Novel thienocycloalkylpyridazinones as useful scaffolds for acetylcholinesterase inhibition and serotonin 5-HT6 receptor interaction
A library of eighteen thienocycloalkylpyridazinones was synthesized for human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBChE) inhibition and serotonin 5-HT6 receptor subtype interaction by following a multitarget-directed ligand approach (MTDL), as a suitable strategy for treatment of...
| Autores: | , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Fecha de publicación: | 2023 |
| País: | España |
| Institución: | Universidad de Santiago de Compostela (USC) |
| Repositorio: | Minerva. Repositorio Institucional de la Universidad de Santiago de Compostela |
| Idioma: | inglés |
| OAI Identifier: | oai:minerva.usc.gal:10347/45856 |
| Acceso en línea: | https://hdl.handle.net/10347/45856 |
| Access Level: | acceso abierto |
| Palabra clave: | Acetylcholinesterase inhibitors 5-HT6 receptor ligands Multitarget-directed ligands Alzheimer’s disease Thienocycloalkylpyridazinone derivatives |
| Sumario: | A library of eighteen thienocycloalkylpyridazinones was synthesized for human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBChE) inhibition and serotonin 5-HT6 receptor subtype interaction by following a multitarget-directed ligand approach (MTDL), as a suitable strategy for treatment of Alzheimer’s disease (AD). The novel compounds featured a tricyclic scaffold, namely thieno[3,2-h]cinnolinone, thienocyclopentapyridazinone and thienocycloheptapyridazinone, connected through alkyl chains of variable length to proper amine moieties, most often represented by N-benzylpiperazine or 1-(phenylsulfonyl)-4-(piperazin-1-ylmethyl)-1H-indole as structural elements addressing AChE and 5-HT6 interaction, respectively. Our study highlighted the versatility of thienocycloalkylpyridazinones as useful architectures for AChE interaction, with several N-benzylpiperazine-based analogues emerging as potent and selective hAChE inhibitors with IC50 in the 0.17–1.23 μM range, exhibiting low to poor activity for hBChE (IC50 = 4.13–9.70 μM). The introduction of 5-HT6 structural moiety phenylsulfonylindole in place of N-benzylpiperazine, in tandem with a pentamethylene linker, gave potent 5-HT6 thieno[3,2-h]cinnolinone and thienocyclopentapyridazinone-based ligands both displaying hAChE inhibition in the low micromolar range and unappreciable activity towards hBChE. While docking studies provided a rational structural explanation for AChE/BChE enzyme and 5-HT6 receptor interaction, in silico prediction of ADME properties of tested compounds suggested further optimization for development of such compounds in the field of MTDL for AD |
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