Design, synthesis, molecular modeling and neuroprotective effects of a new framework of cholinesterase inhibitors for Alzheimer’s disease

Background: Currently approved Alzheimer’s disease medications mainly comprise acetylcholinesterase inhibitors. Many of these inhibitors are either natural compounds or synthetic molecules inspired in natural compounds. Hybrid molecules that can interact with different target sites of the enzyme could lead to the discovery of effective multitarget drugs. Objective: To design, synthesize, and evaluate a series of new aza-resveratrol analogs as in vitro acetyl- and butyrylcholinesterase inhibitors. Methods: The synthesis is achieved by a simple and efficient microwave-assisted method, from commercially available starting materials. Compounds are designed as hybrids of an aza-stilbene nucleus (Schiff base) connected to a tertiary amine by a hydrocarbon chain of variable length, designed to interact both with the peripheric anionic site and the catalytic site of the enzyme. Results: All the derivatives inhibit both enzymes in a concentration-dependent manner, acting as moderate to potent cholinesterase inhibitors. The most potent inhibitors are compounds 12b (IC50 = 0.43 μM) and 12a (IC50 = 0.31 μM) for acetyl- and butyrylcholinesterase, respectively. Compounds 12a and 12b also exhibit significant acetylcholinesterase inhibition in SH-SY5Y human neuroblastoma cells without cytotoxic properties. Enzyme kinetic studies and molecular modeling reveal that inhibitor 12b targets both the catalytic active site and the peripheral anionic site of acetylcholinesterase what makes it able to modulate the self-induced β-amyloid aggregation. Furthermore, the molecular modeling analysis helps to assess the impact of the linker length in the inhibitory activity of this family of new cholinesterase inhibitors. Conclusion: These compounds have the potential to serve as a dual binding site inhibitor and might provide a useful template for the development of new anti-Alzheimer’s disease agents.

Download Full-text

Five-Membered-Ring-Fused Tacrines as Anti-Alzheimer’s Disease Agents

Synlett ◽

10.1055/s-0040-1719823 ◽

2021 ◽

Author(s):

Maria do Carmo Carreiras ◽

José Marco-Contelles

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cell Viability ◽

Therapeutic Agents ◽

Membered Ring ◽

Biological Assessment ◽

Ache Inhibitor ◽

Neuroprotective Effects ◽

Design Synthesis ◽

Self Aggregation

AbstractOur endeavors in the design, synthesis, and biological assessment of five-membered-ring-fused tacrines as potential therapeutic agents for Alzheimer’s disease are summarized. Particularly, we have identified racemic 4-(2-methoxyphenyl)-3-methyl-2,4,6,7,8,9-hexahydropyrazolo[4′,3′:5,6]pyrano[2,3-b]quinolin-5-amine, a pyranopyrazolotacrine, as having the best nontoxic profile at the highest concentrations used (300 μM); this allows cell viability, is less hepatotoxic than tacrine, and is a potent noncompetitive AChE inhibitor (IC50 = 1.52 ± 0.49 μM). It is able to completely inhibit the EeAChE-induced Aβ1–40 aggregation in a statistically significant manner without affecting the Aβ1–40 self-aggregation at 25 μM, and shows strong neuroprotective effects (EC50 = 0.82 ± 0.17 μM).1 Introduction2 Furo-, Thieno-, and Pyrrolotacrines3 Pyrazolo-, Oxazolo-, and Isoxazolotacrines4 Indolotacrines5 Pyrano- and Pyridopyrazolotacrines6 Conclusions and Outlook

Download Full-text