Novel Iodinated Hydrazide-hydrazones and their Analogues as Acetyl- and Butyrylcholinesterase Inhibitors
Jazyk angličtina Země Spojené arabské emiráty Médium print
Typ dokumentu časopisecké články
Grantová podpora
20-19638Y
Czech Science Foundation - International
CZ.02.1.01/0.0/0.0/16_019/0000841
EFSA-CDN (Charles University) - International
PubMed
32814531
DOI
10.2174/1568026620666200819155503
PII: CTMC-EPUB-109315
Knihovny.cz E-zdroje
- Klíčová slova
- 1, 2-diacylhydrazine, Acetylcholinesterase, Butyrylcholinesterase, Enzyme inhibition, Hydrazides, Hydrazones,
- MeSH
- acetylcholinesterasa metabolismus MeSH
- butyrylcholinesterasa metabolismus MeSH
- cholinesterasové inhibitory chemická syntéza chemie farmakologie MeSH
- Electrophorus MeSH
- hydraziny chemická syntéza chemie farmakologie MeSH
- hydrazony chemická syntéza chemie farmakologie MeSH
- koně MeSH
- molekulární struktura MeSH
- simulace molekulového dockingu MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- acetylcholinesterasa MeSH
- butyrylcholinesterasa MeSH
- cholinesterasové inhibitory MeSH
- hydraziny MeSH
- hydrazony MeSH
BACKGROUND: Hydrazide-hydrazones have been known as scaffold with various biological activities including inhibition of acetyl- (AChE) and butyrylcholinesterase (BuChE). Cholinesterase inhibitors are mainstays of dementias' treatment. OBJECTIVE: Twenty-five iodinated hydrazide-hydrazones and their analogues were designed as potential central AChE and BuChE inhibitors. METHODS: Hydrazide-hydrazones were synthesized from 4-substituted benzohydrazides and 2-/4- hydroxy-3,5-diiodobenzaldehydes. The compounds were investigated in vitro for their potency to inhibit AChE from electric eel and BuChE from equine serum using Ellman's method. We calculated also physicochemical and structural parameters for CNS delivery. RESULTS: The derivatives exhibited a moderate dual inhibition with IC50 values ranging from 15.1-140.5 and 35.5 to 170.5 μmol.L-1 for AChE and BuChE, respectively. Generally, the compounds produced a balanced or more potent inhibition of AChE. N'-[(E)-(4-Hydroxy-3,5-diiodophenyl)methylidene]-4- nitrobenzohydrazide 2k and 4-fluoro-N'-(2-hydroxy-3,5-diiodobenzyl)benzohydrazide 3a were the most potent inhibitors of AChE and BuChE, respectively. Structure-activity relationships were established, and molecular docking studies confirmed interaction with enzymes. CONCLUSION: Many novel hydrazide-hydrazones showed lower IC50 values than rivastigmine against AChE and some of them were comparable for BuChE to this drug used for the treatment of dementia. They interact with cholinesterases via non-covalent binding into the active site. Based on the BOILEDEgg approach, the majority of the derivatives met the criteria for blood-brain-barrier permeability.
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