Amide bioisosteric replacement in the design and synthesis of quorum sensing modulators.

The prevention or control of bacterial infections requires continuous search for novel approaches among which bacterial quorum sensing inhibition is considered as a complementary antibacterial strategy. Quorum sensing, used by many different bacteria, functions through a cell-to-cell communication mechanism relying on chemical signals, referred to as autoinducers, such as N-acyl homoserine lactones (AHLs) which are the most common chemical signals in this system. Designing analogs of these autoinducers is one of the possible ways to interfere with quorum sensing. Since bioisosteres are powerful tools in medicinal chemistry, targeting analogs of AHLs or other signal molecules and mimics of known QS modulators built on amide bond bioisosteres is a relevant strategy in molecular design and synthetic routes. This review highlights the application of amide bond bioisosteric replacement in the design and synthesis of novel quorum sensing inhibitors.

The Use of 5-Hydroxymethylfurfural (5-HMF) in Multi-Component Hantzsch Dihydropyridine Synthesis.

The renewable 5-hydroxymethylfurfural (5-HMF) has gained a wide interest from the chemistry community as a valuable biobased platform opening the way to many applications. Despite an impressive number of publications reporting either its preparation or its functionalization, its direct use in fine chemistry, and especially in multi-component reaction (MCR), is less reported. Here, we report a complete study of the use of 5-HMF in the Hantzsch dihydropyridines synthesis. The strategy was applied to a scope of ß-dicarbonyl molecules (including ß-ketoesters and 1,3-diketones) in a 3-component procedure leading to a series of symmetrical 1,4-dihydropyridines derived from 5-HMF in excellent yields. The study was extended to the 4-component protocol using one equivalent of a ß-ketoester and one equivalent of 5,5-dimethyl-1,3-cyclohexanedione (dimedone), which efficiently provided the corresponding unsymmetrical dihydropyridines.

A highly conserved ligand-binding site for AccA transporters of antibiotic and quorum-sensing regulator in Agrobacterium leads to a different specificity.

Plants genetically modified by the pathogenic Agrobacterium strain C58 synthesize agrocinopines A and B, whereas those modified by the pathogenic strain Bo542 produce agrocinopines C and D. The four agrocinopines (A, B, C and D) serve as nutrients by agrobacteria and signaling molecule for the dissemination of virulence genes. They share the uncommon pyranose-2-phosphate motif, represented by the l-arabinopyranose moiety in agrocinopines A/B and the d-glucopyranose moiety in agrocinopines C/D, also found in the antibiotic agrocin 84. They are imported into agrobacterial cytoplasm via the Acc transport system, including the solute-binding protein AccA coupled to an ABC transporter. We have previously shown that unexpectedly, AccA from strain C58 (AccAC58) recognizes the pyranose-2-phosphate motif present in all four agrocinopines and agrocin 84, meaning that strain C58 is able to import agrocinopines C/D, originating from the competitor strain Bo542. Here, using agrocinopine derivatives and combining crystallography, affinity and stability measurements, modeling, molecular dynamics, in vitro and vivo assays, we show that AccABo542 and AccAC58 behave differently despite 75% sequence identity and a nearly identical ligand binding site. Indeed, strain Bo542 imports only compounds containing the d-glucopyranose-2-phosphate moiety, and with a lower affinity compared with strain C58. This difference in import efficiency makes C58 more competitive than Bo542 in culture media. We can now explain why Agrobacterium/Allorhizobium vitis strain S4 is insensitive to agrocin 84, although its genome contains a conserved Acc transport system. Overall, our work highlights AccA proteins as a case study, for which stability and dynamics drive specificity.

In Silico Identification of Potential Inhibitors of the SARS-CoV-2 Main Protease among a PubChem Database of Avian Infectious Bronchitis Virus 3CLPro Inhibitors.

Remarkable structural homologies between the main proteases of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the avian infectious bronchitis virus (IBV) were revealed by comparative amino-acid sequence and 3D structural alignment. Assessing whether reported IBV 3CLPro inhibitors could also interact with SARS-CoV-2 has been undertaken in silico using a PubChem BioAssay database of 388 compounds active on the avian infectious bronchitis virus 3C-like protease. Docking studies of this database on the SARS-CoV-2 protease resulted in the identification of four covalent inhibitors targeting the catalytic cysteine residue and five non-covalent inhibitors for which the binding was further investigated by molecular dynamics (MD) simulations. Predictive ADMET calculations on the nine compounds suggest promising pharmacokinetic properties.

Towards More Practical Methods for the Chemical Synthesis of Thioamides Using Sulfuration Agents: A Decade Update.

Compounds possessing a thioamide function play a crucial role in organic synthesis, serving as key building blocks. They are also important in the pharmaceutical chemistry and drug design, owing to their ability to mimic the amide function in biomolecules while retaining or developing biological activity. From the synthetic viewpoint, several methods have been developed for preparing thioamides using sulfuration agents. The purpose of this review is to give an update of the last decade of contributions focusing on the formation of thioamides employing different sulfur sources. When appropriate, the cleanness and practicality of the new methods are highlighted.

Importance of the 2,6-Difluorobenzamide Motif for FtsZ Allosteric Inhibition: Insights from Conformational Analysis, Molecular Docking and Structural Modifications.

A conformational analysis and molecular docking study comparing 2,6-difluoro-3-methoxybenzamide (DFMBA) with 3-methoxybenzamide (3-MBA) has been undertaken for investigating the known increase of FtsZ inhibition related anti S. aureus activity due to fluorination. For the isolated molecules, the calculations reveal that the presence of the fluorine atoms in DFMBA is responsible for its non-planarity, with a dihedral angle of -27° between the carboxamide and the aromatic ring. When interacting with the protein, the fluorinated ligand can thus more easily adopt the non-planar conformation found in reported co-crystallized complexes with FtsZ, than the non-fluorinated one. Molecular docking studies of the favored non-planar conformation of 2,6-difluoro-3-methoxybenzamide highlights the strong hydrophobic interactions between the difluoroaromatic ring and several key residues of the allosteric pocket, precisely between the 2-fluoro substituent and residues Val203 and Val297 and between the 6-fluoro group and the residues Asn263. The docking simulation in the allosteric binding site also confirms the critical importance of the hydrogen bonds between the carboxamide group with the residues Val207, Leu209 and Asn263. Changing the carboxamide functional group of 3-alkyloxybenzamide and 3-alkyloxy-2,6-difluorobenzamide to a benzohydroxamic acid or benzohydrazide led to inactive compounds, confirming the importance of the carboxamide group.

Structural Variations in the Central Heterocyclic Scaffold of Tripartite 2,6-Difluorobenzamides: Influence on Their Antibacterial Activity against MDR Staphylococcus aureus.

Five series of heterocyclic tripartite 2,6-difluorobenzamides, namely 1,2,3-triazoles, 1,2,4- and 1,3,4-oxadiazoles, analogs of reported model anti-staphylococcal compounds, were prepared. The purpose was to investigate the influence of the nature of the heterocyclic central scaffold on the biological activity against three strains of S. aureus, including two drug-resistant ones. Among the 15 compounds of the new collection, a 3-(4-tert-butylphenyl)-1,2,4-oxadiazole linked via a methylene group with a 2,6-difluorobenzamide moiety (II.c) exhibited a minimal inhibitory concentration between 0.5 and 1 µg/mL according to the strain. Subsequent studies on II.c demonstrated no human cytotoxicity, while targeting the bacterial divisome.

5-Hydroxymethylfurfural and Furfural Chemistry Toward Biobased Surfactants.

Invited for this month's cover is the group of Yves Queneau at the University of Lyon. The cover image shows superb natural architectures with spherical symmetrical shapes evoking that of organized systems, micelles, and bubbles symbolizing creativity and imagination in the molecular design of biobased surfactants. The Review highlights the emerging use of 5-hydroxymethylfurfural and other biobased furans as scaffolds toward novel amphiphiles. The Review itself is available at 10.1002/cssc.202102660.

Synthesis and Biological Evaluation of Benzo[b]thiophene Acylhydrazones as Antimicrobial Agents against Multidrug-Resistant Staphylococcus aureus.

The benzo[b]thiophene nucleus and the acylhydrazone functional group were combined to prepare three new series of compounds for screening against Staphylococcus aureus. The reaction of substituted benzo[b]thiophene-2-carboxylic hydrazide and various aromatic or heteroaromatic aldehydes led to a collection of 26 final products with extensive structural diversification on the aromatic ring and on position 6 of the benzo[b]thiophene nucleus. The screening lead to the identification of eight hits, including (E)-6-chloro-N'-(pyridin-2-ylmethylene)benzo[b]thiophene-2-carbohydrazide (II.b), a non-cytotoxic derivative showing a minimal inhibitory concentration of 4 µg/mL on three S. aureus strains, among which were a reference classical strain and two clinically isolated strains resistant to methicillin and daptomycin, respectively.

5-Hydroxymethylfurfural and Furfural Chemistry Toward Biobased Surfactants.

The use of 5-hydroxymethylfurfural (HMF), furfural, and furan as scaffolds for designing alternative surfactants is a rapidly developing research area. This Review gathers recent examples highlighting the variety of methods for grafting the necessary polar and non-polar appendages, exploiting the specific chemical reactivity of each of these platform molecules. While the furan (or tetrahydrofuran) backbone is maintained in some targeted amphiphiles, alternatives using rearranged HMF or furfural such as cyclopentanols or furanones have also been reported. This topic is an illustration of the diversification of the use of HMF and other biobased furanic platform molecules in the field of fine and specialty chemicals. The surfactants sector, which concerns some of the most largely consumed chemicals in everyday life, and still mostly produced from fossil resources, will benefit from such alternatives enabling increased renewable carbon content and structural innovation.

Biomass: Renewable carbon resource for chemical and energy industry.

Chemistry is indispensable for the elaboration of all products used in everyday life, such as manufactured goods, materials, fuels and devices for energy, construction, transportation, foods, pharmaceutical products, personal care products, and devices for communication. Considering the broadness of this sector and its necessary growth for ensuring development and technical progress to an increasing world population, the time has come for a new chemical era in which the environmental impact of chemical products, in terms of hazards, life cycle, carbon footprint, and sustainability of resources, is minimized. Utilization of biomass to produce chemicals, energy products, and materials is an important route toward sustainable development. This perspective gives a brief overview of the use of biomass as a renewable resource, analyzing its evolution over the years in terms of motives and societal issues, highlighting the seminal contributions, and stressing how the remaining challenges will require contributions from all facets of the chemical sciences.

Heterocyclic Chemistry Applied to the Design of N-Acyl Homoserine Lactone Analogues as Bacterial Quorum Sensing Signals Mimics.

N-acyl homoserine lactones (AHLs) are small signaling molecules used by many Gram-negative bacteria for coordinating their behavior as a function of their population density. This process, based on the biosynthesis and the sensing of such molecular signals, and referred to as Quorum Sensing (QS), regulates various gene expressions, including growth, virulence, biofilms formation, and toxin production. Considering the role of QS in bacterial pathogenicity, its modulation appears as a possible complementary approach in antibacterial strategies. Analogues and mimics of AHLs are therefore biologically relevant targets, including several families in which heterocyclic chemistry provides a strategic contribution in the molecular design and the synthetic approach. AHLs consist of three main sections, the homoserine lactone ring, the central amide group, and the side chain, which can vary in length and level of oxygenation. The purpose of this review is to summarize the contribution of heterocyclic chemistry in the design of AHLs analogues, insisting on the way heterocyclic building blocks can serve as replacements of the lactone moiety, as a bioisostere for the amide group, or as an additional pattern appended to the side chain. A few non-AHL-related heterocyclic compounds with AHL-like QS activity are also mentioned.

Docking-based virtual screening studies aiming at the covalent inhibition of SARS-CoV-2 MPro by targeting the cysteine 145.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the COVID-19 which has infected millions of people worldwide. The main protease of SARS-CoV-2 (MPro) has been recognized as a key target for the development of antiviral compounds. Taking advantage of the X-ray crystal complex with reversible covalent inhibitors interacting with the catalytic cysteine 145 (Cys145), we explored flexible docking studies to select alternative compounds able to target this residue as covalent inhibitors. First, docking studies of three known electrophilic compounds led to results consistent with co-crystallized data validating the method for SARS-CoV-2 MPro covalent inhibition. Then, libraries of soft electrophiles (overall 41 757 compounds) were submitted to docking-based virtual screening resulting in the identification of 17 molecules having their electrophilic group close to the Cys145 residue. We also investigated flexible docking studies of a focused approved covalent drugs library including 32 compounds with various electrophilic functional groups. Among them, the calculations resulted in the identification of four compounds, namely dimethylfumarate, fosfomycin, ibrutinib and saxagliptin, able first, to bind to the active site of the protein and second, to form a covalent bond with the catalytic cysteine.

(2R)- and (2S)- 2-hydroxy- hexanoyl and octanoyl-l-homoserine lactones: New highly potent Quorum Sensing modulators with opposite activities.

The synthesis and the QS modulation activity of diastereoisomerically pure 2-hydroxy-N-acyl-l-homoserine lactones (2-OH-AHLs) are unveiled. (2R)- and (2S)- 2-hydroxy-N-hexanoyl-l-homoserine lactone and 2-hydroxy-N-octanoyl-l-homoserine lactone have been identified as very potent QS agonists and antagonists on the Vibrio fischeri-quorum sensing system with opposite activities depending on the configuration of the carbon atom with the hydroxyl group. Flexible molecular docking showed that the (2R)-OH configuration in the antagonist isomer induces new hydrogen bonds with Tyr70 and Asp79, two importantly conserved residues in the LuxR protein family, while the (2S)-OH agonist configuration exhibits a binding mode comparable to the natural ligand 3-oxo-hexanoyl-l-homoserine lactone (OHHL). For the analogs with long alkyl chain 3a and 3b and aromatic analogs, all are antagonists with no effect of the configuration at C-2.

Esters of Glucose-2-Phosphate: Occurrence and Chemistry.

Phosphodiesters of glucose-2-phosphate (G2P) are found only in few natural compounds such as agrocinopine D and agrocin 84. Agrocinopine D is a G2P phosphodiester produced by plants infected by Agrobacterium fabrum C58 and recognized by the bacterial periplasmic binding protein AccA for being transported into the bacteria before cleavage by the phosphodiesterase AccF, releasing G2P, which promotes virulence by binding the repressor protein AccR. The G2P amide agrocin 84 is a natural antibiotic produced by the non-pathogenic Agrobacterium radiobacter K84 strain used as a biocontrol agent by competing with Agrobacterium fabrum C58. G2P esters are also found in irregular glycogen structures. The rare glucopyranosyl-2-phophoryl moiety found in agrocin 84 is the key structural signature enabling its action as a natural antibiotic. Likewise, G2P and G2P esters can also dupe the Agrobacterium agrocinopine catabolism cascade. Such observations illustrate the importance of G2P esters on which we have recently focused our interest. After a brief review of the reported phosphorylation coupling methods and the choice of carbohydrate building blocks used in G2P chemistry, a flexible access to glucose-2-phosphate esters using the phosphoramidite route is proposed.

Biological Evaluation and Docking Studies of New Carbamate, Thiocarbamate, and Hydrazide Analogues of Acyl Homoserine Lactones as Vibrio fischeri-Quorum Sensing Modulators.

A series of carbamate, thiocarbamate, and hydrazide analogues of acylhomoserine lactones (AHLs) were synthesized and their ability to modulate Vibrio fischeri-quorum sensing was evaluated. The compounds in the series exhibit variable side chain length and the possible presence of a diversely substituted phenyl substituent. Biological evaluation on the Vibrio fischeri quorum sensing system revealed that the ethyl substituted carbamate (1) display a weak agonistic activity whereas compounds with longer chain length or benzyl substituents display significant antagonistic activity. The most active compounds in the series were the 4-nitrobenzyl carbamate and thiocarbamate 7 and 11 which exhibited an IC50 value of about 20 µM. These activities are in the range of other reported of AHL-structurally related quorum sensing (QS) inhibitors. Docking experiments conducted on the LuxR model showed that, compared to the natural ligand OHHL, the additional heteroatom of the carbamate group induces a new hydrogen bond with Tyr70 leading to a different global hydrogen-bond network. Tyr70 is an important residue in the binding site and is strictly conserved in the LuxR family. For the 4-nitrobenzyl carbamate and thiocarbamate analogues, the docking results highlight an additional hydrogen bond between the nitro group and Lys178. For hydrazide analogues, which are deprived of any activity, docking shows that the orientation of the carbonyl group is opposite as compared with the natural ligand, leading to the absence of a H-bond between the C=O with Tyr62. This suggests that, either this later interaction, or the influence of the C=O orientation on the overall ligand conformation, are essential for the biological activity.

Surfaces based on amino acid functionalized polyelectrolyte films towards active surfaces for enzyme immobilization.

Surface based on polyelectrolytes functionalized with amino acids onto amino-terminated solid surfaces of silicon wafers was prepared, with the purpose of evaluate the chemical functionality of the polyelectrolyte films in adsorption and catalytic activity of an enzyme. In this work, the adsorption of the enzyme glucose 6-phosphate dehydrogenase from Leuconostoc mesenteroides (LmG6PD) was studied as model. The polyelectrolytes were obtained from poly (maleic anhydride-alt-vinylpyrrolidone) [poly(MA-alt-VP)] and functionalized with amino acids of different hydropathy index: glutamine (Gln), tyrosine (Tyr) and methionine (Met). The polyelectrolytes were adsorbed onto the amino-terminated silicon wafer at pH 3.5 and 4.5 and at low and high ionic strength. At low ionic strength and pH 3.5, the largest quantity of adsorbed polyelectrolyte was on the films containing glutamine moiety as the most hydrophilic amino acid in the side chain of polymer chain (5.88 mg/m2), whereas at high ionic strength and pH 4.5, the lowest quantity was in films containing tyrosine moiety in the side chain (1.88 mg/m2). The films were characterized by ellipsometry, contact angle measurements and atomic force microscopy (AFM). The polyelectrolyte films showed a moderate degree of hydrophobicity, the methionine derivative being the most hydrophobic film. With the aim of evaluate the effect of the amino acid moieties on the ability of the surface to adsorb enzymes, we study the activity of the enzyme on these surfaces. We observed that the polarity of the side chain of the amino acid in the polyelectrolyte affected the quantity of LmG6PD adsorbed, as well as its specific activity, showing that films prepared from poly(MA-alt-VP) functionalized with Met provide the best enzymatic performance. The results obtained demonstrated that the surfaces prepared from polyelectrolytes functionalized with amino acids could be an attractive and simple platform for the immobilization of enzymes, which could be of interest for biocatalysis applications.

4-Aminoindoles as 1,4-bisnucleophiles for diversity-oriented synthesis of tricyclic indoles bearing 3,4-fused seven-membered rings.

A straightforward access to tricyclic indoles bearing 3,4-fused seven-membered rings has been established by using 4-aminoindoles as 1,4-bisnucleophiles in three-component reactions. 1H-Azepino[4,3,2-cd]indoles, 4,6-dihydro-1H-azepino[4,3,2-cd]indoles and 1,3,4,6-tetrahydro-5H-azepino[4,3,2-cd]indol-5-ones could thus be synthesized in one pot in moderate to good yields. Beyond opening access to 3,4-fused tricyclic indoles, the use of easily accessible 4-aminoindoles as C,N-1,4-bisnucleophiles also provides a new platform to be used in a diversity-oriented synthesis strategy, fully displaying its benefits of maximizing molecular complexity and reaction diversity.

Conformational and docking studies of acyl homoserine lactones as a robust method to investigate bioactive conformations.

A method aiming at investigating possible bioactive conformations of acyl homoserine lactone (AHL) quorum sensing (QS) modulators is established. The method relies on the exhaustive conformational analysis of AHLs by varying torsion angles around the amide group then on the selection of the closest conformation to those known from co-crystallized XRD data of AHL-receptor complexes. These latter are then docked as rigid ligand within the receptor binding site, leading to interactions with binding site residues which are highly consistent as compared with the data arising from XRD studies. The method is first validated using AHLs for which XRD data of their complexes with their cognate receptor are available, then extended to examples for which the binding mode is still unknown. Three compounds were used to validate the method: hexanoyl homoserine lactone (HHL) as an example of autoinducer, 3-oxo-butanoyl homoserine lactone (OBHL), as a representative model of 3-oxo-AHLs, and 4-(4-chlorophenoxy)butanoyl homoserine lactone (CPOBHL) as an example of a QS inhibitor. The conformational analysis of these three compounds to their cognate protein (TraR, SdiA, LasR and CviR) provides the data which enable the next rigid docking step. Further rigid docking of the closest conformations compared to the known bioactive ones within the binding sites allows to recover the expected binding mode with high precision (atomic RMSD < 2 Å). This "conformational analysis/torsion angle filter/rigid ligand docking" method was then used for investigating three non-natural AHL-type QS inhibitors without known co-crystallized XRD structures, namely was 2-hexenoyl homoserine lactone (HenHL), 3-oxo-4-phenylbutanoyl homoserine lactone (OPBHL) and 3-(4-bromophenyl)propanoyl homoserine lactone (BPPHL). Results provide insights into their possible binding mode by identifying specific interactions with some key residues within the receptor binding site, allowing discussion of their biological activity.

Synthesis of a non-natural glucose-2-phosphate ester able to dupe the acc system of Agrobacterium fabrum.

The first non-natural derivative of the rare d-glucose-2-phosphate (G2P), namely glucose-2-(O-lactic acid phosphate) (G2LP), has been synthesized. When used as sole carbon source, G2LP enables bacterial growth of the plant pathogenic strain Agrobacterium fabrum C58 (formerly referred to as Agrobacterium tumefaciens). X-ray crystallography and affinity measurements investigations reveal that G2LP binds the periplasmic binding protein (PBP) AccA similarly to the natural compounds and with the same affinity. Moreover, enzymatic assays show that it is able to serve as substrate of the phosphodiesterase AccF. The properties found for G2LP demonstrate that the very unusual glucose-2-phosphoryl residue, present in G2LP, can be used as structural feature for designing non-natural systems fully compatible with the Acc cascade of A. fabrum.