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

• Published in: European journal of medicinal chemistry Vol. 262; p. 115880
• Main Authors: Waly, Omnia M., El-Sayed, Selwan M., Ghaly, Mariam A., El-Subbagh, Hussein I.
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 15.12.2023; Elsevier
• Subjects: Aβ1-42 aggregation inhibition; Chemistry, Medicinal; hAChE inhibition; hBuChE inhibition; hGSK3β inhibition; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Pyrazolopyridine; Science & Technology; Synthesis; Tau aggregation inhibition; Aβ1-42 aggregation inhibition; Synthesis; hAChE inhibition; hBuChE inhibition; hGSK3β inhibition; Tau aggregation inhibition; Pyrazolopyridine; RAPID COLORIMETRIC ASSAY; PROTEIN-TAU; h BuChE inhibition; SYNTHASE KINASE 3; h AChE inhibition; h GSK3 beta inhibition; POTENT; ACETYLCHOLINESTERASE; PHARMACOLOGY; AMYLOID-BETA-PEPTIDE; DISEASE; SELECTIVE INHIBITORS; HYPERPHOSPHORYLATION; A beta( 1-42 )aggregation inhibition
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2023.115880

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 IC50 values of 0.17 and 0.16 μM, respectively; and proved to be active hBuChE inhibitors with IC50 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 IC50 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 Aβ1-42 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 Fe2+, Cu2+, and Zn2+ 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. [Display omitted] •Compounds 49 and 51 proved to be potent multi-targeted anti-Alzheimer's agents.•Compounds 49 and 51 proved to be potent hAChE, hBuChE and Gsk3β inhibitors.•Compounds 49 and 51 proved to be potent tau protein and Aβ1-42 aggregation inhibitors.•Compounds 49 and 51 showed wide safety margin and metal chelating activity.•Compounds 49 and 51 obeyed Lipinski's rule of five.