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.

A Novel Natural Siderophore Antibiotic Conjugate Reveals a Chemical Approach to Macromolecule Coupling.

Inspired by natural sideromycins, the conjugation of antibiotics to siderophores is an attractive strategy to facilitate "Trojan horse" delivery of antibiotics into bacteria. Genome analysis of a soil bacterium, Dactylosporangium fulvum, found a "hybrid" biosynthetic gene cluster responsible for the production of both an antibiotic, pyridomycin, and a novel chlorocatechol-containing siderophore named chlorodactyloferrin. While both of these natural products were synthesized independently, analysis of the culture supernatant also identified a conjugate of both molecules. We then found that the addition of ferric iron to purified chlorodactyloferrin and pyridomycin instigated their conjugation, leading to the formation of a covalent bond between the siderophore-catechol and the pyridomycin-pyridine groups. Using model reactants, this iron-based reaction was found to proceed through a Michael-type addition reaction, where ferric iron oxidizes the siderophore-catechol group into its quinone form, which is then attacked by the antibiotic pyridyl-nitrogen to form the catechol-pyridinium linkage. These findings prompted us to explore if other "cargo" molecules could be attached to chlorodactyloferrin in a similar manner, and this was indeed confirmed with a pyridine-substituted TAMRA fluorophore as well as with pyridine-substituted penicillin, rifampicin, and norfloxacin antibiotic analogues. The resultant biomimetic conjugates were demonstrated to effectively enter a number of bacteria, with TAMRA-chlorodactyloferrin conjugates causing fluorescent labeling of the bacteria, and with penicillin and rifampicin conjugates eliciting antibiotic activity. These findings open up new opportunities for the design and facile synthesis of a novel class of biomimetic siderophore conjugates with antibiotic activity.

Natural Compounds with Antifungal Properties against Candida albicans and Identification of Hinokitiol as a Promising Antifungal Drug.

Candida albicans is an opportunistic yeast that causes most fungal infections. C. albicans has become increasingly resistant to antifungal drugs over the past decade. Our study focused on the identification of pure natural compounds for the development of antifungal medicines. A total of 15 natural compounds from different chemical families (cinnamic derivatives, aromatic phenols, mono- and sesquiterpenols, and unclassified compounds) were screened in this study. Among these groups, hinokitiol (Hi), a natural monoterpenoid extracted from the wood of the cypress family, showed excellent anti-C. albicans activity, with a MIC value of 8.21 µg/mL. Hi was selected from this panel for further investigation to assess its antifungal and anti-inflammatory properties. Hi exhibited significant antifungal activity against clinically isolated fluconazole- or caspofungin-resistant C. albicans strains. It also reduced biofilm formation and hyphal growth. Treatment with Hi protected Caenorhabditis elegans against infection with C. albicans and enhanced the expression of antimicrobial genes in worms infected with C. albicans. Aside from its antifungal activities against C. albicans, Hi challenge attenuated the LPS-induced expression of pro-inflammatory cytokines (IL-6, IL-1ß, and CCL-2) in macrophages. Overall, Hi is a natural compound with antifungal and anti-inflammatory properties, making Hi a promising platform with which to fight against fungal infections.

Anti-Malassezia Drug Candidates Based on Virulence Factors of Malassezia-Associated Diseases.

Malassezia is a lipophilic unicellular fungus that is able, under specific conditions, to cause severe cutaneous and systemic diseases in predisposed subjects. This review is divided into two complementary parts. The first one discusses how virulence factors contribute to Malassezia pathogenesis that triggers skin diseases. These virulence factors include Malassezia cell wall resistance, lipases, phospholipases, acid sphingomyelinases, melanin, reactive oxygen species (ROS), indoles, hyphae formation, hydrophobicity, and biofilm formation. The second section describes active compounds directed specifically against identified virulence factors. Among the strategies for controlling Malassezia spread, this review discusses the development of aryl hydrocarbon receptor (AhR) antagonists, inhibition of secreted lipase, and fighting biofilms. Overall, this review offers an updated compilation of Malassezia species, including their virulence factors, potential therapeutic targets, and strategies for controlling their spread. It also provides an update on the most active compounds used to control Malassezia species.

Antifungal Properties of Hydrazine-Based Compounds against Candida albicans.

Candida albicans, an opportunistic yeast, is the most common cause of fungal infection. In the past decade, there has been an increase in C. albicans resistance to existing antifungal drugs, which has necessitated the development of new antifungal agents. In the present study, screening 60 compounds from the JUNIA chemical library enabled us to explore an additional 11 hybrid compounds that contain pyrrolidinone rings and hydrazine moieties for their potential antifungal activities. This chemical series was identified with fair to excellent antifungal activities. Among this series, three molecules (Hyd.H, Hyd.OCH3, and Hyd.Cl) significantly reduced C. albicans viability, with rapid fungicidal activity. In addition, these three compounds exhibited significant antifungal activity against clinically isolated fluconazole- or caspofungin-resistant C. albicans strains. Hyd.H, Hyd.OCH3, and Hyd.Cl did not show any cytotoxicity against human cancer cell lines up to a concentration of 50 µg/mL and decreased Candida biofilm formation, with a significant reduction of 60% biofilm formation with Hyd.OCH3. In an infection model of Caenorhabditis elegans with C. albicans, hydrazine-based compounds significantly reduced nematode mortality. Overall, fungicidal activity was observed for Hyd.H, Hyd.OCH3, and Hyd.Cl against C. albicans, and these compounds protected C. elegans from C. albicans infection.

Two New Compounds Containing Pyridinone or Triazine Heterocycles Have Antifungal Properties against Candida albicans.

Candidiasis, caused by the opportunistic yeast Candida albicans, is the most common fungal infection today. Resistance of C. albicans to current antifungal drugs has emerged over the past decade leading to the need for novel antifungal agents. Our aim was to select new antifungal compounds by library-screening methods and to assess their antifungal effects against C. albicans. After screening 90 potential antifungal compounds from JUNIA, a chemical library, two compounds, 1-(4-chlorophenyl)-4-((4-chlorophenyl)amino)-3,6-dimethylpyridin-2(1H)-one (PYR) and (Z)-N-(2-(4,6-dimethoxy-1,3,5-triazin-2-yl)vinyl)-4-methoxyaniline (TRI), were identified as having potential antifungal activity. Treatment with PYR and TRI resulted in a significant reduction of C. albicans bioluminescence as well as the number of fungal colonies, indicating rapid fungicidal activity. These two compounds were also effective against clinically isolated fluconazole- or caspofungin-resistant C. albicans strains. PYR and TRI had an inhibitory effect on Candida biofilm formation and reduced the thickness of the mannan cell wall. In a Caenorhabditis elegans infection model, PYR and TRI decreased the mortality of nematodes infected with C. albicans and enhanced the expression of antimicrobial genes that promote C. albicans elimination. Overall, PYR and TRI showed antifungal properties against C. albicans by exerting fungicidal activities and enhancing the antimicrobial gene expression of Caenorhabditis elegans.

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.

Promising Drug Candidates and New Strategies for Fighting against the Emerging Superbug Candida auris.

Invasive fungal infections represent an expanding threat to public health. During the past decade, a paradigm shift of candidiasis from Candida albicans to non-albicans Candida species has fundamentally increased with the advent of Candida auris. C. auris was identified in 2009 and is now recognized as an emerging species of concern and underscores the urgent need for novel drug development strategies. In this review, we discuss the genomic epidemiology and the main virulence factors of C. auris. We also focus on the different new strategies and results obtained during the past decade in the field of antifungal design against this emerging C. auris pathogen yeast, based on a medicinal chemist point of view. Critical analyses of chemical features and physicochemical descriptors will be carried out along with the description of reported strategies.

Sesamol-based terpenoids as promising bio-sourced crop protection compounds against the wheat pathogen Zymoseptoria tritici.

BACKGROUND: Research into environmentally friendly alternatives to conventional plant protection products, to promote sustainable agriculture and healthy food, is strongly encouraged. RESULTS: In this context, 20 naturally occurring terpenoids and phenolic compounds were selected and evaluated in vitro as crop protection compounds against Zymoseptoria tritici, the causal agent of Septoria tritici blotch of wheat. After selection of the most active compounds, some hemisynthetic modifications were conducted to modify their lipophilicity. These modifications led to the discovery of sesamol esters as promising antifungal agents, with IC50 around 10 µg/mL and a total absence of cytotoxicity against human cells. CONCLUSION: These sesamol-based derivatives should be selected for further evaluations in planta to validate their use as wheat crop protection agents. Moreover, the importance of a balanced hydrophily/lipophilicity ratio should be further studied. © 2021 Society of Chemical Industry.

The receptor for advanced glycation end products is a sensor for cell-free heme.

Heme's interaction with Toll-like receptor 4 (TLR4) does not fully explain the proinflammatory properties of this hemoglobin-derived molecule during intravascular hemolysis. The receptor for advanced glycation end products (RAGE) shares many features with TLR4 such as common ligands and proinflammatory, prothrombotic, and pro-oxidative signaling pathways, prompting us to study its involvement as a heme sensor. Stable RAGE-heme complexes with micromolar affinity were detected as heme-mediated RAGE oligomerization. The heme-binding site was located in the V domain of RAGE. This interaction was Fe3+ -dependent and competitive with carboxymethyllysine, another RAGE ligand. We confirmed a strong basal gene expression of RAGE in mouse lungs. After intraperitoneal heme injection, pulmonary TNF-α, IL1ß, and tissue factor gene expression levels increased in WT mice but were significantly lower in their RAGE-/- littermates. This may be related to the lower activation of ERK1/2 and Akt observed in the lungs of heme-treated, RAGE-/- mice. Overall, heme binds to RAGE with micromolar affinity and could promote proinflammatory and prothrombotic signaling in vivo, suggesting that this interaction could be implicated in heme-overload conditions.

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.

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.

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.

A Small Aromatic Compound Has Antifungal Properties and Potential Anti-Inflammatory Effects against Intestinal Inflammation.

Resistance of the opportunistic pathogen Candida albicans to antifungal drugs has increased significantly in recent years. After screening 55 potential antifungal compounds from a chemical library, 2,3-dihydroxy-4-methoxybenzaldehyde (DHMB) was identified as having potential antifungal activity. The properties of DHMB were then assessed in vitro and in vivo against C. albicans overgrowth and intestinal inflammation. Substitution on the aromatic ring of DHMB led to a strong decrease in its biological activity against C. albicans. The MIC of DHMB was highly effective at eliminating C. albicans when compared to that of caspofungin or fluconazole. Additionally, DHMB was also effective against clinically isolated fluconazole- or caspofungin-resistant C. albicans strains. DHMB was administered to animals at high doses. This compound was not cytotoxic and was well-tolerated. In experimental dextran sodium sulphate (DSS)-induced colitis in mice, DHMB reduced the clinical and histological score of inflammation and promoted the elimination of C. albicans from the gut. This finding was supported by a decrease in aerobic bacteria while anaerobic bacteria populations were re-established in mice treated with DHMB. DHMB is a small organic molecule with antifungal properties and anti-inflammatory activity by exerting protective effects on intestinal epithelial cells.

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.

Selective Pinacol-Coupling Reaction using a Continuous Flow System.

The first continuous flow pinacol coupling reaction of carbonyl compounds was successfully achieved within only 2 min during a single pass through a cartridge filled with zinc(0). The optimized method allowed the efficient production of gram-scale value-added compounds with high productivity. The developed methodology is efficient for aromatic or α,ß-unsaturated aldehydes but gives moderate results for more stable acetophenone derivatives. Moreover, the flow method displayed better results in terms of yield and selectivity in comparison to the corresponding batch methodology.

2-hydroxyisoquinoline-1,3(2H,4H)-diones (HIDs) as human immunodeficiency virus type 1 integrase inhibitors: Influence of the alkylcarboxamide substitution of position 4.

Herein, we report further insight into the biological activities displayed by the 2-hydroxyisoquinoline-1,3(2H,4H)-dione (HID) scaffold. Previous studies have evidenced the marked fruitful effect of substitution of this two-metal binding pharmacophore at position 4 by phenyl and benzyl carboxamido chains. Strong human immunodeficiency virus type 1 integrase (HIV-1 IN) inhibitors in the low nanomolar range with micromolar (even down to low nanomolar) anti-HIV activities were obtained. Keeping this essential 4-carboxamido function, we investigated the influence of the replacement of phenyl and benzyl groups by various alkyl chains. This study shows that the recurrent halogenobenzyl pharmacophore found in the INSTIs can be efficiently replaced by an n-alkyl group. With an optimal length of six carbons, we observed a biological profile and a high barrier to resistance equivalent to those of a previously reported hit compound bearing a 4-fluorobenzyl group.

Selective Pinacol Coupling on Regeneratable Supported Acids in Sole Water.

Efficient pinacol coupling was developed in sole water, using a reusable heterogeneous supported acid source and zinc as cheap available metal source. This medium can be easily regenerated up to 10-fold without loss of activity. Moreover, supported acids enhance the selectivity of the pinacol coupling reaction compared with homogeneous acids.