期刊
BIOMOLECULES
卷 11, 期 1, 页码 -出版社
MDPI
DOI: 10.3390/biom11010003
关键词
acetylcholinesterase; Alzheimer’ s disease; butyrylcholinesterase; fluorene; in vitro; in silico; multi-target directed ligands; N-methyl-d-aspartate receptor
资金
- Czech Health Research Council [NU20-08-00296]
- faculty of Military Health Sciences, University of Defence [FVZ201803]
- MH CZ-DRO (University Hospital Hradec Kralove) [00179906]
- European Regional Development Fund: Project PharmaBrain [CZ.02.1.01/0.0/0.0/16_025/0007444]
- project e-Infrastruktura CZ within the program Projects of Large Research, Development and Innovations Infrastructures [e-INFRA LM2018140]
- Charles University [SVV 260 547]
The study designed and evaluated 15 novel fluoren-9-amine derivatives, demonstrating their potential therapeutic efficacy for Alzheimer's disease. These compounds displayed selective inhibition of BChE and antagonistic activity on the NMDA receptors. Enzyme kinetics and docking studies elucidated their interaction with BChE, revealing a competitive inhibitory mechanism.
Alzheimer's disease (AD) is a complex disorder with unknown etiology. Currently, only symptomatic therapy of AD is available, comprising cholinesterase inhibitors and N-methyl-d-aspartate (NMDA) receptor antagonists. Drugs targeting only one pathological condition have generated only limited efficacy. Thus, combining two or more therapeutic interventions into one molecule is believed to provide higher benefit for the treatment of AD. In the presented study, we designed, synthesized, and biologically evaluated 15 novel fluoren-9-amine derivatives. The in silico prediction suggested both the oral availability and permeation through the blood-brain barrier (BBB). An initial assessment of the biological profile included determination of the cholinesterase inhibition and NMDA receptor antagonism at the GluN1/GluN2A and GluN1/GluN2B subunits, along with a low cytotoxicity profile in the CHO-K1 cell line. Interestingly, compounds revealed a selective butyrylcholinesterase (BChE) inhibition pattern with antagonistic activity on the NMDARs. Their interaction with butyrylcholinesterase was elucidated by studying enzyme kinetics for compound 3c in tandem with the in silico docking simulation. The docking study showed the interaction of the tricyclic core of new derivatives with Trp82 within the anionic site of the enzyme in a similar way as the template drug tacrine. From the kinetic analysis, it is apparent that 3c is a competitive inhibitor of BChE.
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