Structural requirements of benzofuran derivatives dehydro-δ-and dehydro-ε-viniferin for antimicrobial activity against the foodborne pathogen listeria monocytogenes

In a recent study, we investigated the antimicrobial activity of a collection of resveratrol-derived monomers and dimers against a series of foodborne pathogens. Out of the tested molecules, dehydro-\u3b4-viniferin and dehydro-\u3b5-viniferin emerged as the most promising derivatives. To define the structural elements essential to the antimicrobial activity against the foodborne pathogen L. monocytogenes Scott A as a model Gram-positive microorganism, the synthesis of a series of simplified benzofuran-containing derivatives was carried out. The systematic removal of the aromatic moieties of the parent molecules allowed a deeper insight into the most relevant structural features affecting the activity. While the overall structure of compound 1 could not be altered without a substantial loss of antimicrobial activity, the structural simplification of compound 2 (minimal inhibitory concentration (MIC) 16 \u3bc\ub5g/mL, minimal bactericidal concentration (MBC) >512 \u3bc\ub5g/mL) led to the analogue 7 with increased activity (MIC 8 \u3bc\ub5g/mL, MBC 64 \u3bc\ub5g/mL)

Antimicrobial activity of resveratrol-derived monomers and dimers against foodborne pathogens

Plant polyphenolic compounds are considered a promising source for new antibacterial agents. In this study, we evaluated the antimicrobial activity of a collection of resveratrol-derived monomers and dimers screened as single molecules against a panel of nine foodborne pathogens. The results demonstrated that two monomers (i.e., pterostilbene 2 and (E)-3-hydroxy-4\u2032,5-dimethoxystilbene 9) and three dimers (i.e., \u3b4-viniferin 10, viniferifuran 14 and dehydro-\u3b4-viniferin 15) were endowed with significant antibacterial activity against gram-positive bacteria. The exposure of gram-positive foodborne pathogens to 100 \ub5g/mL of 2, 9 and 15 induced severe cell membrane damage, resulting in the disruption of the phospholipid bilayer. The most promising dimeric compound, dehydro-\u3b4-viniferin 15, was tested against Listeria monocytogenes, resulting in a loss of cultivability, viability and cell membrane potential. TEM analysis revealed grave morphological modifications on the cell membrane and leakage of intracellular content, confirming that the cell membrane was the principal biological target of the tested derivative

Inhibition of Pancreatic α-amylase by Resveratrol Derivatives : Biological Activity and Molecular Modelling Evidence for Cooperativity between Viniferin Enantiomers

To improve the current understanding of the role of stilbenoids in the management of diabetes, the inhibition of the pancreatic \u3b1-amylase by resveratrol derivatives was investigated. To approach in a systematic way, the mechanistic and structural aspects of the interaction, potential bioactive agents were prepared as single molecules, that were used for the biological evaluation of the determinants of inhibitory binding. Some dimeric stilbenoids\u2014in particular, viniferin isomers\u2014 were found to be better than the reference drug acarbose in inhibiting the pancreatic \u3b1-amylase. Racemic mixtures of viniferins were more effective inhibitors than the respective isolated pure enantiomers at an equivalent total concentration, and displayed cooperative effects not observed with the individual enantiomers. The molecular docking analysis provided a thermodynamics-based rationale for the measured inhibitory ability and for the observed synergistic effects. Indeed, the binding of additional ligands on the surface of the alpha-amylase was found to decrease the dissociation constant of inhibitors bound to the active site of the enzyme, thus providing a mechanistic rationale for the observed inhibitory synergies

Stilbenoids : A natural arsenal against bacterial pathogens

The escalating emergence of resistant bacterial strains is one of the most important threats to human health. With the increasing incidence of multi-drugs infections, there is an urgent need to restock our antibiotic arsenal. Natural products are an invaluable source of inspiration in drug design and development. One of the most widely distributed groups of natural products in the plant kingdom is represented by stilbenoids. Stilbenoids are synthesised by plants as means of protection against pathogens, whereby the potential antimicrobial activity of this class of natural compounds has attracted great interest in the last years. The purpose of this review is to provide an overview of recent achievements in the study of stilbenoids as antimicrobial agents, with particular emphasis on the sources, chemical structures, and the mechanism of action of the most promising natural compounds. Attention has been paid to the main structure modifications on the stilbenoid core that have expanded the antimicrobial activity with respect to the parent natural compounds, opening the possibility of their further development. The collected results highlight the therapeutic versatility of natural and synthetic resveratrol derivatives and provide a prospective insight into their potential development as antimicrobial agents

Natural and nature-inspired stilbenoids as antiviral agents

Viruses continue to be a major threat to human health. In the last century, pandemics occurred and resulted in significant mortality and morbidity. Natural products have been largely screened as source of inspiration for new antiviral agents. Within the huge class of plant secondary metabolites, resveratrol-derived stilbenoids present a wide structural diversity and mediate a great number of biological responses relevant for human health. However, whilst the antiviral activity of resveratrol has been extensively studied, little is known about the efficacy of its monomeric and oligomeric derivatives. The purpose of this review is to provide an overview of the achievements in this field, with particular emphasis on the source, chemical structures and the mechanism of action of resveratrol-derived stilbenoids against the most challenging viruses. The collected results highlight the therapeutic versatility of stilbene-containing compounds and provide a prospective insight into their potential development as antiviral agents

Structure-dependent biological activities of food-related stilbene derivatives isomers

Resveratrol, piceatannol and pterostilbene are stilbene derivatives in which two aromatic rings linked by an olefin bridge. Many stilbene derivatives have proven beneficial to human health, acting on risk factors for cancer, on cardiovascular and neurodegenerative diseases, on diabetes, and on osteoporosis. All these monomeric polyphenols are particularly prone to oligomerization processes through oxidative coupling, originating complex structures such as dimers or oligomers that may be responsible for their beneficial effects. These natural oligomers present stereogenic centers, that could play a pivotal role in the interaction of this class of molecules with biological targets. In this study, isomers of these compounds were synthesized, purified, and tested as for their ability to inhibit enzymes relevant to glucose metabolism (such as brush-border glucosidase and pancreatic alpha amylase), and to control inflammatory response in a suitable Caco-2 cell model. Results highlight the requirement for peculiar structural features as for eliciting individual effects, both in terms of the polymerization state of these phenolics and in terms of their three-dimensional structure

Inhibition of pancreatic α-amylase by resveratrol-derived viniferins relates to their geometrical features and implies co-operative binding

To improve current understanding of the role of stilbenoids in the management of diabetes, the hypoglycaemic potential of resveratrol derivatives was investigated in terms of alpha-amylase inhibition. To tackle the mechanistic and structural issues of the interaction with the target protein, bioactive agents were prepared as single molecules, to be used for biological evaluation of the binding determinants. Some dimeric stilbenoids \u2013 trans-delta-viniferins, in particular \u2013 were found to be much better inhibitors of pancreatic \u3b1-amylase.than the reference drug, acarbose. Racemic mixtures of viniferins were more effective than the respective isolated pure enantiomers at equivalent total concentration. A markedly sigmoidal inhibition curve was observed for the (S, S) enantiomer of trans-delta-viniferin, with a Hill cooperativity coefficient (n ) close to 4 and a relatively high Kiapp (0.058 mM). In contrast, values of n were close to unity for the (R, R) enantiomer (n = 1.5; Kiapp = 0.043 mM) and for the high-affinity binding of an equimolar mixture of the (R, R) and (S, S) enantiomers (n = 1.2; Kiapp = 0.012 mM). Molecular docking analysis provided a thermodynamics-based rationale for the inhibitory ability of individual stilbenoids, for the cooperative behavior of viniferin enantiomers, and for the synergistic inhibition discussed above. Indeed, binding of additional ligands on the surface of alpha-amylase was found to decrease the dissociation constant of inhibitors bound to the active site of the enzyme. Finally, viniferins do not appear to compete with acarbose in the inhibition of pancreatic \u3b1-amylase. Rather, the evidence gathered so far points to a possible synergy among these classes of inhibitors, in spite of their remarkable structural differences. Studies are in progress to assess whether these synergistic effects could be relevant to developing therapeutic or preventive strategies for diabetes management