Enhanced Recognition Memory through Dual Modulation of Brain Carbonic Anhydrases and Cholinesterases

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.