Rivastigmine structure-based hybrids as potential multi-target anti-Alzheimer's drug candidates.

Autor: Leuci R; Department of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70126 Bari, Italy., Simic S; Department of Pharmaceutical Sciences, Faculty of Life Sciences, University of Vienna, 1090 Vienna, Austria., Carrieri A; Department of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70126 Bari, Italy., Chaves S; Centro de Química Estrutural, Departamento de Engenharia Química, Institute of Molecular Sciences, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, Lisboa 1049-001, Portugal., La Spada G; Department of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70126 Bari, Italy., Brunetti L; Department of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70126 Bari, Italy., Tortorella P; Department of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70126 Bari, Italy., Loiodice F; Department of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70126 Bari, Italy., Laghezza A; Department of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70126 Bari, Italy., Catto M; Department of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70126 Bari, Italy., Santos MA; Centro de Química Estrutural, Departamento de Engenharia Química, Institute of Molecular Sciences, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, Lisboa 1049-001, Portugal., Tufarelli V; Department of Precision and Regenerative Medicine and Jonian Area (DiMePRe-J), Section of Veterinary Science and Animal Production, University of Bari Aldo Moro, Valenzano, 70010, Italy., Wackerlig J; Department of Pharmaceutical Sciences, Faculty of Life Sciences, University of Vienna, 1090 Vienna, Austria., Piemontese L; Department of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70126 Bari, Italy. Electronic address: luca.piemontese@uniba.it.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2024 Oct 18; Vol. 153, pp. 107895. Date of Electronic Publication: 2024 Oct 18.
DOI: 10.1016/j.bioorg.2024.107895
Abstrakt: In recent years, an increasing amount of work has been carried out regarding the study of the etiopathology of Alzheimer's Disease (AD). This neurodegenerative disease is characterized by several organic and molecular correlates, which paint a complex picture that also reflects the historic challenge faced by the worldwide scientific community in finding an effective cure for it. In this paper, we describe the synthesis of novel rivastigmine derivatives and their characterization as wide-spectrum enzyme (AChE, BChE, FAAH, MAO-A and MAO-B) inhibitors with potential application in the therapy of AD following the paradigm of multi-target design. 5 (ROS151) and 23 show similar inhibitory profile compared to donepezil on cholinesterases, and ca. two hundred twenty-three and eighty-seven times more active than rivastigmine on AChE. Moreover, ROS151 was found to be a potential metal chelator. Compounds 6 and 8 are very interesting and original multi-functional promising hybrids, with comparable potency on distinct panels of enzymes. All these promising rivastigmine-like hybrids were assayed for their pharmacokinetic properties by using different bio-analytical techniques, showing interesting applicability profiles. Moreover, cytotoxicity assays displayed a safety profile on three different cell lines.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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