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Iminosugars, a class of polyhydroxylated cyclic alkaloids with intriguing properties, hold promising therapeutic potentials against a broad spectrum of enveloped viruses, including DENV, HCV, HIV, and influenza viruses. Mechanistically, iminosugars act as the competitive inhibitors of host endoplasmic reticular α-glucosidases I and II to disrupt the proper folding of viral nascent glycoproteins, which thereby exerts antiviral effects. Remarkably, the glycoproteins of many enveloped viruses are significantly more dependent on the calnexin pathway of the protein folding than most host glycoproteins. Therefore, extensive interests and efforts have been devoted to exploit iminosugars as broad-spectrum antiviral agents. This review provides the summary and insights into the recent advancements in the development of novel iminosugars as effective and selective antiviral agents against a variety of enveloped viruses, as well as the understandings of their antiviral mechanisms. [ABSTRACT FROM AUTHOR]

Abstract Iminosugars, a class of polyhydroxylated cyclic alkaloids with intriguing properties, hold promising therapeutic potentials against a broad spectrum of enveloped viruses, including DENV, HCV, HIV, and influenza viruses. Mechanistically, iminosugars act as the competitive inhibitors of host endoplasmic reticular α-glucosidases I and II to disrupt the proper folding of viral nascent glycoproteins, which thereby exerts antiviral effects. Remarkably, the glycoproteins of many enveloped viruses are significantly more dependent on the calnexin pathway of the protein folding than most host glycoproteins. Therefore, extensive interests and efforts have been devoted to exploit iminosugars as broad-spectrum antiviral agents. This review provides the summary and insights into the recent advancements in the development of novel iminosugars as effective and selective antiviral agents against a variety of enveloped viruses, as well as the understandings of their antiviral mechanisms. Graphical Abstract

Bacteria are capable of remarkable adaptations to their environment, including undesirable bacterial resistance to antibacterial agents. One of the most serious cases is an infection caused by multidrug-resistant Staphylococcus aureus, which has unfortunately also spread outside hospitals. Therefore, the development of new effective antibacterial agents is extremely important to solve the increasing problem of bacterial resistance. The bacteriolytic enzyme autolysin E (AtlE) is a promising new drug target as it plays a key role in the degradation of peptidoglycan in the bacterial cell wall. Consequently, disruption of function can have an immense impact on bacterial growth and survival. An in silico and in vitro evaluation of iminosugar derivatives as potent inhibitors of S. aureus (AtlE) was performed. Three promising hit compounds (1, 3 and 8) were identified as AtlE binders in the micromolar range as measured by surface plasmon resonance. The most potent compound among the SPR response curve hits was 1, with a KD of 19 μM. The KD value for compound 8 was 88 μM, while compound 3 had a KD value of 410 μM. [ABSTRACT FROM AUTHOR]

This article discusses the synthesis of 7a-substituted pyrrolizidine derivatives through stereocontrolled anionic cyclization. The derivatives have potential therapeutic applications and the authors describe a new route for their synthesis using proline derivatives and epichlorohydrin. The compounds were successfully synthesized with controlled stereochemistry and characterized using spectroscopic techniques. The text provides detailed information on the reactions, yields, physical properties, and spectroscopic data of the compounds, making it a valuable resource for researchers studying organic chemistry and chemical synthesis. [Extracted from the article]

AbstractWe developed new iminosugar-based glycosidase inhibitors against SARS-CoV-2. Known drugs (miglustat, migalastat, miglitol, and swainsonine) were chosen as lead compounds to develop three classes of glycosidase inhibitors (α-glucosidase, α-galactosidase, and mannosidase). Molecular modelling of the lead compounds, synthesis of the compounds with the highest docking scores, enzyme inhibition tests, and in vitro antiviral assays afforded rationally designed inhibitors. Two highly active α-glucosidase inhibitors were discovered, where one of them is the most potent iminosugar-based anti-SARS-CoV-2 agent to date (EC90 = 1.94 µM in A549-ACE2 cells against Omicron BA.1 strain). However, galactosidase inhibitors did not exhibit antiviral activity, whereas mannosidase inhibitors were both active and cytotoxic. As our iminosugar-based drug candidates act by a host-directed mechanism, they should be more resilient to drug resistance. Moreover, this strategy could be extended to identify potential drug candidates for other viral infections.

This document is a special issue of the journal Pharmaceuticals that focuses on the importance of glycomimetics and glycoconjugates in drug discovery. The articles discuss the role of carbohydrates and glycoconjugates in biological events relevant to diseases such as cancer and infection. Topics covered include the interaction of glycomimetics with specific receptors, the synthesis and inhibition abilities of iminosugar clusters, the synthesis and evaluation of glycoconjugates as potential inhibitors of viral protein N-glycosylation, the synthesis and evaluation of a glucoconjugate derivative of an anticancer agent, the synthesis and evaluation of novel compounds with dual-target activity against type 2 diabetes, the production of recombinant glycoproteins with desired glycosylation patterns, and the assembly of peptidoglycan fragments for antibiotic research. The authors hope that this collection of papers will inspire readers in the field of glycosciences. [Extracted from the article]

In this work, we present a metal‐free coupling protocol for the regio‐ and stereoselective C3‐thioarylation of 6‐amino‐2,3,6‐trideoxy‐d‐manno‐oct‐2‐ulosonic acid (iminoKdo). The developed procedure enables the coupling of electron‐rich, electron‐deficient, and hindered arylthiols, providing a series of C3‐modified iminoKdo derivatives in moderate to good yields. Elucidation of active species through controlled experimental studies and time‐lapse 31P NMR analysis provides insights into the reaction mechanism. We demonstrate that, following a tandem Staudinger/aza‐Wittig reaction of an azido‐containing keto ester, an inseparable equimolar mixture of imine/enamine is formed. The enamine then undergoes a Stork‐like nucleophilic attack with the in situ‐formed disulfide reagent, resulting in the formation of the coupling products. Additionally, we describe a rarely reported acid‐promoted aromatization of the C3‐thioarylated iminoKdo skeleton into 3,6‐disubstituted picolinates, which are reminiscent of dichotomines. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: Different novel fused multicyclic iminosugars were synthesized from D‐ribose tosylate, aniline and vinyl ethyl ether by one‐pot three‐component stereoselective [4+2] reaction at different temperatures. The iminium‐ion is the key intermediate for the reaction. As a result, several complex fused iminosugars 3a were obtained by aza‐Diels‐Alder mechanism at 60 °C, while a series of aza‐C‐glycosides 5a were prepared by Mannich reaction at room temperature accompanied by another tetrahydroquinoline‐fused iminosugars 4a (tricyclic derivatives) through aza‐Diels‐Alder cycloaddition. This strategy will help to construct structurally diverse and bioactive iminosugar analogues. [ABSTRACT FROM AUTHOR]

The article discusses a novel hydrothermal and thermal annealing method for enhancing surface active sites by depositing a monolayer of Ru, resulting in robust MoO2/MoNi4@Ru/RuO2 heterogeneous cubic array electrocatalysts. Topics include visible-light-promoted Pd-catalyzed cross-coupling, circularly polarized luminescence of cyanostilbenes, and one-pot stereoselective synthesis of fused multicyclic iminosugars.

Bacteria are capable of remarkable adaptations to their environment, including undesirable bacterial resistance to antibacterial agents. One of the most serious cases is an infection caused by multidrug-resistant Staphylococcus aureus, which has unfortunately also spread outside hospitals. Therefore, the development of new effective antibacterial agents is extremely important to solve the increasing problem of bacterial resistance. The bacteriolytic enzyme autolysin E (AtlE) is a promising new drug target as it plays a key role in the degradation of peptidoglycan in the bacterial cell wall. Consequently, disruption of function can have an immense impact on bacterial growth and survival. An in silico and in vitro evaluation of iminosugar derivatives as potent inhibitors of S. aureus (AtlE) was performed. Three promising hit compounds (1, 3 and 8) were identified as AtlE binders in the micromolar range as measured by surface plasmon resonance. The most potent compound among the SPR response curve hits was 1, with a KD of 19 μM. The KD value for compound 8 was 88 μM, while compound 3 had a KD value of 410 μM.

An efficient and simple one‐pot synthesis of structurally diverse novel tetrahydroquinoline‐fused iminosugars was developed through the aza‐Diels‐Alder mechanism. The adaptability of this method has been demonstrated by a variety of imines and d/l‐ribose tosylates, and both, electron‐donating and ‐withdrawing substituted imines proceed well. In addition, this reaction is characterized by simple operation, good yield, and high atom economy. Some synthetic iminosugars showed moderate anti proliferation of HCT116 tumor cells. [ABSTRACT FROM AUTHOR]

Richard Lerner was a visionary polymath of the 20th century; a medical doctor, chemist, immunologist, inventor, and founder of new scientific fields. As a tribute to his life and scientific achievements, we discuss his connection with Oxford University and the Glycobiology Institute and we discuss our research data on the host glycoprotein folding pathway and how its inhibition can lead to broad spectrum antiviral drugs. This host targeting approach for developing antiviral therapies has the advantage of being effective against many viruses, therefore can be used to prevent new epidemics to become pandemics. [ABSTRACT FROM AUTHOR]

Glycoside hydrolases (GHs) are a class of enzymes with emerging roles in a range of disease. Selective GH inhibitors are sought to better understand their functions and assess the therapeutic potential of modulating their activities. Iminosugars are a promising class of GH inhibitors but typically lack the selectivity required to accurately perturb biological systems. Here, we describe a concise synthesis of iminosugar inhibitors of N‐acetyl‐α‐galactosaminidase (α‐NAGAL), the GH responsible for cleaving terminal α‐N‐acetylgalactosamine residues from glycoproteins and other glycoconjugates. Starting from non‐carbohydrate precursors, this modular synthesis supported the identification of a potent (490 nM) and α‐NAGAL selective (∼200‐fold) guanidino‐containing derivative DGJNGuan. To illustrate the cellular activity of this new inhibitor, we developed a quantitative fluorescence image‐based method to measure levels of the Tn‐antigen, a cellular glycoprotein substrate of α‐NAGAL. Using this assay, we show that DGJNGuan exhibits excellent inhibition of α‐NAGAL within cells using patient derived fibroblasts (EC50=150 nM). Moreover, in vitro and in cell assays to assess levels of lysosomal β‐hexosaminidase substrate ganglioside GM2 show that DGJNGuan is selective whereas DGJNAc exhibits off‐target inhibition both in vitro and within cells. DGJNGuan is a readily produced and selective tool compound that should prove useful for investigating the physiological roles of α‐NAGAL. [ABSTRACT FROM AUTHOR]

Mulberry leaves are rich in biologically active compounds, including phenolics, polysaccharides, and alkaloids. Mulberry leaf iminosugars (MLIs; a type of polyhydroxylated alkaloids), in particular, have been gaining increasing attention due to their health-promoting effects, including anti-diabetic, anti-obesity, anti-hyperglycemic, anti-hypercholesterolemic, anti-inflammatory, and gut microbiota-modulatory activities. Knowledge regarding the in vivo bioavailability and bioactivity of MLis are crucial to understand their role and function and human health. Therefore, this review is aimed to comprehensively summarize the existing studies on the oral pharmacokinetics and the physiological significance of selected MLIs (i.e.,1-deoxynojirimycin, d-fagomine, and 2-O-α-d-galactopyranosyl-DNJ). evidence have suggested that MLIs possess relatively good uptake and safety profiles, which support their prospective use for oral intake; the therapeutic potential of these compounds against metabolic and chronic disorders and the underlying mechanisms behind these effects have also been studied in in vitro and in vivo models. Also discussed are the biosynthetic pathways of MLIs in plants, as well as the agronomic and processing factors that affect their concentration in mulberry leaves-derived products. [ABSTRACT FROM AUTHOR]

The synthesis of four heterodimers in which the copper(I)-catalysed azide-alkyne cycloaddition was employed to connect a 1-deoxynojirimycin moiety with a benzotriazole scaffold is reported. The heterodimers were investigated as inhibitors against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The heterodimers displayed preferential inhibition (> 9) of BuChE over AChE in the micromolar concentration range (IC50 = 7–50 µM). For the most potent inhibitor of BuChE, Cornish-Bowden plots were used, which demonstrated that it behaves as a mixed inhibitor. Modelling studies of the same inhibitor demonstrated that the benzotriazole and 1-deoxynojirimycin moiety is accommodated in the peripheral anionic site and catalytic anionic site, respectively, of AChE. The binding mode to BuChE was different as the benzotriazole moiety is accommodated in the catalytic anionic site.

As a part of our ongoing discovery efforts exploring azasugar as agents for treating various unmet medical needs, we prepared analogs of azasugar as potential anti-hepatitis C virus (HCV) agents. Herein we describe the synthesis of novel 2'β-C-Me 9-deazanucleoside azasugar analogs. [ABSTRACT FROM AUTHOR]

Pharmacological chaperones (PCs) can restore correct enzymatic activity at sub‐inhibitory concentrations and are considered an emerging therapy for Gaucher Disease (GD). Amphiphilic PCs show more favourable cross‐membrane properties and have a higher activity on cells than hydrophilic PCs. To investigate whether the biological activity of amphiphilic iminosugars is related to their state as monomers or as micellar aggregates, we synthesized some novel N‐alkylated iminosugars and performed physico‐chemical characterizations in the solid state and in aqueous dispersion of the best compound in terms of biological activity. The results suggest that the C12 N‐alkylated iminosugar 10 exerts its biological activity in the monomeric state, and that the low cell viability observed in the presence of a 50 μM concentration of compound 10 is not related to the formation of micellar aggregates in solution. [ABSTRACT FROM AUTHOR]

We report a concise and green total synthesis of 1,4-dideoxy-1,4-imino- l -arabinitol hydrochloride from naturally occurring d- xylose. The key step involves a stereospecific substitution of a hydroxy group, without prior derivatization, in which the only byproduct is water. This opens up a novel benign route to iminosugar derivatives with diverse biological activities. [ABSTRACT FROM AUTHOR]

Crimean-Congo haemorrhagic fever virus (CCHFV) is a pathogen of increasing public health concern, being a widely distributed arbovirus and the causative agent of the potentially fatal Crimean-Congo haemorrhagic fever. Hazara virus (HAZV) is a genetically and serologically related virus that has been proposed as a surrogate for antiviral and vaccine testing for CCHFV. Glycosylation analysis of HAZV has been limited; first, we confirmed for the first time the occupation of two N-glycosylation sites in the HAZV glycoprotein. Despite this, there was no apparent antiviral efficacy of a panel of iminosugars against HAZV, as determined by quantification of the total secretion and infectious virus titres produced following infection of SW13 and Vero cells. This lack of efficacy was not due to an inability of deoxynojirimycin (DNJ)-derivative iminosugars to access and inhibit endoplasmic reticulum α-glucosidases, as demonstrated by free oligosaccharide analysis in uninfected and infected SW13 and uninfected Vero cells. Even so, iminosugars may yet have potential as antivirals for CCHFV since the positions and importance of N-linked glycans may differ between the viruses, a hypothesis requiring further evaluation. [ABSTRACT FROM AUTHOR]

Substrate side chain conformation impacts reactivity during glycosylation and glycoside hydrolysis and is restricted by many glycosidases and glycosyltransferases during catalysis. We show that the side chains of gluco and manno iminosugars can be restricted to predominant conformations by strategic installation of a methyl group. Glycosidase inhibition studies reveal that iminosugars with the gauche,gauche side chain conformations are 6‐ to 10‐fold more potent than isosteric compounds with the gauche,trans conformation; a manno‐configured iminosugar with the gauche,gauche conformation is a 27‐fold better inhibitor than 1‐deoxymannojirimycin. The results are discussed in terms of the energetic benefits of preorganization, particularly when in synergy with favorable hydrophobic interactions. The demonstration that inhibitor side chain preorganization can favorably impact glycosidase inhibition paves the way for improved inhibitor design through conformational preorganization. [ABSTRACT FROM AUTHOR]

Minimally protected aminopolyols are novel substrates for the galactose oxidase variant F2. Site-selective oxidation proceeds at the terminal primary alcohol, followed by spontaneous cyclisation to afford stable hemiaminal/hemiacetal anomers of the piperidine and azepane scaffolds, with isolated yields of up to 94%. Simultaneous deprotection and reduction occured readily to afford valuable and biologically relevant iminosugars. [ABSTRACT FROM AUTHOR]

The synthesis of four heterodimers in which the copper(I)-catalysed azide-alkyne cycloaddition was employed to connect a 1-deoxynojirimycin moiety with a benzotriazole scaffold is reported. The heterodimers were investigated as inhibitors against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The heterodimers displayed preferential inhibition (> 9) of BuChE over AChE in the micromolar concentration range (IC50 = 7-50 µM). For the most potent inhibitor of BuChE, Cornish-Bowden plots were used, which demonstrated that it behaves as a mixed inhibitor. Modelling studies of the same inhibitor demonstrated that the benzotriazole and 1-deoxynojirimycin moiety is accommodated in the peripheral anionic site and catalytic anionic site, respectively, of AChE. The binding mode to BuChE was different as the benzotriazole moiety is accommodated in the catalytic anionic site. [ABSTRACT FROM AUTHOR]

[Display omitted] • Galbanic acid and its new amide derivatives 3a-n were evaluated as potent α-glucosidase inhibitors. • All title compounds were more potent than standard drug acarbose. • The most potent compound 3h was 1500-fold more potent than acarbose. • Compound 3h was a competitive inhibitor against α-glucosidase. α-Glucosidase inhibitory activity of galbanic acid and its new amide derivatives 3a–n were investigated. Galbanic acid and compounds 3a–n showed excellent anti-α-glucosidase activity with IC 50 values ranging from 0.3 ± 0.3 μM to 416.0 ± 0.2 μM in comparison to positive control acarbose with IC 50 value of = 750.0 ± 5.6. In the kinetic study, the most potent compound 3h demonstrated a competitive mode of inhibition with K i = 0.57 µM. The interaction of the most potent compound 3h with the α-glucosidase was further elaborated by in vitro Circular dichroism assessment and in silico molecular docking and Molecular dynamics studies. Compound 3h was also non-cytotoxic on human normal cells. In silico study on pharmacokinetics and toxicity profile of the most potent galbanic acid derivatives demonstrated that these compounds are valuable lead compounds for further study in order to achieve new anti-diabetic agents. [ABSTRACT FROM AUTHOR]

Trihydroxypiperidines are a therapeutically valuable class of iminosugar. We applied a one-pot amination-cyclisation cascade reaction to synthesise 3,4,5-trihydroxypiperidine stereoisomers in three steps from commercially available pentoses and in excellent overall yields. Using our methodology, the yields of the syntheses of meso -1, meso -2 and 3L are the highest reported to date. The synthetic methodology was readily extended to the three-step synthesis of N -alkyl derivatives by replacing the ammonia nitrogen source with a primary amine. The trihydroxypiperidines and N -alkyl analogues were screened for enzyme inhibitory activity using Fabrazyme (Fabry disease), GCase (Gaucher's disease), Agrobacterium sp. β-glucosidase, and Escherichia coli β-galactosidase. N -Phenylethyl 3,4,5-trihydroxypiperidine (N -phenylethyl-1-(3 R ,4 R ,5 S)-piperidine-3,4,5-triol) showed good inhibitory activity of Fabrazyme (K i = 46 μM). This activity was abolished when the N -phenylethyl group was removed or replaced with a non-aromatic alkyl chain. [Display omitted] • Trihydroxypiperidine stereoisomers synthesised using one-pot cyclisation cascade. • Method extends to the synthesis of N -alkyl 3,4,5-trihydroxypiperidine derivatives. • Trihydroxypiperidines synthesised from chiral pool starting materials in good overall yields. • Good inhibitory activity of Fabrazyme by N -phenylethyl-1-(3 R ,4 R ,5 S)-piperidine-3,4,5-triol. [ABSTRACT FROM AUTHOR]

Since their discovery, polyhydroxylated indolizidines have been the focus of attention for both biologists and synthetic chemists. They are classified as iminosugar alkaloids: nitrogen‐based carbohydrate mimetics that are potent inhibitors of glycosidases. Many discovered glycosidase inhibitors were found to possess biological activity, and they are therefore considered to be potential therapeutics in the treatment of various diseases such as viral infections, diabetes, or cancer. Not surprisingly, the interest in the preparation of these substances has been enormous. This review presents the latest developments in the synthesis of naturally occurring polyhydroxylated indolizidines and their synthetic enantiomers. In addition, the synthesis of several novel polyhydroxylated indolizidines, which were discovered to have inhibitory activity, is reported. [ABSTRACT FROM AUTHOR]

A series of L‐lyxo and L‐xylo‐ pentofuranose‐mimetic iminosugars and derivatives were efficiently synthesized in a stereoselective manner, through a concise strategy which involves an organocatalyzed Mannich reaction of an imine and a protected dioxanone as key step, using D‐proline as catalyst. A preliminary evaluation of their activity as potential anti‐trypanosomal agents was studied. One of the synthesized compounds showed an interesting activity against bloodstream Trypanosoma brucei brucei (EC50=3.8±1.0 μM). [ABSTRACT FROM AUTHOR]

A series of N-substituted iminosugar C-glycosides were synthesized and tested for α-glucosidase inhibition. The results suggested that 6e is a promising and potent α-glucosidase inhibitor. Enzymatic kinetic assays indicated that compound 6e may be classified as an uncompetitive inhibitor. The study of structure-activity relationships of those iminosugars provided a starting point for the discovery of new α-glucosidase inhibitors. [ABSTRACT FROM AUTHOR]

Recently, the strategy of multivalency has been widely employed to design glycosidase inhibitors, as glycomimetic clusters often induce marked enzyme inhibition relative to monovalent analogs. Polyhydroxylated pyrrolidines, one of the most studied classes of iminosugars, are an attractive moiety due to their potent and specific inhibition of glycosidases and glycosyltransferases, which are associated with many crucial biological processes. The development of multivalent pyrrolidine derivatives as glycosidase inhibitors has resulted in several promising compounds that stand out. Herein, we comprehensively summarized the different synthetic approaches to the preparation of multivalent pyrrolidine clusters, from total synthesis of divalent iminosugars to complex architectures bearing twelve pyrrolidine motifs. Enzyme inhibitory properties and multivalent effects of these synthesized iminosugars were further discussed, especially for some less studied therapeutically relevant enzymes. We envision that this comprehensive review will help extend the applications of multivalent pyrrolidine iminosugars in future studies. [ABSTRACT FROM AUTHOR]

Bambusurils, BU[4] and BU[6], were used for the first time as multivalent scaffolds to link glycosidases inhibitors derived from 1-deoxynojirimycin (DNJ). Two linear DNJ ligands having six or nine carbon alkyl azido linkers or a trivalent DNJ dendron were grafted onto octapropargylated BU[4] and dodecapropargylated BU[6] using copper-catalyzed cycloaddition (CuAAC) to yield corresponding neoglycobambus[4] and neoglycobambus[6]urils bearing 8 to 24 iminosugars. The inhibition potencies of neoglycoBU[4], neoglycoBU[6] and neoglycoBU[6] caging anions were evaluated against Jack Bean α-mannosidase and compared to monovalent DNJ derivatives. Strong affinity enhancements per inhibitory head were obtained for the clusters holding trivalent dendrons with inhibitory constants in the nanomolar range (Ki = 24 nM for BU[4] with 24 DNJ units). Interestingly, the anion (bromide or iodide) encapsulated inside the cavity of BU[6] does not modify the inhibition potency of neoglycoBU[6], opening the way to water-soluble glycosidase-directed anion caging agents that may find applications in important fields such as bio(in)organic chemistry or oncology. [ABSTRACT FROM AUTHOR]

(−)‐D‐Swainsonine is an indolizidine alkaloid molecule with a fused piperidine and pyrrolidine ring system. It has been the first glycoprotein‐processing inhibitor to be selected for clinical testing as an anticancer drug. D‐Swainsonine is an effective inhibitor of both lysosomal α‐mannosidase and Golgi α‐mannosidase II. Lysosomal α‐mannosidase is involved in cellular degradation of polysaccharides, and Golgi α‐mannosidase is the key enzyme in processing asparagine‐linked glycoproteins. A nowadays challenge is to build up D‐swainsonine derivatives/analogues with high selectivity to Golgi α‐mannosidase II, in order to avoid metabolic issues associated with the drug. This review covers the last 18 years of literature in the synthesis of D‐swainsonine and substituted D‐swainsonines from common precursors. The work is organized in four main precursor structures, with the aim to assist in the choice of the synthetic methodology to introduce pertinent substituents at the D‐swainsonine core. [ABSTRACT FROM AUTHOR]

Pharmaceutical chaperones (PCs) are small compounds able to bind and stabilize misfolded proteins, allowing them to recover their native folding and thus their biological activity. In particular, lysosomal storage disorders (LSDs), a class of metabolic disorders due to genetic mutations that result in misfolded lysosomal enzymes, can strongly benefit from the use of PCs able to facilitate their translocation to the lysosomes. This results in a recovery of their catalytic activity. No PC for the GCase enzyme (lysosomal acid-β-glucosidase, or glucocerebrosidase) has reached the market yet, despite the importance of this enzyme not only for Gaucher disease, the most common LSD, but also for neurological disorders, such as Parkinson's disease. This review aims to describe the efforts made by the scientific community in the last 7 years (since 2015) in order to identify new PCs for the GCase enzyme, which have been mainly identified among glycomimetic-based compounds. [ABSTRACT FROM AUTHOR]

GM1 gangliosidosis is a rare lysosomal disease caused by the deficiency of the enzyme β-galactosidase (β-Gal; GLB1; E.C. 3.2.1.23), responsible for the hydrolysis of terminal β-galactosyl residues from GM1 ganglioside, glycoproteins, and glycosaminoglycans, such as keratan-sulfate. With the aim of identifying new pharmacological chaperones for GM1 gangliosidosis, the synthesis of five new trihydroxypiperidine iminosugars is reported in this work. The target compounds feature a pentyl alkyl chain in different positions of the piperidine ring and different absolute configurations of the alkyl chain at C-2 and the hydroxy group at C-3. The organometallic addition of a Grignard reagent onto a carbohydrate-derived nitrone in the presence or absence of a suitable Lewis Acid was exploited, providing structural diversity at C-2, followed by the ring-closure reductive amination step. An oxidation-reduction process allowed access to a different configuration at C-3. The N-pentyl trihydroxypiperidine iminosugar was also synthesized for the purpose of comparison. The biological evaluation of the newly synthesized compounds was performed on leucocyte extracts from healthy donors and identified two suitable β-Gal inhibitors, namely compounds 10 and 12. Among these, compound 12 showed chaperoning properties since it enhanced β-Gal activity by 40% when tested on GM1 patients bearing the p.Ile51Asn/p.Arg201His mutations. [ABSTRACT FROM AUTHOR]

The efficient synthesis of enantiomeric pairs of iminosugars including 1,4-dideoxy-1,4-imino- d -arabinitol (DAB) and 1,4-dideoxy-1,4-imino- l -arabinitol (LAB) analogues with an amidine, hydrazide, hydrazide imide, or amide oxime moiety is described. The preparation of DAB and LAB analogues commenced from l -xylose and d -xylose, respectively. The obtained iminosugars are tested against a panel of glycosidases with pharmaceutical relevance, revealing enhanced activity for the DAB analogues in comparison with the LAB analogues. In particular, the d - arabino -configured amidine behaved as a potent (submicromolar range) and selective inhibitor of α-mannosidase. [ABSTRACT FROM AUTHOR]

The ability of amino acid "customizable units" to generate structural diversity is illustrated by the conversion of 4-hydroxyproline (Hyp) units into a variety of nitrogen heterocycles. After a first common step, where the unit underwent a one-pot decarboxylation–alkylation reaction to afford 2-alkylpyrrolidines with high stereoselectivity, a divergent step was carried out. Thus, the deprotected 4-hydroxy group was used either to initiate a radical scission that afforded aliphatic β-amino aldehydes, or to carry out an elimination reaction, to give 2-alkyl-2,5-dihydro-1H-pyrroles. In the first case, the amines underwent a tandem reductive amination–cyclization to afford β-amino-δ-lactams, an efficient rigidifying unit in peptides. Different lactam N-substituents, such as alkylamines, peptides, and alkenyl chains suitable for olefin metathesis were introduced this way. In the second case, the pyrrole derivatives were efficiently converted into alkaloid and iminosugar derivatives in good global yields and with excellent stereoselectivity. [ABSTRACT FROM AUTHOR]

Hypervalent iodine reagents have undergone significant development and widespread application in the functionalization of carbohydrates. This is primarily attributed to their exceptional properties, including mildness, ease of handling, high selectivity, environmental friendliness, and stability. This review aims to emphasize the utilization of hypervalent iodine compounds in the functionalization of carbohydrates. The present article covers various aspects, including glycal functionalization, C–H or N–H insertion reactions, O -arylations, C-2 deoxy-2-iodo glycoconjugates, iminosugars, and C3-oxo-glycals, achieved through the use of hypervalent iodine reagents/catalysts. Additionally, it explores hypervalent iodine-mediated bioactive 1,3,5-trioxocane synthesis followed by rare sugars synthesis. [Display omitted] • Tuning of carbohydrates using hypervalent iodine reagents. • Functionalization of glycals using hypervalent iodine reagents. • Synthesis of amino-sugars, azido-sugars, halo-sugars. • C–H, N–H, O–H insertion and alkylation/arylation reactions. [ABSTRACT FROM AUTHOR]

Herein we present the direct asymmetric synthesis of tetrazole-functionalized 1-deoxynojirimycin derivatives from simple sugars via a Schwartz’s reagent-mediated reductive amide functionalization followed by a variant of the Ugi–azide multicomponent reaction. The anomeric configurations of two products were unambiguously confirmed by X-ray analysis. This work also describes examples of interesting further transformations of the title products. Finally, some surprising observations regarding the mechanism of their formation were made.

We have designed unprecedented cholinesterase inhibitors based on 1-deoxynojirimycin as potential anti-Alzheimer’s agents. Compounds are comprised of three key structural motifs: the iminosugar, for interaction with cholinesterase catalytic anionic site (CAS); a hydrocarbon tether with variable lengths, and a fragment derived from 2-phenylethanol for promoting interactions with peripheral anionic site (PAS). Title compounds exhibited good selectivity towards BuChE, strongly depending on the substitution pattern and the length of the tether. The lead compounds were found to be strong mixed inhibitors of BuChE (IC50 = 1.8 and 1.9 µM). The presumptive binding mode of the lead compound was analysed using molecular docking simulations, revealing H-bond interactions with the catalytic subsite (His438) and CAS (Trp82 and Glu197) and van der Waals interactions with PAS (Thr284, Pro285, Asn289). They also lacked significant antiproliferative activity against tumour and non-tumour cells at 100 µM, making them promising new agents for tackling Alzheimer’s disease through the cholinergic approach.

We developed new iminosugar-based glycosidase inhibitors against SARS-CoV-2. Known drugs (miglustat, migalastat, miglitol, and swainsonine) were chosen as lead compounds to develop three classes of glycosidase inhibitors (α-glucosidase, α-galactosidase, and mannosidase). Molecular modelling of the lead compounds, synthesis of the compounds with the highest docking scores, enzyme inhibition tests, and in vitro antiviral assays afforded rationally designed inhibitors. Two highly active α-glucosidase inhibitors were discovered, where one of them is the most potent iminosugar-based anti-SARS-CoV-2 agent to date (EC 90 = 1.94 µM in A549-ACE2 cells against Omicron BA.1 strain). However, galactosidase inhibitors did not exhibit antiviral activity, whereas mannosidase inhibitors were both active and cytotoxic. As our iminosugar-based drug candidates act by a host-directed mechanism, they should be more resilient to drug resistance. Moreover, this strategy could be extended to identify potential drug candidates for other viral infections.

We have designed unprecedented cholinesterase inhibitors based on 1-deoxynojirimycin as potential anti-Alzheimer's agents. Compounds are comprised of three key structural motifs: the iminosugar, for interaction with cholinesterase catalytic anionic site (CAS); a hydrocarbon tether with variable lengths, and a fragment derived from 2-phenylethanol for promoting interactions with peripheral anionic site (PAS). Title compounds exhibited good selectivity towards BuChE, strongly depending on the substitution pattern and the length of the tether. The lead compounds were found to be strong mixed inhibitors of BuChE (IC50 = 1.8 and 1.9 µM). The presumptive binding mode of the lead compound was analysed using molecular docking simulations, revealing H-bond interactions with the catalytic subsite (His438) and CAS (Trp82 and Glu197) and van der Waals interactions with PAS (Thr284, Pro285, Asn289). They also lacked significant antiproliferative activity against tumour and non-tumour cells at 100 µM, making them promising new agents for tackling Alzheimer's disease through the cholinergic approach. [ABSTRACT FROM AUTHOR]

This personal account focuses on synthesis of polyhydroxylated piperidines, a subset of compounds within the iminosugar family. Cyclisations to form the piperidine ring include reductive amination, substitution via amines, iminium ions and cyclic nitrones, transamidification (N‐acyl transfer), addition to alkenes, ring contraction and expansion, photoinduced electron transfer, multicomponent Ugi reaction and ring closing metathesis. Enantiomerically pure piperidines are obtained from chiral pool precursors (e. g. sugars, amino acids, Garner's aldehyde) or asymmetric reactions (e. g. epoxidation, dihydroxylation, aminohydroxylation, aldol, biotransformation). Our laboratory have contributed cascades based on reductive amination from glycosyl azide precursors as well as Huisgen azide‐alkene cycloaddition. The latter's combination with allylic azide rearrangement has given substituted piperidines, including those with quaternary centres adjacent to nitrogen. [ABSTRACT FROM AUTHOR]

α-Amylase and α-glucosidase are central enzymes involved in the digestion of carbohydrates. α-Glucosidase includes maltase-glucoamylase and sucrase-isomaltase. We have previously performed the kinetic analysis of the inhibitory effects of powdered or roasted Morus australis leaf extract and its component iminosugars, such as 1-deoxynojirimycin (1-DNJ), fagomine, and 2- O -α- d -galactopyranosyl deoxynojirimycin (GAL-DNJ) on the activity of maltase. In this study, we analyzed the inhibitory effects of the aforementioned compounds against α-amylase, glucoamylase, sucrase, and isomaltase. At pH 6.0 and 37 °C, each leaf extract sample inhibited glucoamylase, sucrase, and isomaltase but not α-amylase. 1-DNJ and fagomine showed weak α-amylase inhibitory activity while GAL-DNJ exhibited none. 1-DNJ showed a strong glucoamylase, sucrase, and isomaltase inhibitory potential. The inhibitory potential against these three enzymes was 18–500 and 1500–3000-fold higher in the case of 1-DNJ than that observed in the case of fagomine and GAL-DNJ, respectively. We also observed that the indigestible dextrin could considerably inhibit α-amylase. When the powdered M. australis leaf extract was blended with indigestible dextrin, the mixture inhibited α-amylase, as well as maltase, glucoamylase, sucrase, and isomaltase. These results suggest that the ingestion of the leaf extract blended with indigestible dextrin might have the potential to efficiently suppress the postprandial blood glucose level increase. [ABSTRACT FROM AUTHOR]

A green synthetic route for the synthesis of some potential enzyme active hydroxypiperidine iminosugars including 1,5-dideoxy-1,5-imino-ribitol and 1,5-dideoxy-1,5-imino-dl-arabinitol, starting from commercially available d-ribose and d-lyxose was tested out. Heterogeneous catalysts including Au/Al2O3, SO42−/Al2O3 as well as environmentally friendly reagents were employed into several critical reaction of the route. The synthetic route resulted in good overall yields of 1,5-dideoxy-1,5-imino-ribitol of 54%, 1,5-dideoxy-1,5-imino-d-arabinitol of 48% and 1,5-dideoxy-1,5-imino-l-arabinitol of 46%. The Au/Al2O3 catalyst can be easily recovered from the reaction mixture and reused with no loss of activity. [ABSTRACT FROM AUTHOR]

Mucopolysaccharidosis type IIIB is a devastating neurological disease caused by a lack of the lysosomal enzyme, α‐N‐acetylglucosaminidase (NAGLU), leading to a toxic accumulation of heparan sulfate. Herein we explored a pharmacological chaperone approach to enhance the residual activity of NAGLU in patient fibroblasts. Capitalizing on the three‐dimensional structures of two modest homoiminosugar‐based NAGLU inhibitors in complex with bacterial homolog of NAGLU, CpGH89, we have synthesized a library of 17 iminosugar C‐glycosides mimicking N‐acetyl‐D‐glucosamine and bearing various pseudo‐anomeric substituents of both α‐ and β‐configuration. Elaboration of the aglycon moiety results in low micromolar selective inhibitors of human recombinant NAGLU, but surprisingly it is the non‐functionalized and wrongly configured β‐homoiminosugar that was proved to act as the most promising pharmacological chaperone, promoting a 2.4 fold activity enhancement of mutant NAGLU at its optimal concentration. [ABSTRACT FROM AUTHOR]

Glycomimetics are structural mimics of naturally occurring carbohydrates and represent important therapeutic leads in several disease treatments. However, the structural and stereochemical complexity inherent to glycomimetics often challenges medicinal chemistry efforts and is incompatible with diversity-oriented synthesis approaches. Here, we describe a one-pot proline-catalyzed aldehyde α-functionalization/aldol reaction that produces an array of stereochemically well-defined glycomimetic building blocks containing fluoro, chloro, bromo, trifluoromethylthio and azodicarboxylate functional groups. Using density functional theory calculations, we demonstrate both steric and electrostatic interactions play key diastereodiscriminating roles in the dynamic kinetic resolution. The utility of this simple process for generating large and diverse libraries of glycomimetics is demonstrated in the rapid production of iminosugars, nucleoside analogues, carbasugars and carbohydrates from common intermediates. Glycomimetics are structural mimics of carbohydrates that can replicate their biological activity but have improved drug-like properties. Here, using proline-catalysed α-halogenation/aldol cascades, carbohydrate building blocks are readily assembled and then diversified into glycomimetics including imino- and carbasugars. [ABSTRACT FROM AUTHOR]

Over the past two decades, organocatalytic aldol reaction emerged as a powerful method for the enantioselective carbon–carbon bond formation, often offering more efficient, economical and environmentally friendly synthesis of chiral molecules. On the other hand, reductive amination is one of the most important reactions in synthesis of biologically active compounds and drug candidates. Coupling these two reactions results in a powerful combination that allows for a rapid, stereoselective access to substituted, highly functionalized five‐ and six‐membered N‐heterocycles. This minireview illustrates the applicability of this approach as the key feature in syntheses of various iminosugars – a class of polyhydroxylated alkaloids with a range of interesting biological activities and high pharmacological potential. [ABSTRACT FROM AUTHOR]