Tacrine–deferiprone hybrids as multi-target-directed metal chelators against Alzheimer's disease: a two-in-one drug

Abstract

Alzheimer's disease (AD) is a severe age-dependent neurodegenerative disorder affecting several million people worldwide. So far, there is no adequate medication to prevent or slow down the progression of the disease, only medication with palliative effects allowing temporary symptomatic reliefs. As part of our continuing efforts into the development of innovative drugs following a polypharmacological strategy, we decided to use a former anti-AD palliative drug (tacrine) and to reposition it by hybridization with a metal chelating drug (deferiprone, DFP). This combination endows the hybrids with good capacity to inhibit acetylcholinesterase (low micromolar range) and self-/Cu-induced Aβ aggregation (up to ca. 90%) as well as a good radical scavenging ability (micromolar range) and metal (M) chelating capacity, with pM (pM = -log[M], C/C = 10, C = 10 M at pH = 7.4, M = Fe, Cu, Zn) values close to those of DFP. The most promising compounds have 2-hydroxypropyl linkers, and a selection of compounds have demonstrated neuroprotective roles in neuroblastoma cells treated with Aβ and ascorbate/iron stressors. Consequently, these hybrids can be considered as attractive multipotent therapeutic molecules that will eventually play key roles against AD progression, namely in the control of cholinergic dysfunction, amyloid peptide aggregation, oxidative stress, and metal modulation, besides presenting a good pharmacokinetic profile.

New Multitarget Hybrids Bearing Tacrine and Phenylbenzothiazole Motifs as Potential Drug Candidates for Alzheimer’s Disease

“…The systematic approach for the synthesis of the designed tacrine-phenylbenzothiazole hybrids (TAC-PhBTA) is shown in Scheme 1. Firstly, alkyl substituted TAC-amines 5 – 10 of different chain lengths were synthesized according to the previously described method by our group [25]. Meanwhile, synthesis of ethyl 2-(4-(benzo[ d ]thiazol-2-yl)-2-methoxyphenoxy)acetate ( 13 ) was carried out by the reaction of ethylbromoacetate with 4-benzothiazol-2-yl-2-methoxy-phenol ( 12 ) which in turn was obtained by condensation reaction of 4-hydroxy-3-methoxy-benzaldehyde ( 11 ) with 2-aminothiophenol.…”

Iron and Ferroptosis as Therapeutic Targets in Alzheimer's Disease

“…Tacrine-(hydroxybenzoyl-pyridone) hybrids, combining acetylcholineserase inhibition and iron-chelating capacity have been developed [174]. There are also tacrine-deferiprone hybrids [175]. Novel dihydropyrimidinone-derived selenoesters have been synthesized with anti-oxidant activity via lipid peroxidation inhibition and iron chelation activity as well as acetylcholinesterase inhibition [176].…”

Therapeutic Potential of Multifunctional Derivatives of Cholinesterase Inhibitors

“…A combination of tacrine and deferiprone provides good AChE inhibitory activity, inhibition of self-/Cu-induced Aβ aggregation, radical scavenging capacity and metal chelating properties (Fe, Cu, Zn). Chand et al [ 96 ] synthesized a series of tacrine-deferiprone hybrids. Besides advantages mentioned above, obtained analogues are characterized by neuroprotection in SH-SY5Y cells treated with Aβ 1-42 ascorbate/iron stressors (9a and 9b).…”