Novel Tacrine−8-Hydroxyquinoline Hybrids as Multifunctional Agents for the Treatment of Alzheimer’s Disease, with Neuroprotective, Cholinergic, Antioxidant, and Copper-Complexing Properties

Abstract

Tacrine and PBT2 (an 8-hydroxyquinoline derivative) are well-known drugs that inhibit cholinesterases and decrease beta-amyloid (Abeta) levels by complexation of redox-active metals, respectively. In this work, novel tacrine-8-hydroxyquinoline hybrids have been designed, synthesized, and evaluated as potential multifunctional drugs for the treatment of Alzheimer's disease. At nano- and subnanomolar concentrations they inhibit human acetyl- and butyrylcholinesterase (AChE and BuChE), being more potent than tacrine. They also displace propidium iodide from the peripheral anionic site of AChE and thus could be able to inhibit Abeta aggregation promoted by AChE. They show better antioxidant properties than Trolox, the aromatic portion of vitamin E responsible for radical capture, and display neuroprotective properties against mitochondrial free radicals. In addition, they selectively complex Cu(II), show low cell toxicity, and could be able to penetrate the CNS, according to an in vitro blood-brain barrier model.

New Tacrine–4-Oxo-4H-chromene Hybrids as Multifunctional Agents for the Treatment of Alzheimer’s Disease, with Cholinergic, Antioxidant, and β-Amyloid-Reducing Properties

“…61 Initially, to determine the optimal length of the aliphatic linker between the two heterocyclic fragments for ChEs inhibition, the synthesis of tacrine−flavonoid hybrids without any substituent in both heterocyclic structures was carried out. In a preliminary experiment, the treatment of N 1 -(1,2,3,4-tetrahydroacridin-9-yl)heptane-1,7-diamine (31) with 4-oxo-4H-chromene-2-carboxylic acid (38) in the presence of N,N′-dicyclohexylcarbodiimide (DCC) and a catalytic amount of N,N-dimethylaminopyridine (DMAP) progressed adequately, but the amide 3 was obtained with an excessive amount of dicyclohexylurea, even after several chromatographic separations. For this reason, we investigated another coupling agent, (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP).…”

N-Acylaminophenothiazines: Neuroprotective agents displaying multifunctional activities for a potential treatment of Alzheimer’s disease

“…Moreover, 3-(pyrrolidin-1-yl)propanoic acid (24) [38] and 3-(4-methylpiperazin-1-yl)propanoic acid (25) [39] were obtained by reacting ethyl 3-chloropropanoate with the corresponding amine (pyrrolidine or 1-methylpiperazine), then followed by alkaline hydrolysis of the ester group. These acids were activated with EDC ([1-ethyl-3-(3-dimethylaminopropyl) carbodiimide]) and coupled with hydrazines 20e23 in anhydrous tetrahydrofuran solutions at room temperature to afford the corresponding N 0 -{2-[(2-nitrophenyl)thio]phenyl}-3-(pyrrolidin-1-yl)propanehydrazide 26e32.…”

Navigating the Chemical Space of Multitarget-Directed Ligands: From Hybrids to Fragments in Alzheimer’s Disease

“…In this respect, Rodriguez-Franco and co-workers reported on a series of tacrine-8HQ hybrids as novel MTDLs with cholinergic, antioxidant and Cu(II)-complexing properties [49]. Youdim et al developed the hybrid compound M30, containing the metal chelator 8HQ core and the propargylamine moiety from FDA-approved anti-Parkinson rasagiline, with anti-MAO-B activity [50].…”