Discovery of Novel Pyrazolopyrimidinone Derivatives as Phosphodiesterase 9A Inhibitors Capable of Inhibiting Butyrylcholinesterase for Treatment of Alzheimer’s Disease

Abstract

Discovery of multitarget-directed ligands (MTDLs), targeting different factors simultaneously to control the complicated pathogenesis of Alzheimer's disease (AD), has become an important research area in recent years. Both phosphodiesterase 9A (PDE9A) and butyrylcholinesterase (BuChE) inhibitors could participate in different processes of AD to attenuate neuronal injuries and improve cognitive impairments. However, research on MTDLs combining the inhibition of PDE9A and BuChE simultaneously has not been reported yet. In this study, a series of novel pyrazolopyrimidinone-rivastigmine hybrids were designed, synthesized, and evaluated in vitro. Most compounds exhibited remarkable inhibitory activities against both PDE9A and BuChE. Compounds 6c and 6f showed the best IC values against PDE9A (6c, 14 nM; 6f, 17 nM) together with the considerable inhibition against BuChE (IC, 6c, 3.3 μM; 6f, 0.97 μM). Their inhibitory potencies against BuChE were even higher than the anti-AD drug rivastigmine. It is worthy mentioning that both showed moderate selectivity for BuChE over acetylcholinesterase (AChE). Molecular docking studies revealed their binding patterns and explained the influence of configuration and substitutions on the inhibition of PDE9A and BuChE. Furthermore, compounds 6c and 6f exhibited negligible toxicity, which made them suitable for the further study of AD in vivo.

Understanding the enzyme–ligand complex: insights from all-atom simulations of butyrylcholinesterase inhibition

“…Alzheimer's Disease, Parkinson's Disease, and preeclampsia are all associated with overactivity of butyrylcholinesterase, or BChE (Darvesh, Hopkins, & Geula, 2003;Dong et al, 2017;Giacobini, 2001;Greig et al, 2005;Mesulam et al, 2002;Rahimi et al, 2013), a non-specific enzyme that hydrolyzes the neurotransmitter acetylcholine and other cholinebased esters (Allderdice et al, 1991). Because these health problems continue to afflict the population, the development of selective and potent BChE inhibitors continues to be a valuable area of research (Akıncıoğlu et al, 2017;Cavallaro, Moglie, Murray, & Radivoy, 2018;Giacobini, 2004;Kamal et al, 2008;Senol et al, 2017;Yu et al, 2017). Organophosphorous compounds constitute one class of inhibitors that have been explored thus far (Fukuto & Metcalf, 1956;Hong & Raushel, 1999;Moretto, 1998).…”

Total Synthesis of Pulmonarin B and Design of Brominated Phenylacetic Acid/Tacrine Hybrids: Marine Pharmacophore Inspired Discovery of New ChE and Aβ Aggregation Inhibitors

“…In 2015, about 1.9 million people died of AD [ 2 ], and in 2017, an estimated 46.8 million AD patients were diagnosed worldwide [ 3 ]. More seriously, the number is expected to triple by 2050 with the aging of the global population [ 4 ].…”

Multitarget Therapeutic Strategies for Alzheimer’s Disease: Review on Emerging Target Combinations

“…Once again, there was a partial amelioration of the deficits induced by the treatment with the best performing compounds of the series. Following a similar approach, hybridization of the pyrazolopyrimidinone skeleton with Rivastigmine led to the identification of another series of promising MTDLs (25, Figure 8) [62]. Even if various groups were used to replace the carbamate functionality of Rivastigmine and different chains were employed to create the linkage between the two pharmacophoric elements, compounds with general structure 25 resulted as the most promising and efficacious analogues of the series.…”