Different Mannich base derivatives have been studied with the aim of addressing the poor aqueous solubility of the recently disclosed 6‐phenethyl‐2,3,4,5‐tetrahydroazepino[4,3‐b]indol‐1(6H)‐one (1), a human butyrylcholinesterase inhibitor (hBChE, IC₅₀13 nM) and protective agent in NMDA‐induced neurotoxicity, in in vivo assays. The N‐(4‐methylpiperazin‐1‐yl)methyl derivative 2 c showed a 50‐fold increase in solubility in pH 7.4‐buffered solution, high stability in serum and (half‐life >24 h) and rapid (<3 min) conversion to 1 at acidic pH. Although less active than 1, 2 c retained moderate hBChE inhibition (IC₅₀=3.35 μM) and a significant protective effect against NMDA‐induced neurotoxicity at 0.1 μM. Moreover, 2 c resulted a weaker serum albumin binder than 1, could pass the blood–brain barrier, and exerted negligible cytotoxicity on HepG2 cells. These findings suggest that 2 c could be a water‐soluble prodrug candidate of 1 for oral administration or a slow‐release injectable derivative in in vivoAlzheimer's disease models.

中文翻译：

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2,3,4,5-四氢氮杂[4,3-b]indol-1(6H)-one水溶性曼尼希碱前药作为阿尔茨海默病多靶点靶向药物的评价

已经研究了不同的曼尼希碱衍生物，目的是解决最近公开的 6-苯乙基-2,3,4,5-四氢氮杂[4,3 - b ]indol-1(6 H )-one ( 1 )，一种人丁酰胆碱酯酶抑制剂 (hBChE，IC ₅₀ 13 nM) 和 NMDA 诱导的神经毒性保护剂，在体内试验中。所述ñ - （4-甲基哌嗪-1-基）甲基衍生物2 C显示在pH 7.4的缓冲溶液中的溶解度为50倍的增加，在血清中高稳定性和（半衰期> 24小时）和快速（<3分钟)在酸性 pH 值下转化为1。虽然不如1 , 2 c活跃保留了中度 hBChE 抑制（IC ₅₀ = 3.35 μM），并在 0.1 μM 时对 NMDA 诱导的神经毒性具有显着的保护作用。此外，2 c导致比1 更弱的血清白蛋白结合物，可以通过血脑屏障，对 HepG2 细胞的细胞毒性可以忽略不计。这些结果表明，2 C可能是一个水溶性前药的候选1用于口服给药或缓释注射衍生物在体内阿尔茨海默氏病的模型。