Novel Vilazodone–Tacrine Hybrids as Potential Multitarget-Directed Ligands for the Treatment of Alzheimer’s Disease Accompanied with Depression: Design, Synthesis, and Biological Evaluation

Abstract

Depression is one of the most frequent psychiatric complications of Alzheimer's disease (AD), affecting up to 50% of the patients. A novel series of hybrid molecules were designed and synthesized by combining the pharmacophoric features of vilazodone and tacrine as potential multitarget-directed ligands for the treatment of AD with depression. In vitro biological assays were conducted to evaluate the compounds; among the 30 hybrids, compound 1e showed relatively balanced profiles between acetylcholinesterase inhibition (IC = 3.319 ± 0.708 μM), 5-HT agonist (EC = 107 ± 37 nM), and 5-HT reuptake inhibition (IC = 76.3 ± 33 nM). Compound 1e displayed tolerable hepatotoxicity and moderate hERG inhibition activity, and could penetrate the blood-brain barrier in vivo. Furthermore, an oral intake of 30 mg/kg 1e·HCl could significantly improve the cognitive function of scopolamine-induced amnesia mice and alleviate the depressive symptom in tail suspension test. The effectivity of 1e validates the rationality of our design strategy.

Therapeutic Potential of Multifunctional Tacrine Analogues

“…Li et al . [169] reported synthesis and biological evaluation of vilazodone-tacrine hybrids as potential multitarget-directed compounds for the treatment of AD with depression. The hybrid 14 in the series of 30 compounds showed tolerable hepatotoxicity and satisfactory inhibition of the human Ether-a-go-go-Related Gene (hERG).…”

Multidirectional in vitro and in cellulo studies as a tool for identification of multi-target-directed ligands aiming at symptoms and causes of Alzheimer’s disease

“…The most explored multifunctional ligands combine anticholinesterase activity with anti-aggregation properties resulting from inhibition of b-secretase or modulation of c-secretase and direct inhibition of processes of aggregation of Ab and tau proteins [15][16][17][18] . Also, many G-protein coupled receptors are explored in combination with anticholinesterase activity, among them cannabinoid receptors CB 1 and CB 2 19-22 , histamine H 3 receptors [23][24][25] or serotonin 5-HT 1A 26 , 5-HT 4 , and 5-HT 6 receptors [27][28][29][30][31] . Here, we present the broadened in vitro and in cellulo studies on the activity of the previously published first-in-class multi-target-directed ligands ( Figure 1) targeting serotonergic 5-HT 6 receptors and cholinesterases 30,31 .…”

“…The most explored multifunctional ligands combine anticholinesterase activity with anti-aggregation properties resulting from inhibition of β-secretase or modulation of γ-secretase and direct inhibition of processes of aggregation of Aβ and tau proteins 15–18 . Also, many G-protein coupled receptors are explored in combination with anticholinesterase activity, among them cannabinoid receptors CB 1 and CB 2 19–22 , histamine H 3 receptors 23–25 or serotonin 5-HT 1A 26 , 5-HT 4 , and 5-HT 6 receptors 27–31 .…”

Design and Synthesis of Novel Hybrid 8-Hydroxy Quinoline-Indole Derivatives as Inhibitors of Aβ Self-Aggregation and Metal Chelation-Induced Aβ Aggregation

“…Unfortunately, there is currently no means to cure or even slow the progression of AD [ 6 ], spurring increased efforts to develop more effective drugs to prevent or treat AD. Due to the complexity of AD and the multitude of factors potentially involved in its progression, a strategy that uses multi-target directed ligands (MTDLs) has drawn much attention as a mainstream therapeutic approach for treatment of this disease [ 7 , 8 , 9 , 10 , 11 ].…”