1. Tacrine - Benzothiazoles: Novel class of potential multitarget anti-Alzheimeŕs drugs dealing with cholinergic, amyloid and mitochondrial systems
- Author
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Jana Janockova, Jana Kubackova, Karel Vales, Petr Jost, João Pina, Zuzana Bednarikova, Jan Korabecny, Katarina Motykova, Eugenie Nepovimova, Luísa Cortes, Zofia Chrienova, Kamil Musilek, Carlos Serpa, Rafael Dolezal, Lucie Svobodova, Lucie Junova, Laura Aitken, Vendula Hepnarova, Martin Vališ, Katarina Chalupova, Ondrej Soukup, Danijela Rostohar, Marketa Chvojkova, Daniel Jun, Lubica Muckova, Catarina S. H. Jesus, Zuzana Gazova, Kamil Kuca, Rebecca E. Hughes, and Tomas Kucera
- Subjects
Amyloid ,Cholinergic Agents ,Pharmacology ,01 natural sciences ,Biochemistry ,chemistry.chemical_compound ,Protein Aggregates ,Structure-Activity Relationship ,In vivo ,Alzheimer Disease ,Drug Discovery ,medicine ,Humans ,Benzothiazoles ,Enzyme Inhibitors ,Molecular Biology ,IC50 ,Amyloid beta-Peptides ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Organic Chemistry ,3-Hydroxyacyl CoA Dehydrogenases ,Acetylcholinesterase ,In vitro ,0104 chemical sciences ,Mitochondria ,010404 medicinal & biomolecular chemistry ,Neuroprotective Agents ,Benzothiazole ,chemistry ,Tacrine ,Cholinergic ,medicine.drug - Abstract
A series of tacrine – benzothiazole hybrids incorporate inhibitors of acetylcholinesterase (AChE), amyloid β (Aβ) aggregation and mitochondrial enzyme ABAD, whose interaction with Aβ leads to mitochondrial dysfunction, into a single molecule. In vitro, several of 25 final compounds exerted excellent anti-AChE properties and interesting capabilities to block Aβ aggregation. The best derivative of the series could be considered 10w that was found to be highly potent and selective towards AChE with the IC50 value in nanomolar range. Moreover, the same drug candidate exerted absolutely the best results of the series against ABAD, decreasing its activity by 23% at 100 µM concentration. Regarding the cytotoxicity profile of highlighted compound, it roughly matched that of its parent compound – 6-chlorotacrine. Finally, 10w was forwarded for in vivo scopolamine-induced amnesia experiment consisting of Morris Water Maze test, where it demonstrated mild procognitive effect. Taking into account all in vitro and in vivo data, highlighted derivative 10w could be considered as the lead structure worthy of further investigation.
- Published
- 2020