We report herein the use of a dual catalytic system comprising a Lewis base catalyst such as quinuclidin‐3‐ol or 4‐dimethylaminopyridine and a photoredox catalyst to generate carbon radicals from either boronic acids or esters. This system enabled a wide range of alkyl boronic esters and aryl or alkyl boronic acids to react with electron‐deficient olefins via radical addition to efficiently form C−C coupled products in a redox‐neutral fashion. The Lewis base catalyst was shown to form a redox‐active complex with either the boronic esters or the trimeric form of the boronic acids (boroxines) in solution.

Target-directed dynamic combinatorial chemistry (tdDCC) enables identification, as well as optimization of ligands for un(der)explored targets such as the anti-infective target 1-deoxy-D-xylulose-5-phosphate synthase (DXPS). We report the use of tdDCC...

In the present manuscript, we describe how we successfully used ligand-based virtual screening (LBVS) to identify two small-molecule, drug-like hit classes with excellent ADMET profiles against the difficult to address...

Abstract:We report herein the use of ad ual catalytic system comprising aL ewis base catalyst such as quinuclidin-3-ol or 4-dimethylaminopyridine and ap hotoredox catalyst to generate carbon radicals from either boronic acids or esters.T his system enabled awide range of alkylboronic esters and aryl or alkylb oronic acids to react with electron-deficient olefins via radical addition to efficiently form C À Cc oupled products in aredox-neutral fashion. The Lewis base catalyst was shown to form ar edox-active complex with either the boronic esters or the trimeric form of the boronic acids (boroxines) in solution.Carbon-centered radicals are as ynthetically powerful class of reactive intermediates.[1] They are particularly attractive in the context of C À Cb ond-forming reactions, [2] overcoming problems often associated with two-electron processes.[3] By enabling visible-light-promoted single electron transfer, photoredox catalysis has become am ethod of choice for the single-electron reduction or oxidation of organic substrates and allows to generate open-shell intermediates in amild and selective fashion.[4] Ar ange of reductive or oxidative carbon radical precursors are now available to generate carbon radicals in the context of ap hotocatalytic cycle.[5] Oxidative carbon radical precursors are often anionic species suffering from poor solubility in common organic solvents.F or example,e xtensively studied organoborates [6] possess an electron-rich B(sp 3 )m oiety that can be subjected to singleelectron oxidation, leading to an eutral carbon radical after CÀBbond cleavage (Scheme 1A).Despite their ubiquity as reagents in organic synthesis [7] and in biologically active molecules, [8] theuse of boronic acid derivatives to generate carbon-centered radicals remains underexplored.[9] Owing to their high oxidation potentials, they have received much less attention in this regard, with few reports making use of strong stoichiometric oxidants or anodic oxidation.[10] We recently demonstrated that benzyl boronic esters can undergo single-electron oxidation under photoredox conditions when their vacant porbital is engaged in ad ative bond with the norbital of as toichiometric Lewis base (LB) additive (Scheme 1B).[11] Lewis base catalysis was introduced as aconcept by Denmark to enhance the reactivity of electrophilic n*, p*, and s*orbitals.[12] Based on this knowledge,w eh ypothesized that the use of ac atalytic amount of an organic Lewis base would be av iable option for the photoredox activation of boronic acids and esters. [13] Herein, we describe adual catalytic method to effectively form alkyl and aryl radicals from aw ide array of boronic esters and acids by direct photoredox single-electron oxidation under mild and safe conditions,without the requirement for stoichiometric activators or oxidants.T hese reactive species were further engaged in intermolecular C À Cb ondforming processes to deliver desirable C(sp 3 )ÀC(sp 3 )a nd C(sp 2 )ÀC(sp 3 )bonds in ar edox-neutral fashion. Thea ddition of electron-rich carbon...

In this work, we demonstrate how important it is to investigate not only on‐target activity but to keep antibiotic activity against critical pathogens in mind. Since antimicrobial resistance is spreading in bacteria such as Mycobacterium tuberculosis, investigations into new targets are urgently needed. One promising new target is 1‐deoxy‐d‐xylulose 5‐phosphate synthase (DXPS) of the 2‐C‐methyl‐d‐erythritol 4‐phosphate (MEP) pathway. We have recently solved the crystal structure of truncated M. tuberculosis DXPS and used it to perform a virtual screening in collaboration with Atomwise Inc. using their deep convolutional neural network‐based AtomNet® platform. Of 94 virtual hit compounds only one showed interesting results in binding and activity studies. We synthesized 30 close derivatives using a straightforward synthetic route that allowed for easy derivatization. However, no improvement in activity was observed for any of the derivatives. Therefore, we tested them against a variety of pathogens and found them to be good inhibitors against Escherichia coli.

<p>Target-directed dynamic combinatorial chemistry (tdDCC) enables the identification, as well as optimization of ligands for un(der)explored targets such as the anti-infective target 1‑deoxy‑d‑xylulose-5-phosphate synthase (DXS). We report the unprecedented use of tdDCC to first identify and subsequently optimize inhibitors of the anti-infective target DXS. Using tdDCC, we were able to generate acylhydrazone-based inhibitors for DXS. The tailored tdDCC runs also provided insights into the structure–activity relationship of this novel class of DXS inhibitors. This approach holds the potential to expedite the drug discovery process and could be generally applied to a range of biological targets.</p>

In the present manuscript, we describe how we successfully used ligand-based virtual screening (LBVS) to identify two small-molecule, drug-like hit classes with excellent ADMET profiles against the difficult to address microbial enzyme 1-deoxy-D-xylulose-5-phosphate synthase (DXPS). In the fight against antimicrobial resistance (AMR) it has become increasingly important to address novel targets such as DXPS, the first enzyme of the 2C-methyl-D-erythritol-4-phosphate (MEP) pathway, which affords the universal isoprenoid precursors. This pathway is absent in humans but essential for pathogens such as Mycobacterium tuberculosis, making it a rich source of drug targets for the development of novel anti-infectives. Standard computer-aided drug-design tools, frequently applied in other areas of drug development, often fail for targets with large, hydrophilic binding sites such as DXPS. Therefore, we introduce the concept of pseudo-inhibitors, combining the benefits of pseudo-ligands (defining a pharmacophore) and pseudo-receptors (defining anchor points in the binding site), for providing the basis to perform a LBVS against M. tuberculosis DXPS. Starting from a diverse set of reference ligands showing weak inhibition of the orthologue from Deinococcus radiodurans DXPS, we identified three structurally unrelated classes with promising in vitro (against M. tuberculosis DXPS) and whole-cell activity including extensively drug-resistant strains of M. tuberculosis. The hits were validated to be specific inhibitors of DXPS and to have a unique mechanism of inhibition. Furthermore, two of the hits have a balanced profile in terms of metabolic and plasma stability and display a low frequency of resistance development, making them ideal starting points for hit-to-lead optimization of antibiotics with an unprecedented mode of action.

In the present manuscript, we describe how we successfully used ligand-based virtual screening (LBVS) to identify two small-molecule, drug-like hit classes with excellent ADMET profiles against the difficult to address microbial enzyme 1-deoxy-D-xylulose-5-phosphate synthase (DXPS). In the fight against antimicrobial resistance (AMR) it has become increasingly important to address novel targets such as DXPS, the first enzyme of the 2C-methyl-D-erythritol-4-phosphate (MEP) pathway, which affords the universal isoprenoid precursors. This pathway is absent in humans but essential for pathogens such as Mycobacterium tuberculosis, making it a rich source of drug targets for the development of novel anti-infectives. Standard computer-aided drug-design tools, frequently applied in other areas of drug development, often fail for targets with large, hydrophilic binding sites such as DXPS. Therefore, we introduce the concept of pseudo-inhibitors, combining the benefits of pseudo-ligands (defining a pharmacophore) and pseudo-receptors (defining anchor points in the binding site), for providing the basis to perform a LBVS against M. tuberculosis DXPS. Starting from a diverse set of reference ligands showing weak inhibition of the orthologue from Deinococcus radiodurans DXPS, we identified three structurally unrelated classes with promising in vitro (against M. tuberculosis DXPS) and whole-cell activity including extensively drug-resistant strains of M. tuberculosis. The hits were validated to be specific inhibitors of DXPS and to have a unique mechanism of inhibition. Furthermore, two of the hits have a balanced profile in terms of metabolic and plasma stability and display a low frequency of resistance development, making them ideal starting points for hit-to-lead optimization of antibiotics with an unprecedented mode of action.