Rare diseases affect a small part of the population, and the most affected are children. Because of the low availability of patients for testing, the pharmaceutical industry cannot develop drugs for the diagnosis of many of these orphan diseases. In this sense, the use of benzothiazole compounds that are highly selective and can act as spectroscopy probes, especially the compound 2-(4'-aminophenyl)benzothiazole (ABT), has been highlighted. This article reports the design of potential contrast agents based on ABT and iron to develop a new material with an efficient mechanism to raise the relaxation rate, facilitating diagnosis. The ABT/δ-FeOOH hybrid material was prepared by grafting (N-(4'-aminophenyl) benzothiazole-2-bromoacetamide) on the surface of the iron oxyhydroxide particles. FTIR spectra confirmed the material formations of the hybrid material ABT/δ-FeOOH. SEM analysis checked the covering of nanoflakes' surfaces in relation to the morphology of the samples. The theoretical calculations test a better binding mode of compound with iron oxyhydroxide. Theoretical findings show the radical capture mechanism in the stabilization of this new material. In this context, Fe3+ ions are an electron acceptor from the organic phase.

• Klíčová slova
• DFT, benzothiazoles, feroxyhyte, hybrid material, molecular docking, spectroscopy probe,
• MeSH
• benzothiazoly chemie   MeSH
• ionty chemie   MeSH
• kontrastní látky chemie   terapeutické užití   MeSH
• lidé MeSH
• magnetické jevy MeSH
• spektrální analýza MeSH
• vzácné nemoci diagnóza   diagnostické zobrazování   patologie   MeSH
• železité sloučeniny chemie   MeSH
• železo chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• benzothiazole MeSH Prohlížeč
• benzothiazoly MeSH
• ferric oxide MeSH Prohlížeč
• ionty MeSH
• kontrastní látky MeSH
• železité sloučeniny MeSH
• železo MeSH

A series of tacrine - benzothiazole hybrids incorporate inhibitors of acetylcholinesterase (AChE), amyloid β (Aβ) aggregation and mitochondrial enzyme ABAD, whose interaction with Aβ leads to mitochondrial dysfunction, into a single molecule. In vitro, several of 25 final compounds exerted excellent anti-AChE properties and interesting capabilities to block Aβ aggregation. The best derivative of the series could be considered 10w that was found to be highly potent and selective towards AChE with the IC50 value in nanomolar range. Moreover, the same drug candidate exerted absolutely the best results of the series against ABAD, decreasing its activity by 23% at 100 µM concentration. Regarding the cytotoxicity profile of highlighted compound, it roughly matched that of its parent compound - 6-chlorotacrine. Finally, 10w was forwarded for in vivo scopolamine-induced amnesia experiment consisting of Morris Water Maze test, where it demonstrated mild procognitive effect. Taking into account all in vitro and in vivo data, highlighted derivative 10w could be considered as the lead structure worthy of further investigation.

• Klíčová slova
• ABAD, Acetylcholinesterase Inhibitors, Alzheimer’s disease, Amyloid β, Benzothiazole, MTDLs, Tacrine,
• MeSH
• 3-hydroxyacyl-CoA-dehydrogenasy antagonisté a inhibitory   metabolismus   MeSH
• acetylcholinesterasa metabolismus   MeSH
• Alzheimerova nemoc farmakoterapie   metabolismus   MeSH
• amyloidní beta-protein antagonisté a inhibitory   metabolismus   MeSH
• benzothiazoly chemie   farmakologie   MeSH
• cholinergní látky chemická syntéza   chemie   farmakologie   MeSH
• inhibitory enzymů chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• mitochondrie účinky léků   metabolismus   MeSH
• molekulární struktura MeSH
• neuroprotektivní látky chemická syntéza   chemie   farmakologie   MeSH
• proteinové agregáty účinky léků   MeSH
• takrin chemie   farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 3-hydroxyacyl-CoA-dehydrogenasy MeSH
• acetylcholinesterasa MeSH
• amyloidní beta-protein MeSH
• benzothiazoly MeSH
• cholinergní látky MeSH
• HSD17B10 protein, human MeSH Prohlížeč
• inhibitory enzymů MeSH
• neuroprotektivní látky MeSH
• proteinové agregáty MeSH
• takrin MeSH

Human 17β-hydroxysteroid dehydrogenase type 10 is a multifunctional protein involved in many enzymatic and structural processes within mitochondria. This enzyme was suggested to be involved in several neurological diseases, e.g., mental retardation, Parkinson's disease, or Alzheimer's disease, in which it was shown to interact with the amyloid-beta peptide. We prepared approximately 60 new compounds based on a benzothiazolyl scaffold and evaluated their inhibitory ability and mechanism of action. The most potent inhibitors contained 3-chloro and 4-hydroxy substitution on the phenyl ring moiety, a small substituent at position 6 on the benzothiazole moiety, and the two moieties were connected via a urea linker (4at, 4bb, and 4bg). These compounds exhibited IC50 values of 1-2 μM and showed an uncompetitive mechanism of action with respect to the substrate, acetoacetyl-CoA. These uncompetitive benzothiazolyl inhibitors of 17β-hydroxysteroid dehydrogenase type 10 are promising compounds for potential drugs for neurodegenerative diseases that warrant further research and development.

• Klíčová slova
• 17β-hydroxysteroid dehydrogenase type 10, ABAD, Alzheimer’s disease, benzothiazole, inhibitor, neurodegeneration,
• MeSH
• 3-hydroxyacyl-CoA-dehydrogenasy antagonisté a inhibitory   chemie   MeSH
• aktivace enzymů MeSH
• Alzheimerova nemoc farmakoterapie   MeSH
• benzothiazoly chemie   MeSH
• inhibitory enzymů chemie   farmakologie   MeSH
• kinetika MeSH
• lidé MeSH
• močovina chemie   farmakologie   MeSH
• molekulární struktura MeSH
• rekombinantní proteiny MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 3-hydroxyacyl-CoA-dehydrogenasy MeSH
• benzothiazoly MeSH
• HSD17B10 protein, human MeSH Prohlížeč
• inhibitory enzymů MeSH
• močovina MeSH
• rekombinantní proteiny MeSH

BACKGROUND: Misfolding of the neuronal protein α-synuclein into amyloid fibrils is a pathological hallmark of Parkinson's disease, a neurodegenerative disorder that has no cure. Inhibition of the fibril growth is considered a promising therapeutic approach. However, the majority of the existing inhibitors are either unspecific or work at high micromolar concentrations. Earlier, we created a protein-based inhibitor of α-synuclein fibril growth that consists of an α-synuclein moiety and a bulky group. It specifically binds to α-synuclein fibril ends and blocks them by creating steric hindrance to subsequent monomer binding. RESULTS: In this work, we prepared a series of inhibitors with modified α-synuclein moieties and bulky groups of different structure, size, and position. We studied the structure-activity relationship of these inhibitors and optimized them by improving affinity to the fibril end and blocking efficiency. The inhibitors were tested in a Thioflavin T-based kinetic assay, and their affinity to the fibril ends was measured by fluorescence anisotropy. We showed that decrease in electrostatic repulsion between inhibitor and fibril end improved the inhibitor efficiency. Inhibitors with rigid β-sheet-rich bulky groups bind to fibril ends stronger than monomeric α-synuclein and therefore have a high inhibition efficiency, showing a linear correlation between Kd and IC50. SIGNIFICANCE: We determined which properties of inhibitor molecules are the most important for good performance and found that the inhibitor affinity to the fibril end is a key feature that determines its inhibition efficiency. Applying this knowledge, we improved existing inhibitors and reached IC50 value of 300 nM.

• Klíčová slova
• Aggregation, Amyloid, Dissociation constant, Inhibitor, Kinetics,
• MeSH
• alfa-synuklein chemie   metabolismus   MeSH
• amyloid chemie   metabolismus   MeSH
• benzothiazoly chemie   metabolismus   MeSH
• fluorescenční polarizace MeSH
• kinetika MeSH
• lidé MeSH
• proteinové agregáty MeSH
• vazba proteinů MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• alfa-synuklein MeSH
• amyloid MeSH
• benzothiazoly MeSH
• proteinové agregáty MeSH
• thioflavin T MeSH Prohlížeč

: It has long been established that mitochondrial dysfunction in Alzheimer's disease (AD) patients can trigger pathological changes in cell metabolism by altering metabolic enzymes such as the mitochondrial 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10), also known as amyloid-binding alcohol dehydrogenase (ABAD). We and others have shown that frentizole and riluzole derivatives can inhibit 17β-HSD10 and that this inhibition is beneficial and holds therapeutic merit for the treatment of AD. Here we evaluate several novel series based on benzothiazolylurea scaffold evaluating key structural and activity relationships required for the inhibition of 17β-HSD10. Results show that the most promising of these compounds have markedly increased potency on our previously published inhibitors, with the most promising exhibiting advantageous features like low cytotoxicity and target engagement in living cells.

• Klíčová slova
• 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10), amyloid binding alcohol dehydrogenase (ABAD), benzothiazole, Alzheimer’s disease (AD), amyloid-beta peptide (Aβ), mitochondria,
• MeSH
• 17-hydroxysteroidní dehydrogenasy antagonisté a inhibitory   chemie   MeSH
• Alzheimerova nemoc farmakoterapie   MeSH
• amyloidní beta-protein metabolismus   MeSH
• benzothiazoly chemie   MeSH
• buněčné linie MeSH
• lidé MeSH
• mitochondrie metabolismus   MeSH
• močovina chemie   MeSH
• molekulární struktura MeSH
• racionální návrh léčiv MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 17-hydroxysteroidní dehydrogenasy MeSH
• amyloidní beta-protein MeSH
• benzothiazoly MeSH
• močovina MeSH

A series of pentamethinium salts with benzothiazolium and indolium side units comprising one or two positive charges were designed and synthesized to determine the relationships among the molecular structure, charge density, affinity to sulfated polysaccharides, and biological activity. Firstly, it was found that the affinity of the pentamethinium salts to sulfated polysaccharides correlated with their biological activity. Secondly, the side heteroaromates displayed a strong effect on the cytotoxicity and selectivity towards cancer cells. Finally, doubly charged pentamethinium salts possessing benzothiazolium side units exhibited remarkably high efficacy against a taxol-resistant cancer cell line.

• Klíčová slova
• Anticancer activity, Cytotoxicity, Fluorescent cyanine, Pentamethinium salt, Recognition, Sulfated polysaccharides,
• MeSH
• antitumorózní látky chemická syntéza   chemie   metabolismus   farmakologie   MeSH
• apoptóza účinky léků   MeSH
• benzothiazoly chemická syntéza   chemie   metabolismus   farmakologie   MeSH
• CHO buňky MeSH
• Cricetulus MeSH
• estery kyseliny sírové metabolismus   MeSH
• glykosaminoglykany metabolismus   MeSH
• hydrofobní a hydrofilní interakce MeSH
• indoly chemická syntéza   chemie   metabolismus   farmakologie   MeSH
• lidé MeSH
• ligandy MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• pyridinové sloučeniny chemická syntéza   chemie   metabolismus   farmakologie   MeSH
• racionální návrh léčiv MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• audiovizuální média MeSH
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antitumorózní látky MeSH
• benzothiazoly MeSH
• estery kyseliny sírové MeSH
• glykosaminoglykany MeSH
• indoly MeSH
• ligandy MeSH
• pyridinové sloučeniny MeSH

INTRODUCTION: Metallothioneins (MTs) are a class of ubiquitously occurring low-molecular-weight cysteine- and metal-rich proteins containing sulfur-based metal clusters. MT-3 exhibits neuro-inhibitory activity. The possibility to enhance the expression of MT-3 or protect it from degradation is an attractive therapeutic target, because low levels of MT-3 were found in brains of Alzheimer's disease (AD) patients. OBJECTIVES: The primary objective of this study was to test an enhancement of MT-3 cellular concentration after MT-3 binding treatment, which could prevent MT-3 degradation. METHODS: MTT assay, flow-cytometry, fluorescence microscopy, quantitative real-time polymerase chain reaction, and immunodetection of MT3 were used for analysis of effect of STOCK1N-26544, STOCK1N-26929, and STOCK1N-72593 on immortalized human microglia-SV40 cell line. RESULTS: All three tested compounds enhanced concentration of MT-3 protein in cells and surprisingly also mRNA concentration. IC50 values of tested molecules exceeded about ten times the concentration that was needed for induction of MT-3 expression. The tested compound Benzothiazolone-2 enhanced apoptosis and necrosis, but it was not of severe effect. About 80% of cells were still viable. There was no serious ROS-generation and no severe decrease in mitochondria numbers or stress induced endoplasmic reticulum changes after test treatments. The selected compound showed stable hydrophobic and electrostatic interaction during MT-3 ligand interaction. CONCLUSION: Benzothiazolone-2 compounds significantly enhanced MT-3 protein and mRNA levels. The compounds can be looked upon as one of the probable lead compounds for future drug designing experiments in the treatment of Alzheimer's disease.

• Klíčová slova
• Alzheimer's disease, flow cytometry, immunodetection, metallothionein‐3, molecular dynamics, qRT‐PCR,
• MeSH
• Alzheimerova nemoc metabolismus   MeSH
• apoptóza účinky léků   MeSH
• benzothiazoly chemie   farmakologie   MeSH
• buněčné linie MeSH
• lidé MeSH
• messenger RNA metabolismus   MeSH
• metalothionein metabolismus   MeSH
• mikroglie účinky léků   metabolismus   MeSH
• mozek účinky léků   metabolismus   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• benzothiazoly MeSH
• messenger RNA MeSH
• metalothionein MeSH
• reaktivní formy kyslíku MeSH

Alzheimer's disease (AD) is a neurodegenerative disorder associated with an excessive accumulation of amyloid-beta peptide (Aβ). Based on the multifactorial nature of AD, preparation of multi-target-directed ligands presents a viable option to address more pathological events at one time. A novel class of asymmetrical disubstituted indolyl thioureas have been designed and synthesized to interact with monoamine oxidase (MAO) and/or amyloid-binding alcohol dehydrogenase (ABAD). The design combines the features of known MAO inhibitors scaffolds (e.g. rasagiline or ladostigil) and a frentizole moiety with potential to interact with ABAD. Evaluation against MAO identified several compounds that inhibited in the low to moderate micromolar range. The most promising compound (19) inhibited human MAO-A and MAO-B with IC50 values of 6.34μM and 0.30μM, respectively. ABAD activity evaluation did not show any highly potent compound, but the compound series allowed identification of structural features to assist the future development of ABAD inhibitors. Finally, several of the compounds were found to be potent inhibitors of horseradish peroxidase (HRP), preventing the use of the Amplex™ Red assay to detect hydrogen peroxide produced by MAO, highlighting the need for serious precautions when using an enzyme-coupled assay.

• Klíčová slova
• 17β-Hydroxysteroid dehydrogenase type 10 (17β-HSD10), Alzheimer's disease (AD), Amyloid-beta peptide (Aβ), Horseradish peroxidase (HRP), Mitochondrial amyloid-binding alcohol dehydrogenase (ABAD), Monoamine oxidase (MAO),
• MeSH
• 3-hydroxyacyl-CoA-dehydrogenasy antagonisté a inhibitory   metabolismus   MeSH
• Alzheimerova nemoc farmakoterapie   metabolismus   MeSH
• benzothiazoly chemie   farmakologie   MeSH
• fenylmočovinové sloučeniny chemie   farmakologie   MeSH
• inhibitory enzymů chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• molekulární struktura MeSH
• monoaminoxidasa metabolismus   MeSH
• thiomočovina chemická syntéza   chemie   farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 3-hydroxyacyl-CoA-dehydrogenasy MeSH
• benzothiazoly MeSH
• fenylmočovinové sloučeniny MeSH
• frentizole MeSH Prohlížeč
• HSD17B10 protein, human MeSH Prohlížeč
• inhibitory enzymů MeSH
• monoaminoxidasa MeSH
• thiomočovina MeSH

Amyloid-beta peptide (Aβ) has been recognized to interact with numerous proteins, which may lead to pathological changes in cell metabolism of Alzheimer's disease (AD) patients. One such known metabolic enzyme is mitochondrial amyloid-binding alcohol dehydrogenase (ABAD), also known as 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10). Altered enzyme function caused by the Aβ-ABAD interaction, was previously shown to cause mitochondrial distress and a consequent cytotoxic effect, therefore providing a feasible target in AD drug development. Based on previous frentizole derivatives studies, we report two novel series of benzothiazolyl ureas along with novel insights into the structure and activity relationships for inhibition of ABAD. Two compounds (37, 39) were identified as potent ABAD inhibitors, where compound 39 exhibited comparable cytotoxicity with the frentizole standard; however, one-fold higher cytotoxicity than the parent riluzole standard. The calculated and experimental physical chemical properties of the most potent compounds showed promising features for blood-brain barrier penetration.

• Klíčová slova
• 17β-Hydroxysteroid dehydrogenase type 10 (17β-HSD10), Alzheimer’s disease (AD), Amyloid binding alcohol dehydrogenase (ABAD), Amyloid-beta peptide (Aβ), Benzothiazole, Mitochondria, Riluzole,
• MeSH
• 3-hydroxyacyl-CoA-dehydrogenasy antagonisté a inhibitory   metabolismus   MeSH
• Alzheimerova nemoc farmakoterapie   MeSH
• benzothiazoly chemie   farmakologie   MeSH
• CHO buňky MeSH
• Cricetulus MeSH
• inhibitory enzymů chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• močovina analogy a deriváty   chemie   farmakologie   MeSH
• molekulární struktura MeSH
• racionální návrh léčiv * MeSH
• viabilita buněk účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 3-hydroxyacyl-CoA-dehydrogenasy MeSH
• benzothiazole MeSH Prohlížeč
• benzothiazoly MeSH
• HSD17B10 protein, human MeSH Prohlížeč
• inhibitory enzymů MeSH
• močovina MeSH

In the current study, sixteen novel derivatives of (R)-1-(6-fluorobenzo[d]thiazol-2-yl)ethanamine were synthesized as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. Chemical structures together with purity of the synthesized compounds were substantiated by IR, (1)H, (13)C, (19)F NMR, high resolution mass spectrometry and elemental analysis. The optical activities were confirmed by optical rotation measurements. The synthesized compounds were evaluated for their AChE and BChE inhibitory activities. In addition, the cytotoxicity of the most active compounds was investigated against human cell lines employing XTT tetrazolium salt reduction assay and xCELLigence system allowing a label-free assessment of the cells proliferation. Our results demonstrated that the inhibitory mechanism was confirmed to be pseudo-irreversible, in line with previous studies on carbamates. Compounds indicated as 3b, 3d, 3l and 3n showed the best AChE inhibitory activity of all the evaluated compounds and were up to tenfold more potent than standard drug rivastigmine. The binding mode was determined using state-of-the-art covalent docking and scoring methodology. The obtained data clearly demonstrated that 3b, 3d, 3l and 3n benzothiazole carbamates possess high inhibitory activity against AChE and BChE and concurrently negligible cytotoxicity. In conclusion, our results indicate, that these derivatives could be promising in an effective therapeutic intervention for Alzheimer's disease.

• Klíčová slova
• Acetylcholinesterase, Butyrylcholinesterase inhibition, Carbamates, Covalent docking, Halogenated benzothiazole, Pseudo-irreversible mechanism,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• benzothiazoly chemická syntéza   chemie   farmakologie   MeSH
• butyrylcholinesterasa metabolismus   MeSH
• cholinesterasové inhibitory chemická syntéza   chemie   farmakologie   MeSH
• hydrofobní a hydrofilní interakce MeSH
• Jurkat buňky MeSH
• karbamáty chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• proliferace buněk účinky léků   MeSH
• simulace molekulového dockingu * MeSH
• viabilita buněk účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• benzothiazoly MeSH
• butyrylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• karbamáty MeSH