LAUSR

The multifactorial nature of Alzheimer’s disease (AD) is now widely recognized, which has increased the interest in compounds that can address more than one AD-associated targets. Herein, we report the inhibitory activity on the human cholinesterases (acetylcholinesterase, hAChE and butyrylcholinesterase, hBChE) and on the AChE-induced β-amyloid peptide (Aβ) aggregation by a series of peptide derivatives designed by mutating aliphatic residues for aromatic ones. We identified peptide W3 (LGWVSKGKLL-NH2) as an interesting scaffold for the development of new anti-AD multitarget-directed drugs. It showed the lowest IC50value against hAChE reported for a peptide (0.99±0.02µM) and inhibited 94.2%±1.2 of AChE-induced Aβ aggregation at 10µM. Furthermore, it inhibited hBChE (IC50, 15.44±0.91µM), showed no in vivo toxicity in brine shrimp and had shown moderated radical scavenging and Fe2+ chelating capabilities in previous studies. The results are in line with multiple reports showing the utility of the indole moiety for the development of cholinesterase inhibitors.