiral recognition in metal-organic frameworks studied by solid-state NMR spectroscopy using chiral solvating agents.

Recently, we have described the synthesis of chiral metal-organic frameworks iPr-ChirUMCM-1 and Bn-ChirUMCM-1 and their use in enantioselective separation. Here, we demonstrate for the first time the use of a chiral solvating agent (1-phenyl-2,2,2-trifluoroethanol, TFPE) for chiral recognition in iPr-ChirUMCM-1 and Bn-ChirUMCM-1 by means of solid-state(13)C NMR spectroscopy.

Application of a chiral metal-organic framework in enantioselective separation.

A modular approach for the synthesis of highly ordered porous and chiral auxiliary (Evans auxiliary) decorated metal-organic frameworks is developed. Our synthesis strategy, which uses known porous structures as model materials for incorporation of chirality via linker modification, can provide access to a wide range of porous materials suitable for enantioselective separation and catalysis. Chiral analogues of UMCM-1 have been synthesized and investigated for the enantioseparation of chiral compounds in the liquid phase and first promising results are reported.

Efficient synthesis of benzofuranones: N-heterocyclic carbene (NHC)/base-catalyzed hydroacylation-Stetter-rearrangement cascade.

A N-heterocyclic carbene/base-catalyzed cascade reaction leading to the formation of functionalized benzofuranones is reported. The reaction proceeds via an intramolecular hydroacylation of unactivated alkynes followed by an intermolecular Stetter reaction and a base-catalyzed chromanone to benzofuranone rearrangement.

N-heterocyclic carbene-catalyzed cross-coupling of aromatic aldehydes with activated alkyl halides.

N-Heterocyclic carbene-catalyzed umpolung of aldehydes followed by their interception with diarylbromomethanes has been reported. This conceptually novel transition-metal-free cross-coupling of aldehydes with alkyl halides works well at low catalyst loadings and under mild reaction conditions leading to the formation of diaryl acetophenone derivatives in good yields. In addition, α-halo ketones and esters can also be used as aldehyde reaction partners.