Multifunctional iron-chelators with protective roles against neurodegenerative diseases

Abstract

The multifactorial nature of Alzheimer's disease (AD), and the absence of a disease modifying drug, makes the development of new multifunctional drugs an attractive therapeutic strategy. Taking into account the hallmarks of AD patient brains, such as low levels of acetylcholine, misfolding of proteins and associated beta-amyloid (Aβ) aggregation, oxidative stress and metal dyshomeostasis, we have developed a series of compounds that merge three different approaches: metal attenuation, anti-Aβ aggregation and anti-acetylcholinesterase activity. Therefore, 3-hydroxy-4-pyridinone (3,4-HP) and benzothiazole molecular moieties were selected as starting frameworks due to their well known affinity for iron and Aβ peptides, respectively. The linkers between these two main functional groups were selected on the basis of virtual screening, so that the final molecule could further inhibit the acetylcholinesterase, responsible for the cholinergic losses. We describe herein the design and synthesis of the new hybrid compounds, followed by the assessment of solution properties, namely iron chelation and anti-oxidant capacity. The compounds were bioassayed for their capacity to inhibit AChE, as well as self- and Zn mediated-Aβ(1-42) aggregation. Finally, we assessed their effects on the viability of neuronal cells stressed with Aβ(42).

Design, synthesis and neuroprotective evaluation of novel tacrine–benzothiazole hybrids as multi-targeted compounds against Alzheimer’s disease

“…30 The IC 50 values for AChE inhibition are summarized in Table 1 35 this feature is expected to reduce the cholinergic-induced aggregation of the Aβ peptide, and thus enhance the overall anti-Aβ aggregation ability of these multifunctional hybrid compounds (see below).…”

“…Cell reduction ability as a surrogate of cell viability was measured by using a quantitative colorimetric assay with MTT according to the method of Mosmann (1983). 30,50 In brief, cells…”

“…Thus, one of the most explored design strategies has been focused on the development of hybrids that combine the ChEs inhibition role, for the enhancement of the cholinergic neurotransmission, with other relevant roles (eg reduction the Aβ fibril self-aggregation, antioxidant and metal depletion). [27][28][29][30] In this context, the development of tacrine-BTA hybrid compounds appears as important challenge, because they could be expected not only to act in the symptomatic effects but also in the underlying molecular etiology of the disease. 22 Therefore, we have designed a series of novel multifunctional compounds by conjugating a tacrine and a benzothiazole (BTA) moiety through different suitable linkers.…”

Tacrine-allyl/propargylcysteine–benzothiazole trihybrids as potential anti-Alzheimer's drug candidates

“…15 The assay solution contained 374 tL of Hepes buffer (50 mM and pH8.0), a variable volume (10- To study the A342 aggregation inhibition, a reported method, based on the fluorescence emission of thioflavin T (ThT), was followed. 16,28,29 It is based on the assumption that …”

“…14,15,16 Very recently, the conjugation of tacrine (TAC) with S-allylcysteine (SAC) and S-propargylcysteine (SPRC), two natural based products with neuroprotective and antioxidant roles (e.g. garlic derivatives), 17,18 resulted in a set of bihybrids (TAC-SAC and TAC-SPRC) with important neuroprotecting properties which, besides the expected AChEI and anti-oxidant properties, presented also inhibitory activity for the self-and Cuinduced Af3 aggregation.…”