Sulfone-based human liver pyruvate kinase inhibitors - Design, synthesis and in vitro bioactivity.

Non-alcoholic fatty liver disease (NAFLD) is a prevalent pathological condition characterised by the accumulation of fat in the liver. Almost one-third of the global population is affected by NAFLD, making it a significant health concern. However, despite its prevalence, there is currently no approved drug specifically designed for the treatment of NAFLD.

Identification of inhibitors targeting the energy-coupling factor (ECF) transporters.

The energy-coupling factor (ECF) transporters are a family of transmembrane proteins involved in the uptake of vitamins in a wide range of bacteria. Inhibition of the activity of these proteins could reduce the viability of pathogens that depend on vitamin uptake. The central role of vitamin transport in the metabolism of bacteria and absence from humans make the ECF transporters an attractive target for inhibition with selective chemical probes.

1-deoxy-D-xylulose-5-phosphate synthase from Pseudomonas aeruginosa and Klebsiella pneumoniae reveals conformational changes upon cofactor binding.

The ESKAPE bacteria are the six highly virulent and antibiotic-resistant pathogens that require the most urgent attention for the development of novel antibiotics. Detailed knowledge of target proteins specific to bacteria is essential to develop novel treatment options. The methylerythritol-phosphate (MEP) pathway, which is absent in humans, represents a potentially valuable target for the development of novel antibiotics.

Exploration of Novel Urolithin C Derivatives as Non-Competitive Inhibitors of Liver Pyruvate Kinase.

The inhibition of liver pyruvate kinase could be beneficial to halt or reverse non-alcoholic fatty liver disease (NAFLD), a progressive accumulation of fat in the liver that can lead eventually to cirrhosis. Recently, urolithin C has been reported as a new scaffold for the development of allosteric inhibitors of liver pyruvate kinase (PKL). In this work, a comprehensive structure-activity analysis of urolithin C was carried out.

Anthraquinone derivatives as ADP-competitive inhibitors of liver pyruvate kinase.

Liver pyruvate kinase (PKL) is a major regulator of metabolic flux and ATP production during liver cell glycolysis and is considered a potential drug target for the treatment of non-alcoholic fatty liver disease (NAFLD). In this study, we report the first ADP-competitive PKL inhibitors and identify several starting points for the further optimization of these inhibitors. Modeling and structural biology guided the optimization of a PKL-specific anthraquinone-based compound.

Unveiling Adatoms in On-Surface Reactions: Combining Scanning Probe Microscopy with van't Hoff Plots.

Scanning probe microscopy has become an essential tool to not only study pristine surfaces but also on-surface reactions and molecular self-assembly. Nonetheless, due to inherent limitations, some atoms or (parts of) molecules are either not imaged or cannot be unambiguously identified. Herein, we discuss the arrangement of two different nonplanar molecular assemblies of -hexaphenyl-dicarbonitrile (Ph(CN)) on Au(111) based on a combined theoretical and experimental approach.

"Clicking" fragment leads to novel dual-binding cholinesterase inhibitors.

Cholinesterase inhibitors are potent therapeutics in the treatment of Alzheimer's disease. Among them, dual binding ligands have recently gained a lot of attention. We discovered novel dual-binding cholinesterase inhibitors, using "clickable" fragments, which bind to either catalytic active site (CAS) or peripheral anionic site (PAS) of the enzyme.

Surface state tunable energy and mass renormalization from homothetic quantum dot arrays.

Quantum dot arrays in the form of molecular nanoporous networks are renowned for modifying the electronic surface properties through quantum confinement. Here we show that, compared to the pristine surface state, the band bottom of the confined states can exhibit downward shifts accompanied by a lowering of the effective masses simultaneous to the appearance of tiny gaps at the Brillouin zone boundaries. We observed these effects by angle resolved photoemission for two self-assembled homothetic (scalable) Co-coordinated metal-organic networks.

Synthesis and biological evaluation of truncated derivatives of abyssomicin C as antibacterial agents.

The synthesis and antibacterial activity of two new highly truncated derivatives of the natural product abyssomicin C are reported. This work outlines the limits of structural truncation of the natural product and consequently provides insights for further structure-activity relationship studies towards novel antibiotics targeting 4-amino-4-deoxychorismate (ADC) synthase. Specifically, it is demonstrated that the synthetically challenging bicyclic motif is essential for activity towards methicillin-resistant (MRSA).

Rational Adaptation of L3MBTL1 Inhibitors to Create Small-Molecule Cbx7 Antagonists.

Chromobox homolog 7 (Cbx7) is an epigenetic modulator that is an important driver of multiple cancers. It is a methyl reader protein that operates by recognizing and binding to methylated lysine residues on specific partners. Herein we report our efforts to create low-molecular-weight inhibitors of Cbx7 by making rational structural adaptations to inhibitors of a different methyl reader protein, L3MBTL1, inhibitors that had previously been reported to be inactive against Cbx7.

Low-Dimensional Metal-Organic Coordination Structures on Graphene.

We report the formation of one- and two-dimensional metal-organic coordination structures from -hexaphenyl-dicarbonitrile (NC-Ph-CN) molecules and Cu atoms on graphene epitaxially grown on Ir(111). By varying the stoichiometry between the NC-Ph-CN molecules and Cu atoms, the dimensionality of the metal-organic coordination structures could be tuned: for a 3:2 ratio, a two-dimensional hexagonal porous network based on threefold Cu coordination was observed, while for a 1:1 ratio, one-dimensional chains based on twofold Cu coordination were formed. The formation of metal-ligand bonds was supported by imaging the Cu atoms within the metal-organic coordination structures with scanning tunneling microscopy.

A combinatorial approach for the discovery of drug-like inhibitors of 15-lipoxygenase-1.

Human 15-lipoxygenase-1 (15-LOX-1) is a mammalian lipoxygenase which plays an important regulatory role in several CNS and inflammatory lung diseases. To further explore the role of this enzyme in drug discovery, novel potent inhibitors with favorable physicochemical properties are required. In order to identify such new inhibitors, we established a combinatorial screening method based on acylhydrazone chemistry.

Comparing the Self-Assembly of Sexiphenyl-Dicarbonitrile on Graphite and Graphene on Cu(111).

A comparative study on the self-assembly of sexiphenyl-dicarbonitrile on highly oriented pyrolytic graphite and single-layer graphene on Cu(111) is presented. Despite an overall low molecule-substrate interaction, the close-packed structures exhibit a peculiar shift repeating every four to five molecules. This shift has hitherto not been reported for similar systems and is hence a unique feature induced by the graphitic substrates.

Dynamic Combinatorial Chemistry to Identify Binders of ThiT, an S-Component of the Energy-Coupling Factor Transporter for Thiamine.

We applied dynamic combinatorial chemistry (DCC) to identify ligands of ThiT, the S-component of the energy-coupling factor (ECF) transporter for thiamine in Lactococcus lactis. We used a pre-equilibrated dynamic combinatorial library (DCL) and saturation-transfer difference (STD) NMR spectroscopy to identify ligands of ThiT. This is the first report in which DCC is used for fragment growing to an ill-defined pocket, and one of the first reports for its application with an integral membrane protein as target.

Enzymatic and solid-phase synthesis of new donepezil-based L- and d-glutamic acid derivatives and their pharmacological evaluation in models related to Alzheimer's disease and cerebral ischemia.

Previously, we have described N-Bz-L-Glu[NH-2-(1-benzylpiperidin-4-yl)ethyl]-O-nHex (IQM9.21, L-1) as an interesting multifunctional neuroprotective compound for the potential treatment of neurodegenerative diseases. Here, we describe new derivatives and different synthetic routes, such as chemoenzymatic and solid-phase synthesis, aiming to improve the previously described route in solution.

Structure-based design of potent small-molecule binders to the S-component of the ECF transporter for thiamine.

Energy-coupling factor (ECF) transporters are membrane-protein complexes that mediate vitamin uptake in prokaryotes. They bind the substrate through the action of a specific integral membrane subunit (S-component) and power transport by hydrolysis of ATP in the three-subunit ECF module. Here, we have studied the binding of thiamine derivatives to ThiT, a thiamine-specific S-component.

Multipotent, permeable drug ASS234 inhibits Aβ aggregation, possesses antioxidant properties and protects from Aβ-induced apoptosis in vitro.

Amyloid beta (Aβ) aggregation and deposition is a key pathological hallmark of AD. Growing evidence suggests that neurotoxicity of this peptide is related to the formation of toxic oligomeric aggregates. Therefore, a deeply investigated therapeutic strategy comes at present from blocking the formation of these species to non-toxic aggregates.

Benzothiazepine CGP37157 and its isosteric 2'-methyl analogue provide neuroprotection and block cell calcium entry.

Benzothiazepine CGP37157 is widely used as tool to explore the role of mitochondria in cell Ca(2+) handling, by its blocking effect of the mitochondria Na(+)/Ca(2+) exchanger. Recently, CGP37157 has shown to exhibit neuroprotective properties. In the trend to improve its neuroprotection profile, we have synthesized ITH12505, an isosteric analogue having a methyl instead of chlorine at C2' of the phenyl ring.

Synthesis, biological assessment, and molecular modeling of racemic 7-aryl-9,10,11,12-tetrahydro-7H-benzo[7,8]chromeno[2,3-b]quinolin-8-amines as potential drugs for the treatment of Alzheimer's disease.

The synthesis, pharmacological analysis and molecular modeling of the readily available racemic tacrine analogs 21-30, bearing the 7-aryl-9,10,11,12-tetrahydro-7H-benzo[7,8]chromeno[2,3-b]quinolin-8-amine heterocyclic ring system (II), prepared by Friedländer reaction of 2-amino-4-aryl-4H-benzo[h]chromene-3-carbonitriles (11-20) with cyclohexanone, are described in this paper. Molecules 21-30 are potent and selective inhibitors of hAChE, in the low micromolar range, one of the most potent inhibitors, 4-(8-amino-9,10,11,12-tetrahydro-7H-benzo[7,8]chromeno[2,3-b]quinolin-7-yl)-2-methoxyphenol (25), showing a IC(50) (hAChE) = 0.33 ± 0.

New tacrine-4-oxo-4H-chromene hybrids as multifunctional agents for the treatment of Alzheimer's disease, with cholinergic, antioxidant, and β-amyloid-reducing properties.

By using fragments endowed with interesting and complementary properties for the treatment of Alzheimer's disease (AD), a new family of tacrine-4-oxo-4H-chromene hybrids has been designed, synthesized, and evaluated biologically. The tacrine fragment was selected for its inhibition of cholinesterases, and the flavonoid scaffold derived from 4-oxo-4H -chromene was chosen for its radical capture and β-secretase 1 (BACE-1) inhibitory activities. At nano- and picomolar concentrations, the new tacrine-4-oxo-4H-chromene hybrids inhibit human acetyl- and butyrylcholinesterase (h-AChE and h-BuChE), being more potent than the parent inhibitor, tacrine.

Α-aryl-N-alkyl nitrones, as potential agents for stroke treatment: synthesis, theoretical calculations, antioxidant, anti-inflammatory, neuroprotective, and brain-blood barrier permeability properties.

We report the synthesis, theoretical calculations, the antioxidant, anti-inflammatory, and neuroprotective properties, and the ability to cross the blood-brain barrier (BBB) of (Z)-α-aryl and heteroaryl-N-alkyl nitrones as potential agents for stroke treatment. The majority of nitrones compete with DMSO for hydroxyl radicals, and most of them are potent lipoxygenase inhibitors. Cell viability-related (MTT assay) studies clearly showed that nitrones 1-3 and 10 give rise to significant neuroprotection.