Development of Receptor for Advanced Glycation End Products (RAGE) ligands through target directed dynamic combinatorial chemistry: a novel class of possible antagonists.

RAGE is a transmembrane receptor of immunoglobulin family that can bind various endogenous and exogenous ligands, initiating the inflammatory downstream signaling pathways, including inflammaging. Therefore, RAGE represents an attractive drug target for age-related diseases. For the development of small-molecule RAGE antagonists, we employed protein-templated dynamic combinatorial chemistry (ptDCC) using RAGE's VC1 domain as a template, the first application of this approach in the context of RAGE. The affinities of DCC hits were validated using microscale thermophoresis. Subsequent screening against AGE2 (glyceraldehyde-modified AGE)-sRAGE (solubleRAGE) (AGE2-BSA/sRAGE) interaction using ELISA tests led to the identification of antagonists with micromolar potency. Our findings not only demonstrate the successful application of ptDCC on RAGE but also highlight its potential to address the pressing need for alternative strategies for the development of small-molecule RAGE antagonists, an area of research that has experienced a slowdown in recent years.

γ-Lactam-Based Antifungal Compounds against the Wheat Pathogen Zymoseptoria tritici.

As new environmentally friendly and effective antifungal agents are deeply needed, efficient ecofriendly strategies were designed to access two series of compounds inspired from natural γ-lactams. Designed compounds were fully characterized and evaluated as antifungal candidates against Zymoseptoria tritici, the main pathogen on wheat crops. The targeted derivatives were prepared from natural resources using green solvents, simple procedures, and limited purification steps. These bio-inspired compounds revealed as good candidates for further development of efficient crop protection products. Indeed, the HIT compounds exhibited IC50 around 1 µg/mL and were more active than the references tebuconazole and bixafen towards some multidrug-resistant strains. Two dozen of derivatives have been obtained for each series and allowed to establish early structure-activity relationships useful for the development of next generation of γ-lactam derivatives with improved efficacy.

Design, synthesis and evaluation of hydrazine and acyl hydrazone derivatives of 5-pyrrolidin-2-one as antifungal agents.

Twenty-eight 5-pyrrolidine-2-ones decorated by hydrazine or acyl hydrazones groups have been designed, synthesized and evaluated as antifungal agents on a panel of twelve fungal strains and three non albicans candida yeasts species which have demonstrated reduced susceptibility to commonly used antifungal drugs. Half of the target compounds exhibited good to high antifungal activities on at least one strain with MIC50 lower than the control antifungal agent - hymexazol or ketoconazole. 5-Arylhydrazino-pyrrolidin-2-ones were found active and the -NH-NH- linker proved to be essential to maintain the antifungal potential. Compound 2a is a broad-spectrum antifungal, active on 60% of the tested strains. Replacing the hydrazine linker by an acylhydrazone one narrowed the spectrum of activity but pyroglutamylaryl hydrazones, mainly aromatic ones, exhibited good activity, adequate "fungicide-like" properties and were devoted of cytotoxicity.

Separations of antifungal compounds in capillary electrophoresis with two anionic cyclodextrins.

CD-CZE methods were developed for complete stereoisomeric separations of a series of six γ-lactam analogues, of which some were neutral, or cationic depending on the background electrolyte nature. The tested cyclodextrin was the versatile sulfobutylether- ß-CD, used either in a phosphate buffer using capillaries dynamically coated with polyethylene oxide or in a borate buffer using uncoated capillaries. Long-end and short-end modes and concentration variations of chiral selectors allowed finding conditions of complete separation of four out of the six derivatives (i.e., 1, 2, 3, and 4) in short run times, confirming their broad range of applications. To separate the two last compounds, the highly sulfated- Î³-CD was examined as chiral selector in acidic phosphate conditions. The enantiomers of the γ-lactam analogues 5 and 6 were baseline resolved with 5.5 and 4%, respectively as concentration in the buffer.

Dynamic covalent chemistry with azines.

Dynamic covalent chemistry is used in many applications that require both the stability of covalent bonds and the possibility to exchange building blocks. Here we present azines as a dynamic covalent functional group that combines the best characteristics of imines and acylhydrazones. We show that azines are stable in the presence of water and that dynamic combinatorial libraries of azines and aldehydes equilibrate in less than an hour.

Comparison of dimethylated and methylchlorinated amylose stationary phases, coated and covalently immobilized on silica, for the separation of some chiral compounds in supercritical fluid chromatography.

The chromatographic properties of a new coated amylose tris(3-chloro-5-methylphenylcarbamate) were evaluated in supercritical fluid chromatography for the separation of enantiomers of chiral 1-aryl-5-aryl-pyrrolidin-2-one derivatives, potential anticancer agents, and some commercial drugs. The mobile phase consisted of CO2-modifier mixtures with 30% of either methanol or ethanol, the flow rate was 3 mL/min. The column oven temperature was 40 °C and the outlet pressure was 15 MPa, in order to limit the compressibility of the CO2, thus limiting density variation along the column. The obtained results were then compared to those observed toward 3 other stationary phases: the coated amylose tris(3,5-dimethylphenylcarbamate), the immobilized amylose tris(3,5-dimethylphenylcarbamate) and the coated amylose tris(5-chloro-2-methylphenylcarbamate). It was shown that the new coated amylose tris(3-chloro-5-methylphenylcarbamate) was the most retentive column whatever the studied compounds, particularly for thalidomide and omeprazole with retention factors up to 73.3 and 29.5for the second enantiomer, respectively. Concerning the enantioselectivity, even most of the compounds are separated on all the four columns, the coated amylose tris(3-chloro-5-methylphenylcarbamate) allows the best resolution for most of the ten studied analytes (except omeprazole for which the resolution values are equal to 7.8 and 9.7 on the coated amylose tris(3-chloro-5-methylphenylcarbamate) and amylose tris(3,5-dimethylphenylcarbamate), respectively). Acting in complementary ways, the two chlorinated stationary phases permitted the complete separation of enantiomers of nine compounds out of the ten.

Analytical and preparative enantioseparations in supercritical fluid chromatography using different brands of immobilized cellulose tris (3,5-dichlorophenylcarbamate) columns: Some differences.

The aim of this study was to determine the impact of the origin and the manufacturing processes of the chiral stationary phases (CSPs) on their chromatographic behaviors. Hence, four chiral stationary phases based on immobilized tris (3,5-dichlorophenylcarbamate) derivative of cellulose supplied by four different manufacturers were evaluated. A set of twenty-nine compounds, including commercially available and in-house synthesized compounds, with a broad range of lipophilicity and polarity was chosen. Three main parameters were evaluated on all stationary phases: retention factor, selectivity and loading capacity. This work highlighted that the retention factor strongly varied according to the manufacturer. Regardless of the characteristic of the tested compounds i.e. neutral, acidic or basic, there was a trend in retention ability of the four chiral stationary phases: retention was increasing from CHIRAL ART Cellulose-SC, REFLECT I-Cellulose C, Chiralpak IC to Lux i-Cellulose-5. On the contrary, selectivity did not follow the same trend as retention. The difference in selectivity between each column towards one compound was quite low while the difference in resolution depended on the nature of the compounds investigated and was significant in certain cases. Finally, the four different columns presented similar and high loading capacity.

Design, synthesis and antifungal activity of pterolactam-inspired amide Mannich bases.

Pterolactam (5-methoxypyrrolidin-2-one) is a heterocycle naturally occurring in plants. In an attempt to identify antifungal agents, a series of novel Mannich bases of amide derivated from Pterolactam have been designed, synthesized and their antifungal activities were evaluated on a panel of nine fungal strains and three non albicans candida yeasts species which have demonstrated reduced susceptibility to commonly used antifungal drugs. A third of the target compounds exhibited good to high antifungal activities on at least one strain with EC50 lower than the control antifungal agent. N,N'-aminals derivated from Pterolactam proved to be good candidates for the development of biosourced fungicides, with compound 3o being the most broader-spectrum agent, active against five strains and devoted of any cytotoxicity.

Performance comparison of chlorinated chiral stationary phases in supercritical fluid chromatography for separation of selected pyrrolidone derivatives.

The effects of two chlorinated chiral stationary phases, namely, Lux Cellulose-2 and Lux i-Cellulose-5, flow-rate, percentage of co-solvent and chemical structures of the compounds on retention and resolution were studied within this article. In this work a backpressure of 150 bar, a temperature of 40 °C and 10% of methanol as co-solvent were chosen as operating conditions. The optimum flow-rate was 2 mL/min. The percentage of co-solvent was studied between 7.5% and 15%. We have observed that 15% of methanol gave the best results for most of the compounds. For all the derivatives, the Lux Cellulose-2 provided better resolutions going from 1.50 to 3.59 compared with Lux i-Cellulose-5.

Separation of enantiomers of native amino acids with polysaccharide-based chiral columns in supercritical fluid chromatography.

In this short communication preliminary results are reported on the separation of enantiomers of underivatized amino acids on polysaccharide-based chiral columns in sub/super-critical fluid chromatography (SFC). Racemic mixtures of 14 amino acids were used to evaluate the chiral recognition ability of 8 different polysaccharide-based chiral columns with coated or covalently immobilized chiral selectors. Among the studied columns, the one based on cellulose (3,5-dichlorophenylcarbamate) exhibited the most universal chiral recognition ability providing baseline resolution for the enantiomers of 10 studied amino acids. In addition, the effect of mobile phase composition (in particular, of the amount of additive used), as well as the potential contribution of evaporative light scattering detector (ELSD) to extra column band-broadening was evaluated.

Performance comparison of chlorinated chiral stationary phases in supercritical fluid chromatography for separation of selected pyrrolidone derivatives / 药物分析学报

The effects of two chlorinated chiral stationary phases, namely, Lux Cellulose-2 and Lux i-Cellulose-5, flow-rate, percentage of co-solvent and chemical structures of the compounds on retention and reso-lution were studied within this article. In this work a backpressure of 150 bar, a temperature of 40 ℃ and 10％ of methanol as co-solvent were chosen as operating conditions. The optimum flow-rate was 2 mL/min. The percentage of co-solvent was studied between 7.5％ and 15％. We have observed that 15％ of methanol gave the best results for most of the compounds. For all the derivatives, the Lux Cellulose-2 provided better resolutions going from 1.50 to 3.59 compared with Lux i-Cellulose-5.