| Autor: |
Poliseno V; Department of Pharmacy and Pharmaceutical Sciences, University of Bari 'A. Moro', via E. Orabona 4, 70125 Bari, Italy.; Centro de Química Estrutural and Departamento de Engenharia Química, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal., Chaves S; Centro de Química Estrutural and Departamento de Engenharia Química, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal., Brunetti L; Department of Pharmacy and Pharmaceutical Sciences, University of Bari 'A. Moro', via E. Orabona 4, 70125 Bari, Italy., Loiodice F; Department of Pharmacy and Pharmaceutical Sciences, University of Bari 'A. Moro', via E. Orabona 4, 70125 Bari, Italy., Carrieri A; Department of Pharmacy and Pharmaceutical Sciences, University of Bari 'A. Moro', via E. Orabona 4, 70125 Bari, Italy., Laghezza A; Department of Pharmacy and Pharmaceutical Sciences, University of Bari 'A. Moro', via E. Orabona 4, 70125 Bari, Italy., Tortorella P; Department of Pharmacy and Pharmaceutical Sciences, University of Bari 'A. Moro', via E. Orabona 4, 70125 Bari, Italy., Magalhães JD; CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal., Cardoso SM; CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal.; Institute of Molecular and Cell Biology, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal., Santos MA; Centro de Química Estrutural and Departamento de Engenharia Química, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal., Piemontese L; Department of Pharmacy and Pharmaceutical Sciences, University of Bari 'A. Moro', via E. Orabona 4, 70125 Bari, Italy. |
| Abstrakt: |
Alzheimer's disease (AD) is generally recognized as a multifactorial neurodegenerative pathology with an increasing impact on society. Tenuazonic acid (TA) is a natural compound that was recently identified as a potential multitarget ligand with anti-cholinesterase, anti-amyloidogenic and antioxidant activities. Using its structure as a chemical scaffold, we synthesized and evaluated new derivatives (1-5), including tenuazonic-donepezil (TA-DNP) hybrids (4 and 5) due to the clinical importance of the anti-AD drug donepezil. These novel compounds all achieved activity in the micromolar range towards all selected targets and demonstrated to be potentially orally absorbed. Moreover, a selected compound (1) was further investigated as a chelating agent towards copper (II), zinc (II) and iron (III) and showed good chelating ability (pFe = 16.6, pCu = 11.6, pZn = 6.0 at pH 7.4). Therefore, the TA motif can be considered an interesting building block in the search for innovative multi-functional anti-neurodegenerative drugs, as exemplified by hybrid 5, a promising non-cytotoxic lead compound adequate for the early stages of AD, and capable of ameliorating the oxidative status of SH-SY5Y human neuroblastoma cells. |
