Novel tetrahydroacridine derivatives with iodobenzoic acid moiety as multifunctional acetylcholinesterase inhibitors

Abstract

New synthesized series of 9-amino-1,2,3,4-tetrahydroacridine derivatives with iodobenzoic acid moiety were studied for their inhibitory activity towards cholinesterase and against β-amyloid aggregation. All novel molecules 3a-3i interacted with both cholinesterases – acetylcholinesterase and butyrylcholinesterase, delivered nanomolar IC₅₀ values. The structure-activity relationship showed that N-butyl moiety derivatives are stronger inhibitors towards AChE and BuChE than N-ethyl and N-propyl moieties compounds. The most potent compound towards acetylcholinesterase was inhibitor 3f (IC₅₀ = 31.2 nM) and it was more active than reference drug, tacrine (IC₅₀ = 100.2 nM). Compound 3f showed strong inhibition of butyrylcholinesterase (IC₅₀ = 8.0 nM), also higher than tacrine (IC₅₀ = 16.3 nM). In the kinetic studies, compound 3f revealed mixed type of acetylcholinesterase inhibition. The computer modeling was carried out. The most active compound 3f was confirmed as peripheral anionic site inhibitor of acetylcholinesterase. Moreover, molecule 3f inhibited β-amyloid aggregation (at the concentration 10 μM – 24.96% of inhibition, 25 μM – 72%, 50 μM – 78.44% and 100 μM – 84.92%). Therefore, among all examined, compound 3f is the most promising molecule for further, more detailed research of novel multi-functional agents in the therapy of Alzheimer's disease.

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New synthesized series of 9-amino-1,2,3,4-tetrahydroacridine derivatives with iodobenzoic acid moiety were studied for their inhibitory activity towards cholinesterase and against β-amyloid aggregation. All novel molecules interacted with both cholinesterases – acetylcholinesterase and butyrylcholinesterase, delivered nanomolar IC₅₀ values. The structure-activity relationship showed that N-butyl moiety derivatives are stronger inhibitors towards AChE and BChE than N-ethyl and N-propyl moieties compounds.

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