8-Hydroxyquinolylnitrones as multifunctional ligands for the therapy of neurodegenerative diseases

Knez, Damijan (author), Meden, Anže (author), Pišlar, Anja (author), Kos, Janko (author), Žakelj, Simon (author), Stojan, Jure (author), Gobec, Stanislav (author), Marco-Contelles, José (author)

We describe the development of quinolylnitrones (QNs) as multifunctional ligands inhibiting cholinesterases (ChEs: acetylcholinesterase and butyrylcholinesterase–hBChE) and monoamine oxidases (hMAO-A/B) for the therapy of neurodegenerative diseases. We identified QN 19, a simple, low molecular weight nitrone, that is readily synthesized from commercially available 8-hydroxyquinoline-2-carbaldehyde. Quinolylnitrone 19 has no typical pharmacophoric element to suggest ChE or MAO inhibition, yet unexpectedly showed potent inhibition of hBChE (IC$_{50}$ = 1.06 ± 0.31 nmol/L) and hMAO-B (IC$_{50}$ = 4.46 ± 0.18 μmol/L). The crystal structures of 19 with hBChE and hMAO-B provided the structural basis for potent binding, which was further studied by enzyme kinetics. Compound 19 acted as a free radical scavenger and biometal chelator, crossed the blood–brain barrier, was not cytotoxic, and showed neuroprotective properties in a 6-hydroxydopamine cell model of Parkinson’s disease. In addition, in vivo studies showed the anti-amnesic effect of 19 in the scopolamine-induced mouse model of AD without adverse effects on motoric function and coordination. Importantly, chronic treatment of double transgenic APPswe-PS1δE9 mice with 19 reduced amyloid plaque load in the hippocampus and cortex of female mice, underscoring the disease-modifying effect of QN 19.

• Language: English
• Keywords: quinolylnitrone, butyrylcholinesterase, monoamine oxidase B, Alzheimer's disease, multifunctional ligands, 6-hydroxydopamine model, passive avoidance task, novel object recognition
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy; MF - Faculty of Medicine
• Publication status: Published
• Publication version: Version of Record
• Year: 2023
• Number of pages: Str. 2152-2175
• Numbering: Vol. 13, iss. 5
• PID: 20.500.12556/RUL-146733
• UDC: 616.831-003.8
• ISSN on article: 2211-3843
• DOI: 10.1016/j.apsb.2023.01.013
• COBISS.SI-ID: 139883267
• Publication date in RUL: 09.06.2023

Record is a part of a journal

• Title: Acta pharmaceutica sinica B
• Publisher: Elsevier, Chinese Pharmaceutical Association, Institute of Materia Medica, Chinese Academy of Medical Sciences
• ISSN: 2211-3843
• COBISS.SI-ID: 524560409

Licences

• License: CC BY-NC-ND 4.0, Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
• Link: http://creativecommons.org/licenses/by-nc-nd/4.0/
• Description: The most restrictive Creative Commons license. This only allows people to download and share the work for no commercial gain and for no other purposes.

Secondary language

• Language: Slovenian
• Keywords: kinolilnitron, butirilholinesteraza, monoaminooksidaza B, multifunkcionalni ligandi, alzheimerjeva bolezen, model 6-hidroksidopamina, naloga pasivnega izogibanja, prepoznavanje novih predmetov, encimska kinetika, nevrodegenerativne bolezni