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

Autor: Nocentini A; Department of NEUROFARBA, Pharmaceutical and Nutraceutical Section, University of Florence, Sesto Fiorentino, Florence 50019, Italy., Costa A; Department of NEUROFARBA, Section of Pharmacology and Toxicology, Laboratory of Ocular and Neuropsychopharmacology (Braeye Lab), University of Florence, Viale Pieraccini 6, Florence 50139, Italy., Bonardi A; Department of NEUROFARBA, Pharmaceutical and Nutraceutical Section, Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Florence, Via U. Schiff 6, Sesto Fiorentino, Florence 50019, Italy., Ammara A; Department of NEUROFARBA, Pharmaceutical and Nutraceutical Section, University of Florence, Sesto Fiorentino, Florence 50019, Italy., Giovannuzzi S; Department of NEUROFARBA, Pharmaceutical and Nutraceutical Section, University of Florence, Sesto Fiorentino, Florence 50019, Italy., Petreni A; Department of NEUROFARBA, Pharmaceutical and Nutraceutical Section, University of Florence, Sesto Fiorentino, Florence 50019, Italy., Bartolucci G; Department of NEUROFARBA, Pharmaceutical and Nutraceutical Section, University of Florence, Sesto Fiorentino, Florence 50019, Italy., Rani B; Department of NEUROFARBA, Section of Pharmacology and Toxicology, Laboratory of Ocular and Neuropsychopharmacology (Braeye Lab), University of Florence, Viale Pieraccini 6, Florence 50139, Italy., Leri M; Department of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Florence, Florence 50134, Italy., Bucciantini M; Department of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Florence, Florence 50134, Italy., Fernández-Bolaños JG; Department of Organic Chemistry, Faculty of Chemistry, University of Seville, Seville 41012, Spain., López Ó; Department of Organic Chemistry, Faculty of Chemistry, University of Seville, Seville 41012, Spain., Passani MB; Department of Health Sciences, Laboratory of Ocular and Neuropsychopharmacology (Braeye Lab), University of Florence, Viale Pieraccini 6, Florence 50139, Italy., Provensi G; Department of NEUROFARBA, Section of Pharmacology and Toxicology, Laboratory of Ocular and Neuropsychopharmacology (Braeye Lab), University of Florence, Viale Pieraccini 6, Florence 50139, Italy., Gratteri P; Department of NEUROFARBA, Pharmaceutical and Nutraceutical Section, Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Florence, Via U. Schiff 6, Sesto Fiorentino, Florence 50019, Italy., Supuran CT; Department of NEUROFARBA, Pharmaceutical and Nutraceutical Section, University of Florence, Sesto Fiorentino, Florence 50019, Italy.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2024 Sep 26; Vol. 67 (18), pp. 16873-16898. Date of Electronic Publication: 2024 Sep 16.
DOI: 10.1021/acs.jmedchem.4c01866
Abstrakt: 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 IC 50 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.
Databáze: MEDLINE