Download Mendeley8-Hydroxyquinolylnitrones as multifunctional ligands for the therapy of neurodegenerative diseases.
Knez, D., Diez-Iriepa, D., Chioua, M., Gottinger, A., Denic, M., Chantegreil, F., Nachon, F., Brazzolotto, X., Skrzypczak-Wiercioch, A., Meden, A., Pislar, A., Kos, J., Zakelj, S., Stojan, J., Salat, K., Serrano, J., Fernandez, A.P., Sanchez-Garcia, A., Martinez-Murillo, R., Binda, C., Lopez-Munoz, F., Gobec, S., Marco-Contelles, J.(2023) Acta Pharm Sin B 13: 2152-2175
- PubMed: 37250172
- DOI: https://doi.org/10.1016/j.apsb.2023.01.013
- Primary Citation of Related Structures:
7QBQ, 7QBR, 7ZPB, 7ZW3 - PubMed 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 (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-PS1 δ E9 mice with 19 reduced amyloid plaque load in the hippocampus and cortex of female mice, underscoring the disease-modifying effect of QN 19 .
Organizational Affiliation:
University of Ljubljana, Faculty of Pharmacy, Ljubljana 1000, Slovenia.
