Naslov
New 4-aminoquinoline-based cholinesterase inhibitors

Autori
Bosak, Anita ; Matošević, Ana ; Zandona, Antonio ; Šinko, Goran ; Komatović, Katarina ; Opsenica, Dejan

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
FFEBS Open Bio 11 (Suppl. 1) / - : FEBS Press, 2021, 310-311

Skup
45th FEBS Congress: Molecules of Life: Towards New Horizons (FEBS 2021)

Mjesto i datum
Ljubljana, Slovenija, 03.07.2021. - 08.07.2021

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
Alzheimer’s disease ; acetylcholinesterase ; butyrlcholinesterase ; 4-aminoquinolines

Sažetak
Medical treatment of Alzheimer’s disease (AD) and related dementias is mainly based on improving the level of the neurotransmitter acetylcholine in the brain by inhibiting the enzymes involved in acetylcholine breakdown, acetylcholinesterase and butyrylcholinesterase. Today, three out of four drugs in the pharmacotherapy of AD are acetylcholinesterase inhibitors that do not cure but only delay the progression of AD symptoms. 4-aminoquinoline represents a simplified tacrine structure and has been identified as the most promising structure for the development of new acetylcholinesterase inhibitors. We synthesised twenty derivatives of 4-aminoquinolines, differing in the substituent attached to the C(4)-amino-group, determined their ability to inhibit the action of acetylcholinesterase and butyrylcholinesterase and evaluated their capacity to pass the blood-brain-barrier. All of the tested compounds reversibly inhibited both acetylcholinesterase and butyrylcholinesterase in low micromolar range, forming noncovalent interactions within the active site of the enzymes with slight preference toward acetylcholinesterase. Generally, acetylcholinesterase showed the highest affinity toward compounds with a longer C(4)-amino aliphatic side chain, pointing to the importance of the existence of high lipophilic substituents. The replacement of a terminal aminogroup by a hydroxy-group generally decreased the inhibition potency of compounds indicating the importance of a basic functional group. Furthermore, all of the tested compounds had the potential for passing the blood-brain- barrier. Our results suggest that the studied 4-aminoquinolines are a solid starting point for further structural refinement in terms of developing novel acetylcholinesterase inhibitors as centrally active drugs for use in the treatment of AD. Acknowledgment: this study was supported by the CSF (IP-2018-01-7683 and IP- 2020-02-9343) and by the MoESTD.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Biologija, Farmacija

POVEZANOST RADA