Azobioisosteres of Curcumin with Pronounced Activity against Amyloid Aggregation,Intracellular Oxidative Stress,and Neuroinflammation |
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Authors: | Julian Hofmann Dr Tiziana Ginex Dr Alba Espargaró Matthias Scheiner Sandra Gunesch Marc Aragó Prof?Dr Christian Stigloher Prof?Dr Raimon Sabaté Prof?Dr F Javier Luque Prof?Dr Michael Decker |
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Institution: | 1. Pharmaceutical and Medicinal Chemistry, Institute of, Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, 97074 Würzburg, Germany;2. Department of Nutrition Food Science and Gastronomy, Faculty of Pharmacy, Institute of Theoretical and Computational, Chemistry and Institute of Biomedicine, Campus Torribera, University of Barcelona, Santa Coloma de Gramenet, 08921 Spain;3. Pharmacy and Pharmaceutical Technology and Physical-Chemistry, School of Pharmacy Institute of Nanoscience and Nanotechnology, (IN2UB), University of Barcelona, 08028 Barcelona, Spain;4. Imaging Core Facility, Biocenter/Theodor-Boveri-Institute, University of Würzburg, Am Hubland, 97074 Würzburg, Germany |
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Abstract: | Many (poly-)phenolic natural products, for example, curcumin and taxifolin, have been studied for their activity against specific hallmarks of neurodegeneration, such as amyloid-β 42 (Aβ42) aggregation and neuroinflammation. Due to their drawbacks, arising from poor pharmacokinetics, rapid metabolism, and even instability in aqueous medium, the biological activity of azobenzene compounds carrying a pharmacophoric catechol group, which have been designed as bioisoteres of curcumin has been examined. Molecular simulations reveal the ability of these compounds to form a hydrophobic cluster with Aβ42, which adopts different folds, affecting the propensity to populate fibril-like conformations. Furthermore, the curcumin bioisosteres exceeded the parent compound in activity against Aβ42 aggregation inhibition, glutamate-induced intracellular oxidative stress in HT22 cells, and neuroinflammation in microglial BV-2 cells. The most active compound prevented apoptosis of HT22 cells at a concentration of 2.5 μm (83 % cell survival), whereas curcumin only showed very low protection at 10 μm (21 % cell survival). |
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Keywords: | amyloid beta bioisosterism natural products neuroprotectivity replica-exchange molecular dynamics |
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