In:
Future Medicinal Chemistry, Future Science Ltd, Vol. 13, No. 9 ( 2021-05), p. 785-804
Abstract:
The authors report on the synthesis and biological evaluation of new compounds whose structure combines tacrine and indole moieties. Tacrine–indole heterodimers were designed to inhibit cholinesterases and β-amyloid formation, and to cross the blood–brain barrier. The most potent new acetylcholinesterase inhibitors were compounds 3c and 4d (IC 50 = 25 and 39 nM, respectively). Compound 3c displayed considerably higher selectivity for acetylcholinesterase relative to human plasma butyrylcholinesterase in comparison to compound 4d (selectivity index: IC 50 [butyrylcholinesterase]/IC 50 [acetylcholinesterase] = 3 and 0.6, respectively). Furthermore, compound 3c inhibited β-amyloid-dependent amyloid nucleation in the yeast-based prion nucleation assay and displayed no dsDNA destabilizing interactions with DNA. Compounds 3c and 4d displayed a high probability of crossing the blood–brain barrier. The results support the potential of 3c for future development as a dual-acting therapeutic agent in the prevention and/or treatment of Alzheimer's disease.
Type of Medium:
Online Resource
ISSN:
1756-8919
,
1756-8927
DOI:
10.4155/fmc-2020-0184
Language:
English
Publisher:
Future Science Ltd
Publication Date:
2021
SSG:
15,3