Sanchis_2023_ChemMedChem__e202200691

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-NH(2)) as an interesting scaffold for the development of new anti-AD multitarget-directed drugs. It showed the lowest IC(50)value against hAChE reported for a peptide (0.99 +/- 0.02 micro M) and inhibited 94.2% +/- 1.2 of AChE-induced Aβ aggregation at 10 micro M. Furthermore, it inhibited hBChE (IC(50), 15.44 +/- 0.91 micro M), showed no 'in vivo' toxicity in brine shrimp and had shown moderated radical scavenging and Fe(2+) 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.