The limited clinical efficacy of current symptomatic treatment and minute effect on progression of Alzheimer's disease has shifted the research focus from single targets towards multi-target-directed ...ligands. Here, a potent selective inhibitor of human butyrylcholinesterase was used as the starting point to develop a new series of multifunctional ligands. A focused library of derivatives was designed and synthesised that showed both butyrylcholinesterase inhibition and good antioxidant activity as determined by the DPPH assay. The crystal structure of compound 11 in complex with butyrylcholinesterase revealed the molecular basis for its low nanomolar inhibition of butyrylcholinesterase (Ki = 1.09 ± 0.12 nM). In addition, compounds 8 and 11 show metal-chelating properties, and reduce the redox activity of chelated Cu2+ ions in a Cu-ascorbate redox system. Compounds 8 and 11 decrease intracellular levels of reactive oxygen species, and are not substrates of the active efflux transport system, as determined in Caco2 cells. Compound 11 also protects neuroblastoma SH-SY5Y cells from toxic Aβ1–42 species. These data indicate that compounds 8 and 11 are promising multifunctional lead ligands for treatment of Alzheimer's disease.
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•Novel piperidine-based multifunctional ligands were designed and synthesised.•Several ligands inhibited butyrylcholinesterase and showed antioxidant activity.•Compounds 8 and 11 also decrease intracellular reactive oxygen species.•Compound 11 protects SH-SY5Y cells from toxic Aβ species.
•Curcuminoids were extracted using different extraction methods.•Highest amount of extract was obtained using ethanol as solvent.•Antioxidant, antifungal and antibacterial activities of extracts have ...been measured.•The highest antioxidant activity was obtained from ethanol extract.•Curcuminoids have been encapsulated in PEG by PGSS™ process.
In this study, the isolation of curcuminoids from turmeric (Curcuma longa L.) was performed using different solvent extraction methods and solvents. Obtained extracts were analyzed for the contents of curcumin, demethoxycurcumin and bisdemethoxycurcumin by HPLC and the radical scavenging and antibacterial activities of extracts were determined. Extract with highest content of curcuminoids was mixed with polyethylene glycol (PEG) and formulated into powder using PGGS™ method. Obtained powder was pressed into tablets and a release study of the curcuminoids from the product was observed in simulated gastric and intestinal fluids.
Results show that the highest yield of extract is obtained using conventional extraction with mixing in ethanol giving the highest concentration of curcuminoids as well. All extracts show strong antifungal properties but weak antibacterial activity. Curcuminoids extract was successfully encapsulated in PEG carrier and a fine powder was obtained, which increased the solubility in aqueous media.
The protein data bank (PDB) is a rich source of protein ligand structures, but ligands are not explicitly used in current docking algorithms. We have developed ProBiS-Dock, a docking algorithm ...complementary to the ProBiS-Dock Database (
4097-4107) that treats small molecules and proteins as fully flexible entities and allows conformational changes in both after ligand binding. A new scoring function is described that consists of a binding site-specific scoring function (ProBiS-Score) and a general statistical scoring function. ProBiS-Dock enables rapid docking of small molecules to proteins and has been successfully validated in silico against standard benchmarks. It enables rapid search for new active ligands by leveraging existing knowledge in the PDB. The potential of the software for drug development has been confirmed in vitro by the discovery of new inhibitors of human indoleamine 2,3-dioxygenase 1, an enzyme that is an attractive target for cancer therapy and catalyzes the first rate-determining step of l-tryptophan metabolism via the kynurenine pathway. The software is freely available to academic users at http://insilab.org/probisdock.
The resurgence of interest in monoamine oxidases (MAOs) has been fueled by recent correlations of this enzymatic activity with cardiovascular, neurological, and oncological disorders. This has ...promoted increased research into selective MAO-A and MAO-B inhibitors. Here, we shed light on how selective inhibition of MAO-A and MAO-B can be achieved by geometric isomers of cis- and trans-1-propargyl-4-styrylpiperidines. While the cis isomers are potent human MAO-A inhibitors, the trans analogues selectively target only the MAO-B isoform. The inhibition was studied by kinetic analysis, UV–vis spectrum measurements, and X-ray crystallography. The selective inhibition of the MAO-A and MAO-B isoforms was confirmed ex vivo in mouse brain homogenates, and additional in vivo studies in mice show the therapeutic potential of 1-propargyl-4-styrylpiperidines for central nervous system disorders. This study represents a unique case of stereoselective activity of cis/trans isomers that can discriminate between structurally related enzyme isoforms.
Poročilo o 34. evropski poletni šoli logike, jezika in informatike (European Summer School of Logic, Language and Information (ESSLLI)), ki je potekala med 31. julijem in 11. avgustom 2023 na ...Fakulteti za računalništvo in informatiko v Ljubljani.
Considering the increasing resistance of numerous bacteria to antibiotics, a novel wound dressing material was developed with naturally acquired olive leaf extract, which shows not only good ...antimicrobial activity, but also very good antioxidant activity. Besides that, the leaves are treated as waste in agriculture, giving an impact on waste management. An environmentally friendly procedure, electrospinning, was used for the first time to prepare polysaccharide nanofibrous mats with incorporated olive leaf extract, with the unique property of releasing the active phenolic components in a prolonged manner over 24 hours. The developed electrospun mats were characterized using scanning electron microscopy, high-performance liquid chromatography and ultraviolet-visible spectroscopy for determination of free radical scavenging activity by 2,2-diphenyl-1-picrylhydrazyl, antimicrobial testing and release kinetics. Antimicrobial tests have shown that electrospun mats with olive leaf extract achieve reduction towards the tested microorganisms: Staphylococcus aureus (G+), Escherichia coli (G-), Enterococcus faecalis (G+) and Pseudomonas aeruginosa (G-), while the high antioxidant activity of olive leaf extract was preserved during the electrospinning procedure. Release of olive leaf extract from electrospun mats was mathematically modeled, and the release kinetics evaluation indicates the appropriateness of the Korsmeyer–Peppas model for fitting the obtained results of release ability due to erosion of polysaccharide nanofiber mats.
Elevated expression of the immunoproteasome has been associated with autoimmune diseases, inflammatory diseases, and various types of cancer. Selective inhibitors of the immunoproteasome are not only ...scarce, but also almost entirely restricted to peptide‐based compounds. Herein, we describe nonpeptidic reversible inhibitors that selectively block the chymotrypsin‐like (β5i) subunit of the human immunoproteasome in the low micromolar range. The most potent of the reversibly acting compounds were then converted into covalent, irreversible, nonpeptidic inhibitors that retained selectivity for the β5i subunit. In addition, these inhibitors discriminate between the immunoproteasome and the constitutive proteasome in cell‐based assays. Along with their lack of cytotoxicity, these data point to these nonpeptidic compounds being suitable for further investigation as β5i‐selective probes for possible application in noncancer diseases related to the immunoproteasome.
Klein und mächtig: Nichtpeptidische reversible Inhibitoren, die die Chymotrypsin‐artige (β5i) Untereinheit des humanen Immunproteasoms selektiv blockieren, wurden entdeckt und zu irreversibel bindenden Inhibitoren modifiziert. Die niedermolekularen Inhibitoren zeigen eine hohe Selektivität für spezifische Untereinheiten, sind nicht zytotoxisch und unterscheiden in zellbasierten Assays zwischen dem Immunproteasom und dem konstitutiven Proteasom.
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