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.

• Klíčová slova
• Alzheimer’s disease, Cholinesterase inhibitor, monoamine oxidase inhibitor, propargyl amines, tacrine,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• Alzheimerova nemoc * farmakoterapie   MeSH
• aminy MeSH
• butyrylcholinesterasa * metabolismus   MeSH
• cholinesterasové inhibitory farmakologie   terapeutické užití   MeSH
• inhibitory MAO farmakologie   MeSH
• lidé MeSH
• ligandy MeSH
• monoaminoxidasa MeSH
• oxidoreduktasy MeSH
• racionální návrh léčiv MeSH
• takrin terapeutické užití   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• aminy MeSH
• butyrylcholinesterasa * MeSH
• cholinesterasové inhibitory MeSH
• inhibitory MAO MeSH
• ligandy MeSH
• monoaminoxidasa MeSH
• oxidoreduktasy MeSH
• takrin MeSH

Alzheimer's disease (AD) is a complex disorder with unknown etiology. Currently, only symptomatic therapy of AD is available, comprising cholinesterase inhibitors and N-methyl-d-aspartate (NMDA) receptor antagonists. Drugs targeting only one pathological condition have generated only limited efficacy. Thus, combining two or more therapeutic interventions into one molecule is believed to provide higher benefit for the treatment of AD. In the presented study, we designed, synthesized, and biologically evaluated 15 novel fluoren-9-amine derivatives. The in silico prediction suggested both the oral availability and permeation through the blood-brain barrier (BBB). An initial assessment of the biological profile included determination of the cholinesterase inhibition and NMDA receptor antagonism at the GluN1/GluN2A and GluN1/GluN2B subunits, along with a low cytotoxicity profile in the CHO-K1 cell line. Interestingly, compounds revealed a selective butyrylcholinesterase (BChE) inhibition pattern with antagonistic activity on the NMDARs. Their interaction with butyrylcholinesterase was elucidated by studying enzyme kinetics for compound 3c in tandem with the in silico docking simulation. The docking study showed the interaction of the tricyclic core of new derivatives with Trp82 within the anionic site of the enzyme in a similar way as the template drug tacrine. From the kinetic analysis, it is apparent that 3c is a competitive inhibitor of BChE.

• Klíčová slova
• Alzheimer’s disease, N-methyl-d-aspartate receptor, acetylcholinesterase, butyrylcholinesterase, fluorene, in silico, in vitro, multi-target directed ligands,
• MeSH
• Alzheimerova nemoc farmakoterapie   enzymologie   genetika   patologie   MeSH
• butyrylcholinesterasa chemie   účinky léků   genetika   MeSH
• CHO buňky MeSH
• cholinesterasové inhibitory chemie   farmakologie   MeSH
• Cricetulus MeSH
• fluoreny chemie   farmakologie   MeSH
• hematoencefalická bariéra účinky léků   MeSH
• inhibitory enzymů farmakologie   MeSH
• lidé MeSH
• počítačová simulace MeSH
• receptory N-methyl-D-aspartátu antagonisté a inhibitory   genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• butyrylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• fluorene MeSH Prohlížeč
• fluoreny MeSH
• inhibitory enzymů MeSH
• N-methyl D-aspartate receptor subtype 2A MeSH Prohlížeč
• NR2B NMDA receptor MeSH Prohlížeč
• receptory N-methyl-D-aspartátu MeSH

Tacrine (THA), the first clinically effective acetylcholinesterase (AChE) inhibitor and the first approved drug for the treatment of Alzheimer's disease (AD), was withdrawn from the market due to its side effects, particularly its hepatotoxicity. Nowadays, THA serves as a valuable scaffold for the design of novel agents potentially applicable for AD treatment. One such compound, namely 7-methoxytacrine (7-MEOTA), exhibits an intriguing profile, having suppressed hepatotoxicity and concomitantly retaining AChE inhibition properties. Another interesting class of AChE inhibitors represents Huprines, designed by merging two fragments of the known AChE inhibitors-THA and (-)-huperzine A. Several members of this compound family are more potent human AChE inhibitors than the parent compounds. The most promising are so-called huprines X and Y. Here, we report the design, synthesis, biological evaluation, and in silico studies of 2-methoxyhuprine that amalgamates structural features of 7-MEOTA and huprine Y in one molecule.

• Klíčová slova
• 2-methoxyhuprine, 7-MEOTA, Alzheimer’s disease, acetylcholinesterase, butyrylcholinesterase, huprine Y, tacrine,
• MeSH
• acetylcholinesterasa MeSH
• aktivace enzymů účinky léků   MeSH
• Alzheimerova nemoc farmakoterapie   MeSH
• aminochinoliny chemická syntéza   chemie   farmakologie   MeSH
• butyrylcholinesterasa MeSH
• cholinesterasové inhibitory chemie   farmakologie   MeSH
• hematoencefalická bariéra metabolismus   MeSH
• heterocyklické sloučeniny tetra- a více cyklické chemie   farmakologie   MeSH
• hydrolýza MeSH
• inhibiční koncentrace 50 MeSH
• katalytická doména MeSH
• lidé MeSH
• molekulární konformace MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• objevování léků * MeSH
• permeabilita MeSH
• racionální návrh léčiv MeSH
• takrin analogy a deriváty   chemie   farmakologie   MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• viabilita buněk účinky léků   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 7-methoxytacrine MeSH Prohlížeč
• acetylcholinesterasa MeSH
• aminochinoliny MeSH
• butyrylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• heterocyklické sloučeniny tetra- a více cyklické MeSH
• huprine Y MeSH Prohlížeč
• takrin MeSH