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

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 mu M, respectively; and proved to be active hBuChE inhibitors with IC50 values 0.17 and 0.69 mu M, eight and two-fold more active than the reference compound rivastigmine, respectively. Compounds 49 and 51 showed potent GSK3 beta inhibition with IC50 values of 0.21 and 0.26 mu M, respectively compared to L807mts. Also, 49 and 51 showed 66.0 and 60.0% as tau protein aggregation inhibitors; and A beta(1-42) self-aggregation inhibitors with 79.0 and 75.0% respectively. Furthermore, 49 and 51 could bind virtually with the PAS affecting A beta aggregation, thus preventing A beta-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.

Automated summary

A series of compounds with a pyrazolopyridine scaffold were synthesized as multi-targeted ligands for the treatment of Alzheimer's disease (AD). Compounds 49 and 51 exhibited potent inhibition against hAChE and hBuChE, as well as GSK3 beta. They also showed significant inhibition of tau protein aggregation and A beta(1-42) self-aggregation. Additionally, these compounds were able to chelate bio-metals and penetrate the blood-brain barrier. They could be considered as potential multi-targeted drugs for AD patients, and the substitution pattern obtained in this study could guide the development of new anti-Alzheimer's agents.