Abstract
Phosphodiesterase-9 (PDE9) is a promising target for treatment of Alzheimer’s disease (AD). To discover multifunctional anti-AD agents with capability of PDE9 inhibition and antioxidant activity, a series of novel pyrazolopyrimidinone derivatives, coupling with the pharmacophore of antioxidants such as ferulic and lipolic acids have been designed with the assistance of molecular docking and dynamics simulations. Twelve out of 14 synthesised compounds inhibited PDE9A with IC50 below 200 nM, and showed good antioxidant capacities in the ORAC assay. Compound 1h, the most promising multifunctional anti-AD agent, had IC50 of 56 nM against PDE9A and good antioxidant ability (ORAC (trolox) = 3.3). The selectivity of 1h over other PDEs was acceptable. In addition, 1h showed no cytotoxicity to human neuroblastoma SH-SY5Y cells. The analysis on structure-activity relationship (SAR) and binding modes of the compounds may provide insight into further modification.
Highlights
Alzheimer’s disease (AD) is the most common type of dementia, which is characterised by progressive memory loss, decline in language skills, and other neurodegenerative disorders[1]
Development of multifunctional anti-AD agents which simultaneously hit more than single target in the AD pathophysiology, has become an important research area in recent years[6,7], especially those hitting at non-Ab targets
According to the calculation results, we found that the compounds with an amide group as the linker had stable MD simulations trajectories and high binding free energies, indicating that they might be potential PDE9A inhibitors
Summary
Alzheimer’s disease (AD) is the most common type of dementia, which is characterised by progressive memory loss, decline in language skills, and other neurodegenerative disorders[1]. The pathogenic mechanism of Alzheimer’s disease is complicated and still has not fully understood yet. Several factors, such as low level of acetylcholine, deposition of b-amyloid (Ab), aggregation of Tau-protein, and oxidative stress have been regarded as important in the pathophysiology of AD3. Current drugs for the treatment of AD include three acetylcholinesterase (AChE) inhibitors (donepezil, rivastigmine, and galantamine) and one N-methyl-d-aspartate receptor antagonist (memantine)[4]. Administration of these drugs only can improve cognition and dementia degree of AD patients, but not reverse the underlying progression. Development of multifunctional anti-AD agents which simultaneously hit more than single target in the AD pathophysiology, has become an important research area in recent years[6,7], especially those hitting at non-Ab targets
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