Knez_2023_Acta.Pharmaceutica.Sinica.B_13_2152

Reference

Title : 8-Hydroxyquinolylnitrones as multifunctional ligands for the therapy of neurodegenerative diseases - Knez_2023_Acta.Pharmaceutica.Sinica.B_13_2152
Author(s) : 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 , Patricia Fernandez AP , Sanchez-Garcia A , Martinez-Murillo R , Binda C , Lopez-Munoz F , Gobec S , Marco-Contelle J
Ref : Acta Pharmaceutica Sinica B , 13 :2152 , 2023
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 micromol/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-PS1deltaE9 mice with 19 reduced amyloid plaque load in the hippocampus and cortex of female mice, underscoring the disease-modifying effect of QN 19
ESTHER : Knez_2023_Acta.Pharmaceutica.Sinica.B_13_2152
PubMedSearch : Knez_2023_Acta.Pharmaceutica.Sinica.B_13_2152
PubMedID: 37250172
Gene_locus related to this paper: human-BCHE

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Gene_locus related to this paper: human-BCHE

Citations formats

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, Patricia Fernandez AP, Sanchez-Garcia A, Martinez-Murillo R, Binda C, Lopez-Munoz F, Gobec S, Marco-Contelle J (2023)
8-Hydroxyquinolylnitrones as multifunctional ligands for the therapy of neurodegenerative diseases
Acta Pharmaceutica Sinica B 13 :2152

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, Patricia Fernandez AP, Sanchez-Garcia A, Martinez-Murillo R, Binda C, Lopez-Munoz F, Gobec S, Marco-Contelle J (2023)
Acta Pharmaceutica Sinica B 13 :2152