This study introduces a novel multitargeting strategy that combines carbonic anhydrase (CA) activators and cholinesterase (ChE) inhibitors to enhance cognitive functions. A series of tacrine-based derivatives with amine/amino acid moieties were synthesized and evaluated for their dual activity on brain CA isoforms and ChEs (AChE and BChE). Several derivatives, notably compounds 26, 30, 34, and 40, demonstrated potent CA activation, particularly of hCA II and VII, and strong ChE inhibition with subnanomolar to low nanomolar IC₅₀ values. In vivo studies using a mouse model of social recognition memory showed that these derivatives significantly improved memory consolidation at doses 10–100 times lower than the reference compounds (either alone or in combination). Molecular modeling and ADMET predictions elucidated the compound binding modes and confirmed favorable pharmacokinetic and safety profiles. The findings suggest that dual modulation of CA and ChE activities is a promising strategy for treating cognitive deficits associated with neurodegenerative and psychiatric disorders.

中文翻译：

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通过脑碳酸酐酶和胆碱酯酶的双重调节增强识别记忆


本研究介绍了一种新的多靶向策略，该策略结合了碳酸酐酶 （CA） 激活剂和胆碱酯酶 （ChE） 抑制剂以增强认知功能。合成了一系列具有胺/氨基酸部分的基于他克林的衍生物，并评估了它们对脑 CA 亚型和 ChEs （AChE 和 BChE） 的双重活性。几种衍生物，特别是化合物 26、30、34 和 40，显示出有效的 CA 激活，特别是 hCA II 和 VII，以及亚纳摩尔至低纳摩尔 IC₅₀ 值的强 ChE 抑制。使用社交识别记忆小鼠模型的体内研究表明，这些衍生物在剂量比参考化合物低 10-100 倍（单独或组合）时显着改善了记忆巩固。分子建模和 ADMET 预测阐明了化合物结合模式，并证实了良好的药代动力学和安全性特征。研究结果表明，CA 和 ChE 活性的双重调节是治疗与神经退行性和精神疾病相关的认知缺陷的一种有前途的策略。