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Privileged multi-target directed propargyl-tacrines combining cholinesterase and monoamine oxidase inhibition activities

Z. Chrienova, E. Nepovimova, R. Andrys, R. Dolezal, J. Janockova, L. Muckova, L. Fabova, O. Soukup, P. Oleksak, M. Valis, J. Korabecny, J. Marco-Contelles, K. Kuca

. 2022 ; 37 (1) : 2605-2620. [pub] -

Language English Country England, Great Britain

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc22024165

Twenty-four novel compounds bearing tetrahydroacridine and N-propargyl moieties have been designed, synthesised, and evaluated in vitro for their anti-cholinesterase and anti-monoamine oxidase activities. Propargyltacrine 23 (IC50 = 21 nM) was the most potent acetylcholinesterase (AChE) inhibitor, compound 20 (IC50 = 78 nM) showed the best inhibitory human butyrylcholinesterase (hBChE) profile, and ligand 21 afforded equipotent and significant values on both ChEs (human AChE [hAChE]: IC50 = 0.095 ± 0.001 μM; hBChE: IC50 = 0.093 ± 0.003 μM). Regarding MAO inhibition, compounds 7, 15, and 25 demonstrated the highest inhibitory potential towards hMAO-B (IC50 = 163, 40, and 170 nM, respectively). In all, compounds 7, 15, 20, 21, 23, and 25 exhibiting the most balanced pharmacological profile, were submitted to permeability and cell viability tests. As a result, 7-phenoxy-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydroacridin-9-amine hydrochloride (15) has been identified as a permeable agent that shows a balanced pharmacological profile [IC50 (hAChE) = 1.472 ± 0.024 μM; IC50 (hBChE) = 0.659 ± 0.077 μM; IC50 (hMAO-B) = 40.39 ± 5.98 nM], and consequently, as a new hit-ligand that deserves further investigation, in particular in vivo analyses, as the preliminary cell viability test results reported here suggest that this is a relatively safe therapeutic agent.

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$a Chrienova, Zofia $u Department of Chemistry, Faculty of Science, University of Hradec Kralove, Hradec Kralove, Czech Republic
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$a Twenty-four novel compounds bearing tetrahydroacridine and N-propargyl moieties have been designed, synthesised, and evaluated in vitro for their anti-cholinesterase and anti-monoamine oxidase activities. Propargyltacrine 23 (IC50 = 21 nM) was the most potent acetylcholinesterase (AChE) inhibitor, compound 20 (IC50 = 78 nM) showed the best inhibitory human butyrylcholinesterase (hBChE) profile, and ligand 21 afforded equipotent and significant values on both ChEs (human AChE [hAChE]: IC50 = 0.095 ± 0.001 μM; hBChE: IC50 = 0.093 ± 0.003 μM). Regarding MAO inhibition, compounds 7, 15, and 25 demonstrated the highest inhibitory potential towards hMAO-B (IC50 = 163, 40, and 170 nM, respectively). In all, compounds 7, 15, 20, 21, 23, and 25 exhibiting the most balanced pharmacological profile, were submitted to permeability and cell viability tests. As a result, 7-phenoxy-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydroacridin-9-amine hydrochloride (15) has been identified as a permeable agent that shows a balanced pharmacological profile [IC50 (hAChE) = 1.472 ± 0.024 μM; IC50 (hBChE) = 0.659 ± 0.077 μM; IC50 (hMAO-B) = 40.39 ± 5.98 nM], and consequently, as a new hit-ligand that deserves further investigation, in particular in vivo analyses, as the preliminary cell viability test results reported here suggest that this is a relatively safe therapeutic agent.
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$a Nepovimova, Eugenie $u Department of Chemistry, Faculty of Science, University of Hradec Kralove, Hradec Kralove, Czech Republic $1 https://orcid.org/000000030281246X
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$a Andrys, Rudolf $u Department of Chemistry, Faculty of Science, University of Hradec Kralove, Hradec Kralove, Czech Republic
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$a Muckova, Lubica $u Biomedical Research Centre and Department of Neurology, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic $u Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Hradec Kralove, Czech Republic $1 https://orcid.org/0000000166936061
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$a Fabova, Lenka $u Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Republic
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$a Valis, Martin $u Biomedical Research Centre and Department of Neurology, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic $u Faculty of Medicine in Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Republic
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$a Korabecny, Jan $u Biomedical Research Centre and Department of Neurology, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic $u Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Hradec Kralove, Czech Republic
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$a Marco-Contelles, José $u Institute of General Organic Chemistry (CSIC), Laboratory of Medicinal Chemistry, Madrid, Spain
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