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Novel tacrine-based multi-target directed Ligands: Enhancing cholinesterase inhibition, NMDA receptor antagonism, and CNS bioavailability for Alzheimer's disease treatment

B. Svobodova, Z. Moravcova, A. Misiachna, G. Novakova, A. Marek, V. Finger, J. Odvarkova, J. Pejchal, JZ. Karasova, J. Netolicky, M. Ladislav, M. Hrabinova, A. Sorf, L. Muckova, L. Fikejzlova, M. Benkova, M. Novak, L. Prchal, J. Capek, J. Handl,...

. 2025 ; 292 (-) : 117678. [pub] 20250422

Language English Country France

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc25015115

Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder for which current treatments provide only symptomatic relief, primarily through cholinesterase (ChE) inhibition and N-methyl-d-aspartate receptor (NMDAR) antagonism. To improve therapeutic efficacy and safety, we designed and synthesized 16 novel tacrine derivatives modified at position 7 with various (hetero)aryl groups or deuterium substitution. Initially, in silico screening predicted favorable CNS permeability and oral bioavailability. Subsequent in vitro evaluations demonstrated significant inhibitory potency against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with derivatives 5i and 5m displaying particularly promising profiles. Metabolic stability assessed using human liver microsomes revealed enhanced stability for compound 5e, whereas 5i and 5m underwent rapid metabolism. Notably, compound 7 showed improved metabolic stability attributed to deuterium incorporation. The newly synthesized compounds were further tested for antagonistic activity on the GluN1/GluN2B subtype of NMDAR, with compound 5m exhibiting the most potent and voltage-independent inhibition. The ability of these compounds to permeate the blood-brain barrier (BBB) was confirmed through in vitro PAMPA assays. In preliminary hepatotoxicity screening (HepG2 cells), most derivatives exhibited higher cytotoxicity than tacrine, emphasizing the ongoing challenge in hepatotoxicity management. Based on its overall favorable profile, compound 5m advanced to in vivo pharmacokinetic studies in mice, demonstrating efficient CNS penetration, with brain concentrations exceeding plasma levels (brain-to-plasma ratio 2.36), indicating active transport across the BBB. These findings highlight compound 5m as a promising tacrine-based multi-target-directed ligand, supporting further preclinical development as a potential therapeutic candidate for AD.

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$a Svobodova, Barbora $u Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic; Department of Toxicology and Military Pharmacy, Military Faculty of Medicine, University of Defence, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic
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$a Novel tacrine-based multi-target directed Ligands: Enhancing cholinesterase inhibition, NMDA receptor antagonism, and CNS bioavailability for Alzheimer's disease treatment / $c B. Svobodova, Z. Moravcova, A. Misiachna, G. Novakova, A. Marek, V. Finger, J. Odvarkova, J. Pejchal, JZ. Karasova, J. Netolicky, M. Ladislav, M. Hrabinova, A. Sorf, L. Muckova, L. Fikejzlova, M. Benkova, M. Novak, L. Prchal, J. Capek, J. Handl, T. Rousar, KE. Greber, K. Ciura, M. Horak, O. Soukup, J. Korabecny
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$a Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder for which current treatments provide only symptomatic relief, primarily through cholinesterase (ChE) inhibition and N-methyl-d-aspartate receptor (NMDAR) antagonism. To improve therapeutic efficacy and safety, we designed and synthesized 16 novel tacrine derivatives modified at position 7 with various (hetero)aryl groups or deuterium substitution. Initially, in silico screening predicted favorable CNS permeability and oral bioavailability. Subsequent in vitro evaluations demonstrated significant inhibitory potency against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with derivatives 5i and 5m displaying particularly promising profiles. Metabolic stability assessed using human liver microsomes revealed enhanced stability for compound 5e, whereas 5i and 5m underwent rapid metabolism. Notably, compound 7 showed improved metabolic stability attributed to deuterium incorporation. The newly synthesized compounds were further tested for antagonistic activity on the GluN1/GluN2B subtype of NMDAR, with compound 5m exhibiting the most potent and voltage-independent inhibition. The ability of these compounds to permeate the blood-brain barrier (BBB) was confirmed through in vitro PAMPA assays. In preliminary hepatotoxicity screening (HepG2 cells), most derivatives exhibited higher cytotoxicity than tacrine, emphasizing the ongoing challenge in hepatotoxicity management. Based on its overall favorable profile, compound 5m advanced to in vivo pharmacokinetic studies in mice, demonstrating efficient CNS penetration, with brain concentrations exceeding plasma levels (brain-to-plasma ratio 2.36), indicating active transport across the BBB. These findings highlight compound 5m as a promising tacrine-based multi-target-directed ligand, supporting further preclinical development as a potential therapeutic candidate for AD.
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$a Moravcova, Zuzana $u Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Kralove, Charles University, Akademika Heyrovskeho 1203, 50005, Hradec Kralove, Czech Republic
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$a Misiachna, Anna $u Department of Neurochemistry, Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 20, Prague, Czech Republic; Department of Physiology, Faculty of Science, Charles University in Prague, Albertov 6, Prague 2, 12843, Czech Republic
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$a Novakova, Gabriela $u Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo nam. 2, Prague 6, 166 10, Czech Republic
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$a Marek, Ales $u Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo nam. 2, Prague 6, 166 10, Czech Republic
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$a Finger, Vladimir $u Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic
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$a Odvarkova, Jitka $u Department of Toxicology and Military Pharmacy, Military Faculty of Medicine, University of Defence, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic
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$a Netolicky, Jakub $u Department of Neurochemistry, Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 20, Prague, Czech Republic; Department of Physiology, Faculty of Science, Charles University in Prague, Albertov 6, Prague 2, 12843, Czech Republic
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$a Ladislav, Marek $u Department of Neurochemistry, Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 20, Prague, Czech Republic; Department of Physiology, Faculty of Science, Charles University in Prague, Albertov 6, Prague 2, 12843, Czech Republic
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$a Hrabinova, Martina $u Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic; Department of Toxicology and Military Pharmacy, Military Faculty of Medicine, University of Defence, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic
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$a Benkova, Marketa $u Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic
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$a Novak, Martin $u Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic
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$a Capek, Jan $u Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentska 573, 532 10, Pardubice, Czech Republic
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$a Handl, Jiri $u Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentska 573, 532 10, Pardubice, Czech Republic
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$a Greber, Katarzyna Ewa $u Department of Physical Chemistry, Faculty of Pharmacy, Medical University of Gdansk, Aleja Generała Jozefa Hallera 107, 80-416, Gdansk, Poland
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