Amiridine-piperazine hybrids as cholinesterase inhibitors and potential multitarget agents for Alzheimer's disease treatment
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00179906%3A_____%2F21%3A10429157" target="_blank" >RIV/00179906:_____/21:10429157 - isvavai.cz</a>
Result on the web
<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=YlCT-vH02~" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=YlCT-vH02~</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1016/j.bioorg.2021.104974" target="_blank" >10.1016/j.bioorg.2021.104974</a>
Alternative languages
Result language
angličtina
Original language name
Amiridine-piperazine hybrids as cholinesterase inhibitors and potential multitarget agents for Alzheimer's disease treatment
Original language description
We synthesized eleven new amiridine-piperazine hybrids 5a-j and 7 as potential multifunctional agents for Alzheimer's disease (AD) treatment by reacting N-chloroacetylamiridine with piperazines. The compounds displayed mixed-type reversible inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Conjugates were moderate inhibitors of equine and human BChE with negligible fluctuation in anti-BChE activity, whereas anti-AChE activity was substantially dependent on N4-substitution of the piperazine ring. Compounds with para-substituted aromatic moieties (5g, 5h, and bis-amiridine 7) had the highest anti-AChE activity in the low micromolar range. Top-ranked compound 5h, N-(2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinolin-9yl)-2-[4-(4-nitro-phenyl)-piperazin-1-yl]-acetamide, had an IC50 for AChE = 1.83 +/- 0.03 mu M (Ki = 1.50 +/- 0.12 and alpha Ki = 2.58 +/- 0.23 mu M). The conjugates possessed low activity against carboxylesterase, indicating a likely absence of unwanted drug-drug interactions in clinical use. In agreement with analysis of inhibition kinetics and molecular modeling studies, the lead compounds were found to bind effectively to the peripheral anionic site of AChE and displace propidium, indicating their potential to block AChE-induced beta-amyloid aggregation. Similar propidium displacement activity was first shown for amiridine. Two compounds, 5c (R = cyclohexyl) and 5e (R = 2-MeO-Ph), exhibited appreciable antioxidant capability with Trolox equivalent antioxidant capacity values of 0.47 +/- 0.03 and 0.39 +/- 0.02, respectively. Molecular docking and molecular dynamics simulations provided insights into the structure-activity relationships for AChE and BChE inhibition, including the observation that inhibitory potencies and computed pKa values of hybrids were generally lower than those of the parent molecules. Predicted ADMET and physicochemical properties of conjugates indicated good CNS bioavailability and safety parameters comparable to those of amiridine and therefore acceptable for potential lead compounds at the early stages of anti-AD drug development.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30104 - Pharmacology and pharmacy
Result continuities
Project
<a href="/en/project/GC20-29633J" target="_blank" >GC20-29633J: Hybrid structures based on Amiridine as potential multitarget drugs for Alzheimer's disease treatment</a><br>
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Others
Publication year
2021
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Bioorganic Chemistry
ISSN
0045-2068
e-ISSN
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Volume of the periodical
112
Issue of the periodical within the volume
July
Country of publishing house
US - UNITED STATES
Number of pages
18
Pages from-to
104974
UT code for WoS article
000661870700001
EID of the result in the Scopus database
2-s2.0-85107052871