Novel Tacrine-Scutellarin Hybrids as Multipotent Anti-Alzheimer’s Agents: Design, Synthesis and Biological Evaluation
| Autor: | Petr Jost, Daniel Jun, Jan Korabecny, Tomas Kucera, Ondrej Soukup, Martina Hrabinova, Eva Mezeiova, Rafael Dolezal, Daniel Kaping, Lubica Muckova, Vendula Sepsova, Katarina Spilovska, Kamil Kuca, Jana Janockova |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
6-chlorotacrine
enzyme inhibitor Pharmaceutical Science Glucuronates 01 natural sciences Article Analytical Chemistry Structure-Activity Relationship chemistry.chemical_compound Alzheimer Disease Drug Discovery medicine Humans Apigenin Physical and Theoretical Chemistry IC50 Butyrylcholinesterase Scutellarin biology 010405 organic chemistry Organic Chemistry Biological activity acetylcholinesterase scutellarin Acetylcholinesterase 0104 chemical sciences Enzyme Activation Molecular Docking Simulation 010404 medicinal & biomolecular chemistry chemistry Biochemistry Blood-Brain Barrier Chemistry (miscellaneous) Docking (molecular) Enzyme inhibitor Drug Design Tacrine biology.protein Molecular Medicine Cholinesterase Inhibitors Alzheimer’s disease butyrylcholinesterase medicine.drug |
| Zdroj: | Molecules; Volume 22; Issue 6; Pages: 1006 Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry |
| ISSN: | 1420-3049 |
| DOI: | 10.3390/molecules22061006 |
| Popis: | A novel series of 6-chlorotacrine-scutellarin hybrids was designed, synthesized and the biological activity as potential anti-Alzheimer’s agents was assessed. Their inhibitory activity towards human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE), antioxidant activity, ability to cross the blood-brain barrier (BBB) and hepatotoxic profile were evaluated in vitro. Among these compounds, hybrid K1383, bearing two methylene tether between two basic scaffolds, was found to be very potent hAChE inhibitor (IC50 = 1.63 nM). Unfortunately, none of the hybrids displayed any antioxidant activity (EC50 ≥ 500 μM). Preliminary data also suggests a comparable hepatotoxic profile with 6-Cl-THA (established on a HepG2 cell line). Kinetic studies performed on hAChE with the most active compound in the study, K1383, pointed out to a mixed, non-competitive enzyme inhibition. These findings were further corroborated by docking studies. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|