Morphing cholinesterase inhibitor amiridine into multipotent drugs for the\ntreatment of Alzheimer’s disease

0584241 - ÚEM 2025 RIV NL eng J - Journal Article
Mezeiová, E. - Prchal, L. - Hrabinová, M. - Mucková, L. - Pulkrabková, L. - Soukup, O. - Misiachna, Anna - Janoušek, J. - Fibigar, J. - Kučera, T. - Horák, Martin - Makhaeva, G.F. - Korabecný, J.
Morphing cholinesterase inhibitor amiridine into multipotent drugs for the
treatment of Alzheimer’s disease.
Biomedicine & Pharmacotherapy. Roč. 173, april. (2024), č. článku 116399. ISSN 0753-3322. E-ISSN 1950-6007
R&D Projects: GA ČR(CZ) GA22-24384S; GA MŠMT(CZ) EH22_008/0004562
Institutional support: RVO:68378041
Keywords : amiridine * acetylcholinesterase * antioxidant capacity * butyrylcholinesterase * multi-target directed ligands * NMDA receptors
OECD category: Neurosciences (including psychophysiology
Impact factor: 7.5, year: 2022
Method of publishing: Open access
https://www.sciencedirect.com/science/article/pii/S075333222400283X?via%3Dihub

The search for novel drugs to address the medical needs of Alzheimer’s disease (AD) is an ongoing process relying
on the discovery of disease-modifying agents. Given the complexity of the disease, such an aim can be pursued by
developing so-called multi-target directed ligands (MTDLs) that will impact the disease pathophysiology more
comprehensively. Herewith, we contemplated the therapeutic efficacy of an amiridine drug acting as a cholinesterase
inhibitor by converting it into a novel class of novel MTDLs. Applying the linking approach, we have
paired amiridine as a core building block with memantine/adamantylamine, trolox, and substituted benzothiazole
moieties to generate novel MTDLs endowed with additional properties like N-methyl-D-aspartate
(NMDA) receptor affinity, antioxidant capacity, and anti-amyloid properties, respectively. The top-ranked
amiridine-based compound 5d was also inspected by in silico to reveal the butyrylcholinesterase binding differences
with its close structural analogue 5b. Our study provides insight into the discovery of novel amiridinebased
drugs by broadening their target-engaged profile from cholinesterase inhibitors towards MTDLs with
potential implications in AD therapy.
Permanent Link: https://hdl.handle.net/11104/0352201