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 (IC₅₀ = 3.319 ± 0.708 μM), 5-HT_1A agonist (EC₅₀ = 107 ± 37 nM), and 5-HT reuptake inhibition (IC₅₀ = 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.

中文翻译：

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新型Vilazodone-他克林杂种作为潜在的多靶点定向配体，用于治疗伴有抑郁症的阿尔茨海默氏病：设计，合成和生物学评估

抑郁症是阿尔茨海默氏病（AD）最常见的精神疾病并发症之一，影响多达50％的患者。通过结合维拉唑酮和他克林的药效学特征作为潜在的多靶点定向配体，设计和合成了一系列新的杂合分子，用于治疗抑郁症的AD。进行了体外生物学测定以评估化合物；在30个杂种中，化合物1e在乙酰胆碱酯酶抑制（IC ₅₀ = 3.319±0.708μM），5-HT _1A激动剂（EC ₅₀ = 107±37 nM）和5-HT再摄取抑制（IC ₅₀ = 76.3 ）之间表现出相对平衡的分布±33 nM）。化合物1e显示出可耐受的肝毒性和中等的hERG抑制活性，并且可以在体内穿透血脑屏障。此外，口服30 mg / kg 1e·HCl可以显着改善东pol碱引起的失忆症小鼠的认知功能，并减轻尾部悬吊试验中的抑郁症状。1e的有效性验证了我们设计策略的合理性。