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 amiridine-based drugs by broadening their target-engaged profile from cholinesterase inhibitors towards MTDLs with potential implications in AD therapy.

Charles University Prague Department of Physiology Faculty of Science Albertov 6 Prague 2 Czech Republic

Institute of Experimental Medicine of the Czech Academy of Sciences Department of Neurochemistry Videnska 1083 Prague 14220 Czech Republic

Russian Academy of Sciences Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry Severny proezd 1 Chernogolovka 142432 Russia

University Hospital Hradec Kralove Biomedical Research Centre Sokolska 581 Hradec Kralove 500 05 Czech Republic

University of Defence Military Faculty of Medicine Department of Toxicology and Military Pharmacy Trebesska 1575 Hradec Kralove 500 01 Czech Republic

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