Novel Iodinated Hydrazide-hydrazones and their Analogues as Acetyl- and Butyrylcholinesterase Inhibitors
Language English Country United Arab Emirates Media print
Document type Journal Article
Grant support
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-resources
- Keywords
- 1, 2-diacylhydrazine, Acetylcholinesterase, Butyrylcholinesterase, Enzyme inhibition, Hydrazides, Hydrazones,
- MeSH
- Acetylcholinesterase metabolism MeSH
- Butyrylcholinesterase metabolism MeSH
- Cholinesterase Inhibitors chemical synthesis chemistry pharmacology MeSH
- Electrophorus MeSH
- Hydrazines chemical synthesis chemistry pharmacology MeSH
- Hydrazones chemical synthesis chemistry pharmacology MeSH
- Horses MeSH
- Molecular Structure MeSH
- Molecular Docking Simulation MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Acetylcholinesterase MeSH
- Butyrylcholinesterase MeSH
- Cholinesterase Inhibitors MeSH
- Hydrazines MeSH
- Hydrazones 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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