Comparative analysis of sulfated and sulfonated disaccharide analogs as TLR4 modulators and heparanase inhibitors
El-Abid, J.; Koffi Teki, D. S.-E. K. L. C.; Bil, A.; Denys, A.; Vallin, A.; Lefebvre, C.; Allain, F.; Chagnault, V.; Kovensky, J.
New J. Chem. 2024.
This article delves into the synthesis and biological evaluation of sulfated and sulfonated disaccharide analogs, exploring their interactions with toll-like receptor 4 (TLR4) and their potential as drug candidates for inflammatory diseases. A significant aspect of the study is the examination of these analogs as inhibitors of heparanase, an enzyme that cleaves glycosidic linkages in heparan sulfate, producing proinflammatory fragments that activate TLR4. The research presents a comparative analysis of sulfate and sulfonate groups in these compounds, evaluating their synthesis, biological activity, and specific roles in TLR4-mediated immune responses, with a particular focus on their ability to modulate heparanase activity. Compound 9 (6,6′-disulfonated disaccharide from methyl cellobioside) emerged as a potent TLR4 activator and a promising candidate for inflammatory drug development, exhibiting notable specificity and efficacy. The IC50 values for heparanase inhibition varied, highlighting distinct efficacy profiles for sulfonated and sulfated analogs, with cellobiose derivatives showing notable differences in inhibition capabilities.
https://dx.doi.org/10.1039/D4NJ01326C

New Selective Inhibitors of α-Glucosidase for the Treatment of Type 2 Diabetes Mellitus
Khanchouch, T.; Vallin, A.; Alali, U.; Benazza, M.; Abidi, R.; Bonnet, V.
Helv. Chim. Acta n/a, e202300222.
Abstract Type 2 diabetes mellitus is a metabolic dreadful disease caused by an uncontrolled glucose level in the bloodstream, particularly high after a meal. Inhibitors of glucosidases, involved in the digestion of carbohydrates, can regulate this post-prandial increase in glucose concentration. The traditional drugs act as competitive inhibitors of both pancreatic α-amylase and α-glucosidases and this unselective inhibition is behind severe gastrointestinal side effects related to the concomitant inhibition of α-amylase. We described herein some perglycosylated cyclodextrins as efficient and selective inhibitors of α-glucosidase with low micromolar IC50 (3.64-7.98 μM) compared to the acarbose (IC50 212 μM), clinically used for patients suffering from type 2 diabetes. On the other hand, they do not inhibit α-amylase (IC50>500 μM). Structure/activity relationship rationalization suggests multiple interactions between the described inhibitors and α-glucosidase, which support the existence of both active site and allosteric interactions.
https://dx.doi.org/10.1002/hlca.202300222

Synthesis and Antibacterial Activities of New 6- Aryl-4-Oxo-1,4-Dihydropyrimidine Derivatives
Die, R. C.; Fanté, B.; Ambeu-Loko, N. C. M.; Hiebel, M. A.; Vallin, A.; Suzenet, F.; Chagnault, V.
RASAYAN Journal of Chemistry 2023, 16, 1835-1843.
Pyrimidine derivatives are an important class of compounds in medicinal chemistry. In this study, a series of 6-aryl4-oxo-1,4-dihydropyrimidine-5-carbonitrile derivatives were synthesized using a multicomponent reaction, followed by S-alkylation with different halogenated derivatives, and then evaluated for their antibacterial activities. Ciprofloxacin was used as the reference antibiotic. The prepared compounds were characterized by 1H, 13C NMR, FTIR spectroscopy, and LC-and HR-MS spectrometry. All compounds were screened in vitro against Pseudomonas aeruginosa and Escherichia coli (Gram-negative bacteria), as well as Staphylococcus aureus and Enterococcus faecalis (Gram-positive bacteria). The results showed that S-alkylation is beneficial in improving the antibacterial activity of the thiouracil derivatives offering a few compounds with antibacterial activity against Gram-positive bacteria.
https://dx.doi.org/10.31788/rjc.2023.1638242

Synthesis of novel S- and O-disaccharide analogs of heparan sulfate for heparanase inhibition
Koffi Teki, D. S. E.; Coulibaly, B.; Bil, A.; Vallin, A.; Lesur, D.; Fanté, B.; Chagnault, V.; Kovensky, J.
Org. Biomol. Chem. 2022.
Heparan sulfate (HS), a glycosaminoglycan related to heparin, is a linear polysaccharide, consisting of repeating disaccharide units. This compound is involved in multiple biological processes such as inflammation, coagulation, angiogenesis and viral infections. Our work focuses on the synthesis of simple HS analogs for the study of structure–activity relationships, with the aim of modulating these biological activities. Thioglycoside analogs, in which the interglycosidic oxygen is replaced by a sulfur atom, are very interesting compounds in terms of therapeutic applications. Indeed, the thioglycosidic bond leads to an improvement of their stability and can allow the inhibition of enzymes involved in physiological and pathological processes. In our previous work, we developed a synthetic sequence which led to a non-sulfated thiodisaccharide analog of HS. In this paper, we report our results of the development of a new synthetic method allowing access to the novel sulfated S-disaccharide, as well as to their oxygenated analogues (O-disaccharide and sulfated O-disaccharide). These 4 compounds were also tested for the inhibition of heparanase, an enzyme involved in biological processes like tumor growth and inflammation. The obtained IC50 values in the micromolar range showed the impact of the interglycosidic sulfur atom and the 6-sulfate group.
https://dx.doi.org/10.1039/d2ob00250g

Design, Synthesis and Antibacterial Activity Evaluation of 4,5-Diphenyl-1H-Imidazoles Derivatives
Bamoro, C.; Bamba, F.; Steve-Evanes, K. T. D.; Aurélie, V.; Vincent, C.
Open Journal of Medicinal Chemistry 2021, 11, 17-26.
Due to the continuous emergence and rapid spread of drug-resistant strains of bacteria, there is an urgent need for the development of novel antimicrobials. Along this line, the synthesis and antibacterial activity of 4,5-diphenylimidazol-2-thiol derivatives 2a-g and 6a-e are reported. The structures of the synthesized compounds were confirmed by Nuclear Magnetic Resonance (NMR) and High Resolution Mass Spectrometry (HRMS). All compounds were screened in vitro for their antibacterial activity against Pseudomonas aeruginosa and Escherichia coli (Gram-negative bacteria) and also against Staphyloccocus aureus and Enterococcus faecalis (Gram-positive bacteria). The results showed most of the synthesized compounds have no antibacterial activity. However compound 6d was two-fold potent than ciprofloxacin against Staphylococcus aureus with Minimum Inhibitory Concentration (MIC) of 4 μg/mL and 6c showed moderate biological activity against Staphylococcus aureus (16 μg/mL) and Enterococcus faecalis (16 μg/mL).
https://dx.doi.org/10.4236/ojmc.2021.112002

Uncommon Strong Inhibition of α-Glucosidase by Multivalent Glycoclusters built on Cyclodextrins Scaffolds
Alali, U.; Vallin, A.; Bil, A.; Khanchouche, T.; Mathiron, D.; Przybylski, C.; Beaulieu, R. R.; Kovensky, J.; Benazza, M.; Bonnet, V.
Org. Biomol. Chem. 2019.
The homeostasis disruption of D-glucose causes diabetes, a dramatic world wide chronic disease. The type 1 diabetes is a succesfully treatable form, where the blood D-glucose is regulated by insulin treatement. In contrast the type 2 diabetes , the non Insulin dependent one, is problematic. The control of the D-glucose blood level via intestinal α-D-glucosidase inactivation can be achieved by using competitive inhibitors as iminosugars (e.g. acarbose) or sulfonium sugar derivatives (e.g. salacinol). Recently, an unprecedented result showed that multivalent diamond nanoparticules grafted with unmodified sugars displayed α-glucosidase inhibition at low micromolar concentrations. We describe herein the synthesis of multivalent glycoclusters using cyclodextrines (CDs) as scaffolds and their assessment as inhibithors of α-D-glucosidase. The glycoclusters were efficiently obtained from per-azido α, β and γ-CDs derivatives and propargyl glycosides using click-chemistry under microwave irradiation. The methodology was successfully applied to various protected and non-protected propargylated monosaccharides, including both O- and S- glycosides, giving clear evidences of its versatility. The targeted 6-per-glycosylated CDs were isolated in moderate to excellent yields (30-90 %) by silica gel chromatography. The results showed inhibition of α-glucosidase from Saccharomyces cerevisiae with IC50 values in a 32-132 µM range, lower than that of acarbose (IC50 ~250µM), a well knowm competitive inhibitor used in clinical treatment of type 2 diabetes. Preliminary experiments suggest a mixed-type non-competitive inhibition mode of these new glycoclusters.
https://dx.doi.org/10.1039/C9OB01344J