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Publication Abstract from PubMed

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 mumol/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.

8-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 AP, Sanchez-Garcia A, Martinez-Murillo R, Binda C, Lopez-Munoz F, Gobec S, Marco-Contelles J Acta Pharm Sin B. 2023 May;13(5):2152-2175. doi: 10.1016/j.apsb.2023.01.013. Epub , 2023 Jan 19. PMID:37250172^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.