Clinical Effect of Thioglycosides Extracted from White Mustard on Dental Plaque and Gingivitis: Randomized, Single-Blinded Clinical Trial.

The antibacterial and anti-inflammatory effect of thioglycosides has already been established. This study investigates the effects of thioglycosides extracted from white mustard, specifically the "Bamberka" variety, in the context of oral hygiene. The aim of the study is to clarify an evidence-based link between the documented antibacterial and anti-inflammatory effects attributed to thioglycosides and their practical application in oral care. A randomized, single-blinded (patient-blinded) clinical study was performed on 66 patients using mustard-based toothpaste for oral hygiene. The patients were examined at baseline and after 6 and 12 months. The values of the Approximal Plaque Index (API), the Plaque Index (PI), and Bleeding on probing (BOP) were taken into consideration. The results show a significant reduction in plaque accumulation, especially after 6 months of using mustard-based toothpaste in all examined parameters. This suggests that thioglycosides from mustard contribute to a considerable decrease in dental plaque accumulation, confirming their potential in natural oral care solutions, which is indicated in the main conclusions or interpretations.

Photosensitizer-thioglycosides enhance photodynamic therapy by augmenting cellular uptake.

Photodynamic therapy (PDT) uses photosensitizing agents along with light to ablate tissue, including cancers. Such light-driven localized delivery of free-radical oxygen to kill target tissue depends on photosensitizer cell penetration efficacy. While the attachment of monosaccharides and disaccharides to photosensitizers has been shown to potentially provide improved photosensitizer delivery, the range of glycan entities tested thus far is limited. We sought to expand such knowledge by coupling N-acetylglucosamine (GlcNAc) to pyropheophorbides as thioglycosides, and then testing photosensitizer efficacy. To this end, GlcNAc was conjugated to both pyropheophorbide-a and methyl pyropheophorbide-a. Among the entities tested, the conjugation of N-acetylglucosamine to methyl pyropheophorbide-a ('PSe') as thioglycoside enhanced cell uptake both in the presence and absence of human serum proteins, relative to other compounds tested. The enhanced PSe penetrance into cells resulted in higher cell death upon illumination with 665 nm light. While acting as a potent photosensitizer, PSe did not affect cellular carbohydrate profiles. Overall, the study presents a new pyropheophorbide glycoconjugate with strong in vitro PDT efficacy.

Thioglycosides Act as Metabolic Inhibitors of Bacterial Glycan Biosynthesis.

Glycans that coat the surface of bacteria are compelling antibiotic targets because they contain distinct monosaccharides that are linked to pathogenesis and are absent in human cells. Disrupting glycan biosynthesis presents a path to inhibiting the ability of a bacterium to infect the host. We previously demonstrated that O-glycosides act as metabolic inhibitors and disrupt bacterial glycan biosynthesis. Inspired by a recent study which showed that thioglycosides (S-glycosides) are 10 times more effective than O-glycosides at inhibiting glycan biosynthesis in mammalian cells, we crafted a panel of S-glycosides based on rare bacterial monosaccharides. The novel thioglycosides altered glycan biosynthesis and fitness in pathogenic bacteria but had no notable effect on glycosylation or growth in beneficial bacteria or mammalian cells. In contrast to findings in mammalian cells, S-glycosides and O-glycosides exhibited comparable potency in bacteria. However, S-glycosides exhibited enhanced selectivity relative to O-glycosides. These novel metabolic inhibitors will allow selective perturbation of the bacterial glycocalyx for functional studies and set the stage to expand our antibiotic arsenal.

New 1,2,3-Triazole-Coumarin-Glycoside Hybrids and Their 1,2,4-Triazolyl Thioglycoside Analogs Targeting Mitochondria Apoptotic Pathway: Synthesis, Anticancer Activity and Docking Simulation.

Toxicity and resistance to newly synthesized anticancer drugs represent a challenging phenomenon of intensified concern arising from variation in drug targets and consequently the prevalence of the latter concern requires further research. The current research reports the design, synthesis, and anticancer activity of new 1,2,3-triazole-coumarin-glycosyl hybrids and their 1,2,4-triazole thioglycosides as well as acyclic analogs. The cytotoxic activity of the synthesized products was studied against a panel of human cancer cell lines. Compounds 8, 10, 16 and 21 resulted in higher activities against different human cancer cells. The impact of the hybrid derivative 10 upon different apoptotic protein markers, including cytochrome c, Bcl-2, Bax, and caspase-7 along with its effect on the cell cycle was investigated. It revealed a mitochondria-apoptotic effect on MCF-7 cells and had the ability to upregulate pro-apoptotic Bax protein and downregulate anti-apoptotic Bcl-2 protein and thus implies the apoptotic fate of the cells. Furthermore, the inhibitory activities against EGFR, VEGFR-2 and CDK-2/cyclin A2 kinases for 8, 10 and 21 were studied to detect the mechanism of their high potency. The coumarin-triazole-glycosyl hybrids 8 and 10 illustrated excellent broad inhibitory activity (IC50= 0.22 ± 0.01, 0.93 ± 0.42 and 0.24 ± 0.20 µM, respectively, for compound 8), (IC50 = 0.12 ± 0.50, 0.79 ± 0.14 and 0.15± 0. 60 µM, respectively, for compound 10), in comparison with the reference drugs, erlotinib, sorafenib and roscovitine (IC50 = 0.18 ± 0.05, 1.58 ± 0.11 and 0.46 ± 0.30 µM, respectively). In addition, the docking study was simulated to afford better rationalization and put insight into the binding affinity between the promising derivatives and their targeted enzymes and that might be used as an optimum lead for further modification in the anticancer field.

Synthesis of novel pyridine and pyrimidine thioglycoside phosphoramidates for the treatment of COVID-19 and influenza A viruses.

A novel series of pyridine, cytosine, and uracil thioglycoside analogs (4a-i, 9a,b, and 13a,b, respectively) and their corresponding phosphoramidates (6a-I, 10a,b, and 14a,b, respectively) were synthesized and assessed for their antiviral inhibitory activities in a dual-pathogen screening protocol against SARS-CoV-2 and influenza A virus (IAV). MTT cytotoxicity (TC50) and plaque reduction assays were used to explore inhibition and cytotoxicity percentage values for H5N1 influenza virus strain and the half-maximal cytotoxic concentration (CC50) and inhibitory concentration (IC50) for SARS-CoV-2 virus. Most of the tested compounds demonstrated dose-dependent inhibition behavior. Both cytosine thioglycoside phosphoramidates 10a and 10b exhibited the most potent profiles with 83% and 86% inhibition at 0.25 µM concentration against H5N1 and IC50 values of 12.16 µM, 14.9 µM against SARS-CoV-2, respectively. Moreover, compounds 10a and 10b have been shown to have the highest selectivity index (SI) among all the tested compounds against SARS-CoV-2 with 28.2 and 26.9 values, respectively.

Synthesis of novel pyrimidine thioglycosides as structural analogs of favipiravir (avigan) and their antibird flu virus activity.

Novel class of amino pyrimidine thioglycoside derivatives were designed from sodium 2-cyano-3-(arylamino)prop-1-ene-1,1-bis(thiolate) 1a-d and guanidine hydrochloride 2 to afford the corresponding sodium 2,6-diamino-5-aryl-1,2-dihydropyrimidine-4-thiolate 3a-d, which in coupling with peracylated α-D-gluco- and galactopyranosyl bromides 5a,b in DMF gave the corresponding pyrimidine thioglycosides 6a-h. Acidification of 2,6-diamino-5-aryl-1,2-dihydropyrimidine-4-thiolate salts 3a-d with hydrochloric acid formed the corresponding pyrimidine-4-thioles 4a-d. The latter were stirred with peracetylated halo sugars α-D-gluco- and galacto-pyranosyl bromides in sodium hydride and DMF to yield the pyrimidine thioglycosides 6a-h. Deacetylation of the pyrimidine thioglycosides gave the corresponding free pyrimidine thioglycosides 7a-h. The compounds were characterized by 13C NMR, 1H NMR, and IR. The pyrimidine thioglycosides 6a-h and free pyrimidine thioglycosides 7a-h were tested against H5N1 virus strain and exhibited high to moderate activity.

Thiosialoside-decorated polymers use a two-step mechanism to inhibit both early and late stages of influenza virus infection.

We describe the preparation of thiosialoside-modified poly (methyl vinyl ether-alt-maleic anhydride) as second-generation polymeric conjugates for the inhibition of influenza virus infection. These synthetic glycopolymers show significantly enhanced neuraminidase inhibitory and antiviral activity in enzyme and cellular levels, respectively. The polyvalent thiosialosides also exhibit comparable inhibitory activity to the first-line anti-influenza drugs Zanamivir® and Oseltamivir® against the PR8 influenza virus strain in virus growth inhibition assays, which may be attributed to multivalent binding to neuraminidase on the virion particles, leading to the virion aggregation and further inhibiting the attaching/fusion and releasing steps in the influenza virus life-cycle. These findings suggest that attaching monomeric sialoside with neuraminidase inhibitory activity to a polymeric scaffold will synergistically disturb both the early and late stages of influenza virus infection, and provides a basis for the development of efficacious anti-viral agents against both wild-type and drug-resistant mutant strains.

Synthesis and Cytotoxic Activity of New 1,3,4-Thiadiazole Thioglycosides and 1,2,3-Triazolyl-1,3,4-Thiadiazole N-glycosides.

New 1,3,4-thiadiazole thioglycosides linked to substituted arylidine systems were synthesized via glycosylation of the prepared 1,3,4-thiadiazole thiol compounds. Click strategy was also used for the synthesis of new 1,3,4-thiadiazole and 1,2,3-triazole hybrid glycosides by reaction of the acetylenic derivatives with different glycosyl azids followed by deacetylation process. The cytotoxic activities of the prepared compounds were studied against HCT-116 (human colorectal carcinoma) and MCF-7 (human breast adenocarcinoma) cell lines using the MTT assay. The results showed that the key thiadiazolethione compounds 2 and 3, the triazole glycosides linked to p-methoxyarylidine derivatives 14 and 15 in addition to the free hydroxyl glycoside 20 were found potent in activity comparable to the reference drug doxorubicin against MCF-7 human cancer cells. The acetylenic derivative 2 and glycoside 20 were also found highly active against HCT-116 cell lines.

Novel purine thioglycoside analogs: synthesis, nanoformulation and biological evaluation in in vitro human liver and breast cancer models.

Background: A series of novel pyrazolopyrimidine and pyrazololpyridine thioglycosides were synthesized and confirmed via their spectral analyses. Purpose: To evaluate the effect of these anti-metabolic compounds against proliferation of Huh-7 and Mcf-7 as in vitro models of human liver and breast cancers, respectively. Vero cells were used as an example of normal green monkey kidney cells. Methods: The most promising compound was subjected to a nanoformulation by its encapsulation into chitosan nanoparticles to increase its anti-cancerous activity. Nanoformulation was confirmed by TEM and FT-IR to ensure encapsulation and screened for their cytotoxicity against Huh-7 and Mcf-7 cells using MTT colorimetric assay and morphological examination. Genotoxic effect was performed by cellular DNA fragmentation assay. Simulated CompuSyn software (linear interaction effect) was conducted to predict the possible synergistic effect of nanocomposite as anticancerous activity. Apoptotic effect was further analyzed by detection of apoptotic proteins using ELISA assay. Results: The nano preparation was successfully prepared by encapsulation of compound 14 into chitosan nanoparticles, controlled to a size at 105 nm and zeta charges at 40.2 mV. Treatment of Huh-7 and Mcf-7 showed that compound 14 was the most cytotoxic compound on both cancer cell lines where IC50 was 24.59 (9.836 µg/mL) and 12.203 (4.8812 µg/mL) on Huh-7 and Mcf-7 respectively. But IC50 of the nano preparation was 37.19 and 30.68 µg/mL on Huh-7 and Mcf-7, respectively, indicating its aggressiveness on human breast cancer cells as confirmed by DNA fragmentation assay and theoretically by CompuSyn tool. Conclusion: A novel series of pyrazolopyrimidine thioglycosides and pyrazolopyridine thioglycosides were synthesized. Nanoformulation of compound 14 into chitosan nanoparticles demonstrated anticancer activity and can be used as a drug delivery system, but further studies are still required.

Water soluble thioglycosylated BODIPYs for mitochondria targeted cytotoxicity.

The facile synthesis of water-soluble mitochondria targeting thioglycosylated BODIPYs is reported. Thioglycosylated BODIPYs were synthesized in 25-26% yields via thioglycosylated dipyrromethanes in four steps. The dipyrromethanes and thioglycosylated BODIPYs were characterized by various techniques including HRMS, NMR spectroscopy and X-ray crystallography. In-vitro cellular investigations in skin keratinocyte (HaCaT) and cervical (HeLa) cancer cells revealed significant cytotoxicities with IC50 values between 23.83 to 48.61 µM. The flow cytometry experiments revealed significant cellular uptake of thioglycosylated BODIPYs into HaCaT cells and thioglucosyl substituted BODIPY (9) showed higher cellular uptake and ROS generation than the rest of the molecules. The highlight of this study is the mitochondrial targeting by the neutral BODIPYs, as judged by the colocalization experiments using confocal microscopy.

Novel Synthesis and Biological Evaluation of the First Pyrazole Thioglycosides as Pyrazofurin Analogues.

This study reports a novel and efficient method for the synthesis of the first reported novel class of pyrazole thioglycosides 6a-h. These series of compounds were designed through the reaction of sodium 2-cyano-3-oxo-3-(4-substitutedphenylamino)prop-1-ene-1,1-bis(thiolate) salts 2 with hydrazine hydrate in ethanol at room temperature to give the corresponding sodium 5-amino-4-(substitutedphenylcarbamoyl)-1H-pyrazole-3-thiolates 3a-d. The latter compounds were treated with protected α-D-gluco- and galacto-pyranosyl bromides 4a,b in DMF at ambient temperature to give in a high yields the corresponding pyrazole thioglycosides 6a-h. Treatment of pyrazole salts 3a-d with hydrochloric acid at amobient temperature afforded the corresponding 3-mercaptopyrazole derivatives 5. The latter compounds were treated with peracetylated sugars 4 in sodium hydride in ethanol at ambient temperature to tolerate the S-glycosyl 6a-h compounds. Ammonolysis of the pyrazole thioglycosides 6a-h afforded the corresponding free thioglycosides 7a-h. The toxicity and antitumor activities of the synthesized compounds were studied.

New bis-thioglycosyl-1,1'-disulfides from Nasturtium officinale R. Br. and their anti-neuroinflammatory effect.

As a part of our continuing search for bioactive constituents from Brassicaceae family, three new bis-thioglycosides (1-3) were isolated from the 80% MeOH extract of Nasturtium officinale, together with 13 known compounds (4-16). The chemical structures of three new bis-thioglycosides (1-3) were elucidated using NMR techniques (1H and 13C NMR, 1H-1H COSY, HSQC, and HMBC), HRESIMS, and a chemical method. All the compounds were evaluated for their inhibitory effects on nitric oxide (NO) levels in lipopolysaccharide (LPS)-stimulated murine microglia BV-2 cells. Among the isolates, compound 5 exhibited a strong inhibitory effect on NO production, and compounds 4 and 15 showed moderate inhibitory activities, suggesting the neuroprotective and anti-neuroinflammatory effects of bis-thioglycosides from N. officinale.

Thioglycosides Are Efficient Metabolic Decoys of Glycosylation that Reduce Selectin Dependent Leukocyte Adhesion.

Metabolic decoys are synthetic analogs of naturally occurring biosynthetic acceptors. These compounds divert cellular biosynthetic pathways by acting as artificial substrates that usurp the activity of natural enzymes. While O-linked glycosides are common, they are only partially effective even at millimolar concentrations. In contrast, we report that N-acetylglucosamine (GlcNAc) incorporated into various thioglycosides robustly truncate cell surface N- and O-linked glycan biosynthesis at 10-100 µM concentrations. The >10-fold greater inhibition is in part due to the resistance of thioglycosides to hydrolysis by intracellular hexosaminidases. The thioglycosides reduce ß-galactose incorporation into lactosamine chains, cell surface sialyl Lewis-X expression, and leukocyte rolling on selectin substrates including inflamed endothelial cells under fluid shear. Treatment of granulocytes with thioglycosides prior to infusion into mouse inhibited neutrophil homing to sites of acute inflammation and bone marrow by ∼80%-90%. Overall, thioglycosides represent an easy to synthesize class of efficient metabolic inhibitors or decoys. They reduce N-/O-linked glycan biosynthesis and inflammatory leukocyte accumulation.

Rare Thioglycosides from the Roots of Wasabia japonica.

Six new thioglycosides (1-6) were characterized from the roots of Wasabia japonica along with a known analogue (7). Of these compounds, 1-3 possess a disulfide bridge connecting the carbohydrate motif and the aglycone, which is extremely rare in Nature. In particular, compound 1 forms an unusual 1,4,5-oxadithiocane ring system. The structures of the isolated compounds were determined through conventional NMR and HRMS data analysis procedure, and computational methods with advanced statistics were used for the configurational assignments of 1 and two pairs of inseparable epimers, 2/3 and 4/5. All compounds were evaluated for their anti-inflammatory, neuroprotective, and cytotoxic activities, with 1 showing weak anti-inflammatory activity (IC50 41.2 µM).

Novel Uridine Glycoconjugates, Derivatives of 4-Aminophenyl 1-Thioglycosides, as Potential Antiviral Compounds.

A novel series of uridine glycoconjugates, derivatives of 4-aminophenyl 1-thioglycosides, was designed and synthesized. All compounds were evaluated in vitro for their antiviral activity against hepatitis C virus (HCV) and classical swine fever virus (CSFV), two important human and animal viral pathogens for which new or improved therapeutic options are needed. The antiviral activity of all synthesized compounds was confirmed using pseudo-plaque reduction assays in which a significant arrest of CSFV and HCV growth was observed in the presence of these compounds. Two of the synthesized compounds, 9 and 12, displayed a significant inhibitory effect on HCV and CSFV propagation with IC50 values of 4.9 and 13.5 µM for HCV and 4.2 and 4 µM for CSFV, respectively, with low cytotoxicity. Using various infection and replication models, we have shown that both compounds were able to significantly reduce viral genome replication by up to 90% with IC50 values in the low micromolar range. A structure activity analysis of the synthesized compounds showed that the high antiviral activity was attributed to the hydrophobicity of glycoconjugates and the introduction of elements capable to coordinate metal ions into the spacer connecting the sugar and uridine moiety, which can be useful in the development of new antiviral compounds in the future.

Design and synthesis of naphthalimide group-bearing thioglycosides as novel ß-N-acetylhexosaminidases inhibitors.

GH20 human ß-N-acetylhexosaminidases (hsHex) and GH84 human O-GlcNAcase (hOGA) are involved in numerous pathological processes and emerged as promising targets for drug discovery. Based on the catalytic mechanism and structure of the catalytic domains of these ß-N-acetylhexosaminidases, a series of novel naphthalimide moiety-bearing thioglycosides with different flexible linkers were designed, and their inhibitory potency against hsHexB and hOGA was evaluated. The strongest potency was found for compound 15j (Ki = 0.91 µM against hsHexB; Ki > 100 µM against hOGA) and compound 15b (Ki = 3.76 µM against hOGA; Ki = 30.42 µM against hsHexB), which also exhibited significant selectivity between these two enzymes. Besides, inhibitors 15j and 15b exhibited an inverse binding patterns in docking studies. The determined structure-activity relationship as well as the established binding models provide the direction for further structure optimizations and the development of specific ß-N-acetylhexosaminidase inhibitors.

Selective inhibition of ß-N-acetylhexosaminidases by thioglycosyl-naphthalimide hybrid molecules.

To develop selective inhibitors for ß-N-acetylhexosaminidases which are involved in a myriad of physiological processes, a series of novel thioglycosyl-naphthalimide hybrid inhibitors were designed, synthesized and evaluated for inhibition activity against glycosyl hydrolase family 20 and 84 (GH20 and GH84) ß-N-acetylhexosaminidases. These compounds which incorporate groups with varied sizes and lengths at the linker region between thioglycosyl moiety and naphthalimide moiety are designed to improve the selectivity and stacking interactions. The GH84 human O-GlcNAcase (hOGA) was sensitive to the subtle changes in the linker region and the optimal choice is a small size linker with six atoms length. And the GH20 insect ß-N-acetylhexosaminidase OfHex1 could tolerate compounds with a hydrophobic bulky linker. Especially, the compound 5c (hOGA, Ki = 3.46 µM; OfHex1, Ki > 200 µM) and the compound 6f (hOGA, Ki > 200 µM; OfHex1, Ki = 21.81 µM) displayed high selectivity. The molecular docking results indicated that the inhibition mechanism was different between the two families due to their different structural characteristics beyond the active sites. These results provide some promising clues to improve selectivity of potent molecules against ß-N-acetylhexosaminidases.

Synthesis and anticancer activity of new [(Indolyl)pyrazolyl]-1,3,4-oxadiazole thioglycosides and acyclic nucleoside analogs.

New [(Indolyl)pyrazolyl]-1,3,4-oxadiazole compounds and their derived thioglycosides as well as the corresponding sugar hydrazones were synthesized. The acyclo C-nucleoside analogs of the oxadiazoline base system were also prepared by reaction of acid hydrazides with aldehydo sugars followed by one pot process encompassing acetylation and cyclization of the synthesized hydrazones. The anticancer activity of the newly synthesized compounds was studied against colorectal carcinoma (HCT116), breast adenocarcinoma (MCF7) and prostate cancer (PC3) human tumor cell lines and a number of compounds showed moderate to high activities.

Novel thioglycosyl analogs of glycosyltransferase substrates as antiviral compounds against classical swine fever virus and hepatitis C virus.

Hepatitis C virus (HCV) and classical swine fever virus (CSFV) are important pathogens for which new therapeutic approaches are in high demand. Herein, we report the synthesis of newly designed thioglycosyl analogs of glycosyltransferase substrates which were evaluated using cell-based assays for cytotoxicity and antiviral activity against both viruses. The antiviral activity of synthesized compounds against CSFV and HCV was confirmed using pseudo-plaque reduction assays where a significant arrest of viral growth was observed in the presence of selected compounds. We showed that compounds 13 and 14 exerted the most significant inhibitory effect on in vitro CSFV and HCV infections in the series. Glycoconjugates 13 and 14 not only inhibited both viral propagation with IC50 values in low micromolar range, but efficiently suppressed the production of viral proteins in a dose-dependent manner. In addition, studies using in vitro HCV infection and replication models have shown that both compounds are able to significantly reduce viral genomic replication. We demonstrated that compounds 13 and 14 showed a strong inhibition, up to 90% of replication which inscribe them in the promising alternative approach for the development of new anti-CSFV and anti-HCV drugs.

Synthesis and biological evaluation of 5-fatty-acylamido-1, 3, 4-thiadiazole-2-thioglycosides.

In the present study, the synthesis of 1, 3, 4-thiadiazole-based thioglycosides were accomplished in good yields with employing a convergent synthetic route. The starting material 5-amino-1, 3, 4-thiadiazole-2-thiol and followed by a series of 5-fatty-acylamido-1, 3, 4-thiadiazole-2-thiols (4a-4j) were synthesized with different fatty acid chlorides. The glycosylation of compounds 4a-4j were achieved with trichloroacetimidate methodology. Antimicrobial and cytotoxicity activities of title compounds were evaluated. Among the entire compounds lauric acid and myristic acid derivatives showed good and moderate antimicrobial activity. In case of cytotoxicity results of compounds 8a-8j and 9a-9j, the acetate protected short chain (C6:0, C8:0, C10:0) compounds and the free hydroxyl long chain saturated (C16:0, C18:0) and unsaturated (C18:1, C22:1) compounds exhibited good activity against different cancer cell lines. Further, the free hydroxyl compounds 9a, 9c-9j did not show any toxicity towards normal CHO-K1 cell line whereas acylated compounds 8a-8j exhibited toxicity.