Waly_2023_Eur.J.Med.Chem_262_115880

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 microM, respectively; and proved to be active hBuChE inhibitors with IC(50) values 0.17 and 0.69 microM, eight and two-fold more active than the reference compound rivastigmine, respectively. Compounds 49 and 51 showed potent GSK3beta inhibition with IC(50) values of 0.21 and 0.26 microM, respectively compared to L807mts. Also, 49 and 51 showed 66.0 and 60.0% as tau protein aggregation inhibitors; and Abeta(1-42) self-aggregation inhibitors with 79.0 and 75.0% respectively. Furthermore, 49 and 51 could bind virtually with the PAS affecting Abeta aggregation, thus preventing Abeta-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.