Synthesis, biological evaluation, and molecular modeling simulations of new heterocyclic hybrids as multi-targeted anti-Alzheimer's agents

The widespread and the recognition of the multifactorial nature of Alzheimer disease (AD) increased the demands for multi-targeted directed ligands (MTDLs) to overcome possible drug-drug interactions of the combination therapy, and to acquire superior therapeutic profile than single targeted molecules. Two main scaffolds namely: pyrazolopyridine and tetrahydroacridine (THA) were used to synthesize four different series of integrated multi-targeted synthons possessing ChE (hAChE or hBuChE), Aβ_1-42 aggregation inhibition potency, in addition to optimum metal chelating capability. Structure modifications were performed to 9-amino function of THA core of tacrine and the pyrazolopyridine scaffolds linked to a variety of cyclic secondary amines directly or using amide spacers or ethylamine bridge or engaging THA with pyrazolopyridine to produce hybrid compounds. Different 9-amino substitutions improved the in vitro hAChE activity of 7- or 6,7-disubstituted THA derivatives. Compounds 16 and 28 proved to be multimodal anti-AD agents as they were potent hAChE inhibitors, in addition, they could bind with the amino acids of the peripheral anionic site (PAS) affecting Aβ aggregation and hence Aβ-dependent neurotoxicity especially compound 16 which was almost twofold more active than donepezil. Furthermore, both compounds directly inhibited Aβ_1-42 self-aggregation and chelated bio-metals such as Fe²⁺, Zn²⁺ and Cu²⁺ preventing reactive oxygen species (ROS) generation by Aβ and its oxidative damage in the brain regions of AD patients. Compound 28 had superior privilege by its dual ChE activity resulting in better cognitive improvement. Compounds 16 and 28 showed acceptable relative safety upon hepG2 cell line and excellent BBB penetration with wide safety margin as their LD₅₀ were higher than 120 mg/kg.