Design, synthesis and multitarget biological profiling of second-generation anti-Alzheimer rhein-huprine hybrids

Francisco Javier Pérez-Areales, Nibal Betari, Antonio Viayna, Caterina Pont, Alba Espargaró, Manuela Bartolini, Angela De Simone, José Fernando Rinaldi Alvarenga, Belén Pérez, Raimon Sabate, Rosa Maria Lamuela-Raventós, Vincenza Andrisano, Francisco Javier Luque, Diego Muñoz-Torrero

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15 Citations (Scopus)

Abstract

© 2017 Future Science Ltd. Aim: Simultaneous modulation of several key targets of the pathological network of Alzheimer's disease (AD) is being increasingly pursued as a promising option to fill the critical gap of efficacious drugs against this condition. Materials & Methods: A short series of compounds purported to hit multiple targets of relevance in AD has been designed, on the basis of their distinct basicities estimated from high-level quantum mechanical computations, synthesized, and subjected to assays of inhibition of cholinesterases, BACE-1, and Aβ42 and tau aggregation, of antioxidant activity, and of brain permeation. Results: Using, as a template, a lead rhein-huprine hybrid with an interesting multitarget profile, we have developed second-generation compounds, designed by the modification of the huprine aromatic ring. Replacement by [1,8]-naphthyridine or thieno[3,2-e]pyridine systems resulted in decreased, although still potent, acetylcholinesterase or BACE-1 inhibitory activities, which are more balanced relative to their Aβ42 and tau antiaggregating and antioxidant activities. Conclusion: Second-generation naphthyridine- and thienopyridine-based rhein-huprine hybrids emerge as interesting brain permeable compounds that hit several crucial pathogenic factors of AD.
Original languageEnglish
Pages (from-to)965-981
JournalFuture Medicinal Chemistry
Volume9
Issue number10
DOIs
Publication statusPublished - 1 Jun 2017

Keywords

  • BACE-1 inhibitors
  • antiaggregating agents
  • anticholinesterasic agents
  • antioxidants
  • molecular hybridization
  • multitarget agents

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    Pérez-Areales, F. J., Betari, N., Viayna, A., Pont, C., Espargaró, A., Bartolini, M., De Simone, A., Rinaldi Alvarenga, J. F., Pérez, B., Sabate, R., Lamuela-Raventós, R. M., Andrisano, V., Luque, F. J., & Muñoz-Torrero, D. (2017). Design, synthesis and multitarget biological profiling of second-generation anti-Alzheimer rhein-huprine hybrids. Future Medicinal Chemistry, 9(10), 965-981. https://doi.org/10.4155/fmc-2017-0049