About: 7-Methoxytacrine-Adamantylamine Heterodimers as Cholinesterase Inhibitors in Alzheimer's Disease Treatment - Synthesis, Biological Evaluation and Molecular Modeling Studies     Goto   Sponge   Distinct   Permalink

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Description
  • A structural series of 7-MEOTA-adamantylamine thioureas was designed, synthesized and evaluated as inhibitors of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE). The compounds were prepared based on the multi-target-directed ligand strategy with different linker lengths (n = 2-8) joining the well-known NMDA antagonist adamantine and the hAChE inhibitor 7-methoxytacrine (7-MEOTA). Based on in silico studies, these inhibitors proved dual binding site character capable of simultaneous interaction with the peripheral anionic site (PAS) of hAChE and the catalytic active site (CAS). Clearly, these structural derivatives exhibited very good inhibitory activity towards hBChE resulting in more selective inhibitors of this enzyme. The most potent cholinesterase inhibitor was found to be thiourea analogue 14 (with an IC50 value of 0.47 mu M for hAChE and an IC50 value of 0.11 mu M for hBChE, respectively). Molecule 14 is a suitable novel lead compound for further evaluation proving that the strategy of dual binding site inhibitors might be a promising direction for development of novel AD drugs.
  • A structural series of 7-MEOTA-adamantylamine thioureas was designed, synthesized and evaluated as inhibitors of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE). The compounds were prepared based on the multi-target-directed ligand strategy with different linker lengths (n = 2-8) joining the well-known NMDA antagonist adamantine and the hAChE inhibitor 7-methoxytacrine (7-MEOTA). Based on in silico studies, these inhibitors proved dual binding site character capable of simultaneous interaction with the peripheral anionic site (PAS) of hAChE and the catalytic active site (CAS). Clearly, these structural derivatives exhibited very good inhibitory activity towards hBChE resulting in more selective inhibitors of this enzyme. The most potent cholinesterase inhibitor was found to be thiourea analogue 14 (with an IC50 value of 0.47 mu M for hAChE and an IC50 value of 0.11 mu M for hBChE, respectively). Molecule 14 is a suitable novel lead compound for further evaluation proving that the strategy of dual binding site inhibitors might be a promising direction for development of novel AD drugs. (en)
Title
  • 7-Methoxytacrine-Adamantylamine Heterodimers as Cholinesterase Inhibitors in Alzheimer's Disease Treatment - Synthesis, Biological Evaluation and Molecular Modeling Studies
  • 7-Methoxytacrine-Adamantylamine Heterodimers as Cholinesterase Inhibitors in Alzheimer's Disease Treatment - Synthesis, Biological Evaluation and Molecular Modeling Studies (en)
skos:prefLabel
  • 7-Methoxytacrine-Adamantylamine Heterodimers as Cholinesterase Inhibitors in Alzheimer's Disease Treatment - Synthesis, Biological Evaluation and Molecular Modeling Studies
  • 7-Methoxytacrine-Adamantylamine Heterodimers as Cholinesterase Inhibitors in Alzheimer's Disease Treatment - Synthesis, Biological Evaluation and Molecular Modeling Studies (en)
skos:notation
  • RIV/00216208:11160/13:10133341!RIV14-MSM-11160___
http://linked.open...avai/riv/aktivita
http://linked.open...avai/riv/aktivity
  • I, P(EE2.3.30.0012), P(GAP303/11/1907), S
http://linked.open...iv/cisloPeriodika
  • 2
http://linked.open...vai/riv/dodaniDat
http://linked.open...aciTvurceVysledku
http://linked.open.../riv/druhVysledku
http://linked.open...iv/duvernostUdaju
http://linked.open...titaPredkladatele
http://linked.open...dnocenehoVysledku
  • 119966
http://linked.open...ai/riv/idVysledku
  • RIV/00216208:11160/13:10133341
http://linked.open...riv/jazykVysledku
http://linked.open.../riv/klicovaSlova
  • butyrylcholinesterase; acetylcholinesterase; Alzheimer's disease; inhibitor; amantadine; 7-MEOTA (en)
http://linked.open.../riv/klicoveSlovo
http://linked.open...odStatuVydavatele
  • CH - Švýcarská konfederace
http://linked.open...ontrolniKodProRIV
  • [466229313277]
http://linked.open...i/riv/nazevZdroje
  • Molecules
http://linked.open...in/vavai/riv/obor
http://linked.open...ichTvurcuVysledku
http://linked.open...cetTvurcuVysledku
http://linked.open...vavai/riv/projekt
http://linked.open...UplatneniVysledku
http://linked.open...v/svazekPeriodika
  • 18
http://linked.open...iv/tvurceVysledku
  • Drtinová, Lucie
  • Kuča, Kamil
  • Musílek, Kamil
  • Král, Jan
  • Soukup, Ondřej
  • Korábečný, Jan
  • Horová, Anna
  • Špilovská, Katarína
  • Gažová, Zuzana
  • Šipošová, Katarína
http://linked.open...ain/vavai/riv/wos
  • 000315400600078
issn
  • 1420-3049
number of pages
http://bibframe.org/vocab/doi
  • 10.3390/molecules18022397
http://localhost/t...ganizacniJednotka
  • 11160
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