Enhanced Recognition\nMemory through Dual Modulation\nof Brain Carbonic Anhydrases and Cholinesterases

This study introduces a novel multitargeting strategy\nthat combines\ncarbonic anhydrase (CA) activators and cholinesterase (ChE) inhibitors\nto enhance cognitive functions. A series of tacrine-based derivatives\nwith amine/amino acid moieties were synthesized and evaluated for\ntheir dual activity on brain CA isoforms and ChEs (AChE and BChE).\nSeveral derivatives, notably compounds <b>26</b>, <b>30</b>, <b>34</b>, and <b>40</b>, demonstrated potent CA activation,\nparticularly of hCA II and VII, and strong ChE inhibition with subnanomolar\nto low nanomolar IC<sub>50</sub> values. <i>In vivo</i> studies\nusing a mouse model of social recognition memory showed that these\nderivatives significantly improved memory consolidation at doses 10–100\ntimes lower than the reference compounds (either alone or in combination).\nMolecular modeling and ADMET predictions elucidated the compound binding\nmodes and confirmed favorable pharmacokinetic and safety profiles.\nThe findings suggest that dual modulation of CA and ChE activities\nis a promising strategy for treating cognitive deficits associated\nwith neurodegenerative and psychiatric disorders.