A Novel Multifunctional 5,6-Dimethoxy-Indanone-Chalcone- Carbamate Hybrids Alleviates Cognitive Decline in Alzheimer’s Disease by Dual Inhibition of Acetylcholinesterase and Inflammation.

Backgrounds: Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease. The treatment of AD through multiple pathological targets may generate therapeutic efficacy better. The multifunctional molecules that simultaneously hit several pathological targets have been of great interest in the intervention of AD. Methods: Here, we combined the chalcone scaffold with carbamate moiety and 5,6-dimethoxy-indanone moiety to generate a novel multi-target-directed ligand (MTDL) molecule (E)-3-((5,6-dimethoxy-1-oxo-1,3-dihydro-2H-inden-2-ylidene)- methyl)phenylethyl(methyl) carbamate (named AP5). In silico approaches were used to virtually predict the binding interaction of AP5 with AChE, the drug-likeness, and BBB penetrance, and later validated by evaluation of pharmacokinetics (PK) in vivo by LCMS/ MS. Moreover, studies were conducted to examine the potential of AP5 for inhibiting AChE and AChE-induced amyloid-b (Ab) aggregation, attenuating neuroinflammation, and providing neuroprotection in the APP/PS1 model of AD. Results: We found that AP5 can simultaneously bind to the peripheral and catalytic sites of AChE by molecular docking. AP5 exhibited desirable pharmacokinetic (PK) characteristics including oral bioavailability (67.2%), >10% brain penetrance, and favorable drug-likeness. AP5 inhibited AChE activity and AChE-induced Ab aggregation in vivo and in vitro. Further, AP5 lowered Ab plaque deposition and insoluble Ab levels in APP/PS1 mice. Moreover, AP5 exerted anti-inflammatory responses by switching microglia to a disease-associated microglia (DAM) phenotype and preventing A1 astrocytes formation. The phagocytic activity of microglial cells to Ab was recovered upon AP5 treatment. Importantly, chronic AP5 treatment significantly prevented neuronal and synaptic damage and memory deficits in AD mice. Conclusion: Together, our work demonstrated that AP5 inhibited the AChE activity, decreased Ab plaque deposition by interfering Ab aggregation and promoting microglial Ab phagocytosis, and suppressed inflammation, thereby rescuing neuronal and synaptic damage and relieving cognitive decline. Thus, AP5 can be a new promising candidate for the treatment of AD [ABSTRACT FROM AUTHOR]