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 <b>26</b>, <b>30</b>, <b>34</b>, and <b>40</b>, demonstrated potent CA activation, particularly of hCA II and VII, and strong ChE inhibition with subnanomolar to low nanomolar IC<sub>50</sub> values. <i>In vivo</i> 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.
Authors
- Alessandro Bonardi (ORCID: https://orcid.org/0000-0002-5520-740X)
- Simone Giovannuzzi (ORCID: https://orcid.org/0000-0002-0669-7481)
- Óscar López (ORCID: https://orcid.org/0000-0003-2896-6993)
- Alessia Costa (ORCID: https://orcid.org/0000-0002-3693-3019)
- Alessio Nocentini (ORCID: https://orcid.org/0000-0003-3342-702X)
- Barbara Rani (ORCID: https://orcid.org/0000-0002-5602-7021)
- Maria Beatrice Passani (ORCID: https://orcid.org/0000-0002-7729-9069)
- Andrea Petreni
- Andrea Ammara (ORCID: https://orcid.org/0000-0001-7364-1499)
- Claudiu T. Supuran (ORCID: https://orcid.org/0000-0003-4262-0323)
- Gustavo Provensi (ORCID: https://orcid.org/0000-0002-6182-6848)
- Paola Gratteri (ORCID: https://orcid.org/0000-0002-9137-2509)
- José G. Fernández‐Bolaños (ORCID: https://orcid.org/0000-0003-1499-0650)
- Monica Bucciantini (ORCID: https://orcid.org/0000-0002-5243-9301)
- Gianluca Bartolucci (ORCID: https://orcid.org/0000-0002-5631-8769)
- Manuela Leri (ORCID: https://orcid.org/0000-0002-3785-0805)
Institutions
- University of Florence (IT)
- Universidad de Sevilla (ES)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-09-16
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01866
- Citations
- 7
- Primary Topic
- Cholinesterase and Neurodegenerative Diseases
- Type
- article
- Field-Weighted Citation Impact
- 3.13
Funders
- Junta de Andalucía
- Ministero dell'Università e della Ricerca
- Agencia Estatal de Investigación