Bioorganic & medicinal chemistry

Synthesis, biological evaluation and molecular modeling of new tetrahydroacridine derivatives as potential multifunctional agents for the treatment of Alzheimer's disease.

PMID 26242241


A novel series of 9-amino-1,2,3,4-tetrahydroacridine derivatives with 4-dimethylaminobenzoic acid moiety was synthesized and tested towards inhibition of cholinesterases and amyloid β aggregation. Target compounds were designed as dual binding site cholinesterase inhibitors able to bind to both the catalytic and the peripheral site of the enzyme and therefore potentially endowed with other properties. The obtained derivatives were very potent inhibitors of both cholinesterases (EeAChE, EqBChE) with IC50 values ranging from sub-nanomolar to nanomolar range, and the inhibitory potency of the most promising agents was higher than that of the reference drugs (rivastigmine and tacrine). The kinetic studies of the most active compound 3a revealed competitive type of AChE inhibition. Moreover, all target compounds were more potent inhibitors of human AChE than tacrine with the most active compound 3b (IC50 = 19 nM). Compound 3a was also tested and displayed inhibitory potency against AChE-induced Aβ 1-42 aggregation (80.6% and 91.3% at 50 μM and 100 μM screening concentration, respectively). Moreover, cytotoxicity assay performed on A549 cells did not indicate toxicity of this agent. Compound 3a is a promising candidate for further development of novel multi-functional agents in the therapy of AD.

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Acetylthiocholine iodide, ≥99.0% (AT)