Copper(II) complexation of tacrine hybrids with potential anti-neurodegenerative roles

The complexity and multifactorial nature of neurodegenerative diseases turn quite difficult the development of adequate drugs for their treatment. Multi-target analogues, in conjugation with natural moieties, have been developed in order to combine acetylcholinesterase (AChE) inhibition with antioxidant properties, metal-binding capacity and inhibition of amyloid-β (Aβ) aggregation. Due to the recent interest on natural-based drugs and also the importance of studying the role of transition metal ions in the disease process, we herein evaluate the copper chelating capacity and inhibitory ability for self- and Cu-induced Aβ1-42 aggregation of two nature-base hybrid model compounds obtained from conjugation of a tacrine moiety with a S-allylcystein (1) or S-propargylcystein (2) moiety. Both compounds show a moderate chelating power towards Cu(II) (pCu 7.13-7.51, CL/CCu=10, CCu=10(-6)M, pH7.4), with predominant formation of 1:1 complex species (CuL, CuH-1L) for which the coordination sphere involves the N-amide and the NH2 amine of the cysteine derivative as well as the NH of tacrine. The compounds are able to improve the inhibition of Aβ aggregation in the presence of Cu(II) and this is slightly more relevant for the allyl derivative (1), a stronger copper chelator, than for the propargyl (2). Moreover, the presence of a chloro atom in the tacrine moiety and the size of the chain length between the two NH groups appeared also to improve the inhibition capacity for Aβ aggregation.