8-Hydroxyquinolylnitrones as multifunctional ligands for the therapy of neurodegenerative diseases.
10.1016/j.apsb.2023.01.013
- Author:
Damijan KNEZ
1
;
Daniel DIEZ-IRIEPA
2
,
3
;
Mourad CHIOUA
2
,
3
;
Andrea GOTTINGER
4
;
Milica DENIC
5
;
Fabien CHANTEGREIL
5
;
Florian NACHON
5
;
Xavier BRAZZOLOTTO
5
;
Anna SKRZYPCZAK-WIERCIOCH
6
;
Anže MEDEN
1
;
Anja PIŠLAR
1
;
Janko KOS
1
;
Simon ŽAKELJ
1
;
Jure STOJAN
7
;
Kinga SAŁAT
8
;
Julia SERRANO
9
;
Ana Patricia FERNÁNDEZ
9
;
Aitana SÁNCHEZ-GARCÍA
10
;
Ricardo MARTÍNEZ-MURILLO
9
;
Claudia BINDA
4
;
Francisco LÓPEZ-MUÑOZ
11
;
Stanislav GOBEC
1
;
José MARCO-CONTELLES
2
,
3
Author Information
1. University of Ljubljana, Faculty of Pharmacy, Ljubljana 1000, Slovenia.
2. Laboratory of Medicinal Chemistry (Institute of Organic Chemistry, CSIC)
3. Madrid 28006, Spain.
4. Department of Biology and Biotechnology, University of Pavia, Pavia 27100, Italy.
5. Département de Toxicologie et Risques Chimiques, Institut de Recherche Biomédicale des Armées, Paris 91220, France.
6. Department of Animal Anatomy and Preclinical Sciences, University Centre of Veterinary Medicine JU-UA, University of Agriculture in Krakow, Krakow 30-059, Poland.
7. Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana 1000, Slovenia.
8. Department of Pharmacodynamics, Chair of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow 30-688, Poland.
9. Department of Translational Neurobiology, Neurovascular Research Group, Cajal Institute (CSIC), Madrid 28002, Spain.
10. Biotechnology and Vegetal Biology Department, Escuela Técnica Superior de Ingeniería Agronómica, Alimentaria y de Biosistemas, Universidad Politécnica de Madrid, Madrid 28040, Spain.
11. Faculty of Health, Camilo José Cela University of Madrid (UCJC), Neuropsychopharmacology Unit, "Hospital 12 de Octubre" Research Institute, Madrid 28692, Spain.
- Publication Type:Journal Article
- Keywords:
6-Hydroxydopamine model;
Alzheimer's disease;
Butyrylcholinesterase;
Monoamine oxidase B;
Multifunctional ligands;
Novel object recognition;
Passive avoidance task;
Quinolylnitrone
- From:
Acta Pharmaceutica Sinica B
2023;13(5):2152-2175
- CountryChina
- Language:English
-
Abstract:
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 (IC50 = 1.06 ± 0.31 nmol/L) and hMAO-B (IC50 = 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.
