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.
- 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
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.
- 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
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.
- 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
INTRODUCTION: Determination of acetylcholinesterase and butyrylcholinesterase activity has become an important tool in drug design and discovery as well as in medicine and toxicology. There are a large number of compounds that are able to modulate cholinesterase activity. These compounds can be used for pharmacological management of various disorders (e.g., Alzheimer's disease, myasthenia Gravis). Moreover, organophosphate poisoning is frequently diagnosed via a cholinesterase activity assay. This broad variety of methods has been developed over the past decades for cholinesterase activity quantification. AREAS COVERED: This review provides a summary of the methods that are based on specific properties of cholinesterases and their interactions with native or artificial substrates. The authors also aim to provide an overview of different techniques used for the determination of quantitative cholinesterase activity. Specifically, the authors describe and discuss the manometric, potentiometric, titrimetric, photometric, fluorometric, and radioisotopic methods. EXPERT OPINION: Existing methods are able to cover most of the problems that arise during cholinesterase activity determination. Colorimetry according to Ellman has proved to be the most useful and versatile approach. It may be used in various protocols for the determination of pesticide or nerve agent exposure or for the development of new drugs. Its possible improvement lies in optimization of hemoglobin-rich samples. The progress of the most common methods (including Ellman) depends on miniaturization and modern physical platforms (e.g., optical fibers, chip methods, or nanotechnologies).
- MeSH
- Alzheimerova nemoc farmakoterapie metabolismus MeSH
- butyrylcholinesterasa analýza metabolismus MeSH
- chemické bojové látky farmakologie MeSH
- chemické techniky analytické metody MeSH
- cholinesterasové inhibitory farmakologie MeSH
- cholinesterasy analýza metabolismus MeSH
- lidé MeSH
- myasthenia gravis farmakoterapie metabolismus MeSH
- racionální návrh léčiv MeSH
- referenční hodnoty MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
A new tacrine based cholinesterase inhibitor, N-(bromobut-3-en-2-yl)-7-methoxy-1,2,3,4-tetrahydroacridin-9-amine (1), was designed and synthesized to interact with specific regions of human acetylcholinesterase and human butyrylcholinesterase. Its inhibitory ability towards cholinesterases was determined and compared to tacrine (THA) and 9-amino-7-methoxy-1,2,3,4-tetrahydroacridine (7-MEOTA). The assessment of IC50 values revealed 1 as a weak inhibitor of both tested enzymes.
- MeSH
- akridiny chemická syntéza chemie farmakologie MeSH
- Alzheimerova nemoc farmakoterapie enzymologie MeSH
- butyrylcholinesterasa chemie farmakologie MeSH
- cholinesterasové inhibitory chemická syntéza chemie farmakologie MeSH
- cholinesterasy chemie MeSH
- heterocyklické sloučeniny tricyklické chemická syntéza chemie farmakologie MeSH
- lidé MeSH
- preklinické hodnocení léčiv MeSH
- takrin chemie farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
