Synthesis, pharmacology and molecular docking on multifunctional tacrine-ferulic acid hybrids as cholinesterase inhibitors against Alzheimer’s disease

<p>The cholinergic hypothesis has long been a “polar star” in drug discovery for Alzheimer’s disease (AD), resulting in many small molecules and biological drug candidates. Most of the drugs marketed for AD are cholinergic. Herein, we report our efforts in the discovery of cholinesterases inhibitors (ChEIs) as multi-target-directed ligands. A series of tacrine-ferulic acid hybrids have been designed and synthesised. All these compounds showed potent acetyl-(AChE) and butyryl cholinesterase(BuChE) inhibition. Among them, the optimal compound <b>10g</b>, was the most potent inhibitor against AChE (electrophorus electricus (eeAChE) half maximal inhibitory concentration (IC₅₀) = 37.02 nM), it was also a strong inhibitor against BuChE (equine serum (eqBuChE) IC₅₀ = 101.40 nM). Besides, it inhibited amyloid β-protein self-aggregation by 65.49% at 25 μM. In subsequent <i>in vivo</i> scopolamine-induced AD models, compound <b>10g</b> obviously ameliorated the cognition impairment and showed preliminary safety in hepatotoxicity evaluation. These data suggest compound <b>10g</b> as a promising multifunctional agent in the drug discovery process against AD.</p

Synthesis and bioevaluation of new tacrine-cinnamic acid hybrids as cholinesterase inhibitors against Alzheimer’s disease

<p>Small molecule cholinesterases inhibitor (ChEI) provides an effective therapeutic strategy to treat Alzheimer’s disease (AD). Currently, the discovery of new ChEI with multi-target effect is still of great importance. Herein, we report the synthesis, structure–activity relationship study and biological evaluation of a series of tacrine-cinnamic acid hybrids as new ChEIs. All target compounds are evaluated for their <i>in vitro</i> cholinesterase inhibitory activities. The representatives which show potent activity on cholinesterase, are evaluated for the amyloid β-protein self-aggregation inhibition and <i>in vivo</i> assays. The optimal compound <b>19</b>, <b>27</b>, and <b>30</b> (human AChE IC₅₀ = 10.2 ± 1.2, 16.5 ± 1.7, and 15.3 ± 1.8 nM, respectively) show good performance in ameliorating the scopolamine-induced cognition impairment and preliminary safety in hepatotoxicity evaluation. These compounds deserve further evaluation for the development of new therapeutic agents against AD.</p