Multi-targeted anti-Alzheimer's agents: Synthesis, biological evaluation, and molecular modeling study of some pyrazolopyridine hybrids.

Autor: Waly OM; Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt; Pharmacy Center of Scientific Excellence, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt., El-Sayed SM; Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt; Pharmacy Center of Scientific Excellence, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt., Ghaly MA; Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt. Electronic address: mariamaghaly@mans.edu.eg., El-Subbagh HI; Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt; Pharmacy Center of Scientific Excellence, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt. Electronic address: subbagh@mans.edu.eg.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2023 Dec 15; Vol. 262, pp. 115880. Date of Electronic Publication: 2023 Oct 20.
DOI: 10.1016/j.ejmech.2023.115880
Abstrakt: A new series of compounds bearing a pyrazolopyridine scaffold was synthesized as integrated anti-Alzheimer's disease (AD) multi-targeted ligands. Compounds 49 and 51 showed remarkable activity as hAChE inhibitors with IC 50 values of 0.17 and 0.16 μM, respectively; and proved to be active hBuChE inhibitors with IC 50 values 0.17 and 0.69 μM, eight and two-fold more active than the reference compound rivastigmine, respectively. Compounds 49 and 51 showed potent GSK3β inhibition with IC 50 values of 0.21 and 0.26 μM, respectively compared to L807mts. Also, 49 and 51 showed 66.0 and 60.0% as tau protein aggregation inhibitors; and Aβ 1-42 self-aggregation inhibitors with 79.0 and 75.0% respectively. Furthermore, 49 and 51 could bind virtually with the PAS affecting Aβ aggregation, thus preventing Aβ-dependent neurotoxicity. They proved to have the ability to chelate bio-metals such as Fe 2+ , Cu 2+ , and Zn 2+ preventing their oxidative damage in the brain of AD patients, in addition to their safety upon WI-38 cell line. Both compounds could virtually penetrate BBB and obeyed Lipinski's rule of five. Compounds 49 and 51 could be considered as MTDLs for AD patients and the obtained model and pattern of substitution could be used for further development of new multi-targeted anti-Alzheimer's agents.
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 © 2023 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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