title: 7-Methoxytacrine-adamantylamine heterodimers as cholinesterase inhibitors in Alzheimer's disease treatment--synthesis, biological evaluation and molecular modeling studies.
abstract: 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 µM for hAChE and an IC₅₀ value of 0.11 µM 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.
authors: Department of Toxicology, Trebesska 1575, Faculty of Military Health Sciences, University of Defence, 50001 Hradec Kralove, Czech Republic.
authors: Katarina
authors: K
authors: Spilovska
authors: Jan
authors: J
authors: Korabecny
authors: Jan
authors: J
authors: Kral
authors: Anna
authors: A
authors: Horova
authors: Kamil
authors: K
authors: Musilek
authors: Ondrej
authors: O
authors: Soukup
authors: Lucie
authors: L
authors: Drtinova
authors: Zuzana
authors: Z
authors: Gazova
authors: Katarina
authors: K
authors: Siposova
authors: Kamil
authors: K
authors: Kuca
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy*; D000547:Amantadine / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D019281:Dimerization; D057075:Enzyme Assays; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D012015:Reference Standards; D013619:Tacrine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D013890:Thiourea / Q000737:chemistry
chemical_list: D002800:Cholinesterase Inhibitors; D013619:Tacrine; C016222:7-methoxytacrine; D000547:Amantadine; D000110:Acetylcholinesterase; D013890:Thiourea