Design, Synthesis, and Biological Evaluation of Orally Available First-Generation Dual-Target Selective Inhibitors of Acetylcholinesterase (AChE) and Phosphodiesterase 5 (PDE5) for the Treatment of Alzheimer’s Disease

Abstract

Through drug discovery strategies of repurposing and redeveloping existing drugs, a series of novel tadalafil derivatives were rationally designed, synthesized, and evaluated to seek dual-target AChE/PDE5 inhibitors as good candidate drugs for Alzheimer's disease (AD). Among these derivatives, 1p and 1w exhibited excellent selective dual-target AChE/PDE5 inhibitory activities and improved blood-brain barrier (BBB) penetrability. Importantly, 1w·Cit (citrate of 1w) could reverse the cognitive dysfunction of scopolamine-induced AD mice and exhibited an excellent effect on enhancing cAMP response element-binding protein (CREB) phosphorylation in vivo, a crucial factor in memory formation and synaptic plasticity. Moreover, the molecular docking simulations of 1w with hAChE and hPDE5A confirmed that our design strategy was rational. In summary, our research provides a potential selective dual-target AChE/PDE5 inhibitor as a good candidate drug for the treatment of AD, and it could also be regarded as a small molecule probe to validate the novel AD therapeutic approach in vivo.

Multitarget Approach to Drug Candidates against Alzheimer’s Disease Related to AChE, SERT, BACE1 and GSK3β Protein Targets

“…From Protein Data Bank for each target three crystal structures of the studied receptors in complex with an inhibitor were selected. Therefore, for AChE we used complexes with (−)-huperzine A (IC 50 = 0.084 µM [29], ID: 4EY5 [30]), donepezil (IC 50 = 0.013 µM [29], ID: 4EY7 [30]) and (−)-galantamine (IC 50 and N-[4-(isoquinolin-7-yl)pyridin-2-yl]cyclopropanecarboxamide (2WF, IC50 = 0.074 µM, ID: 4PTE [37]); for SERT, complexes with paroxetine (IC 50 = 0.0021 µM [38], ID: 5I6X [39]), S-citalopram (IC 50 = 0.01 µM [40], ID: 5I71 [39]) and sertraline (IC 50 = 0.010 µM [41], ID: 6AWO [42]). According to the molecular dynamics results, it can be assumed that the interaction between the potential inhibitor and the amino acid residues of the catalytic triad of the AChE is not necessary, but the interactions with Trp86, Tyr133, Gly202 or Phe295 can have a significant effect on the activity of the potential inhibitor (Figure S1).…”

Tadalafil: 15 years' journey in male erectile dysfunction and beyond

“…The novel analogues act as inhibitors to both AChE and PDE5 and are investigated as a novel therapeutic method for the treatment of AD. The lead compound ( 42 ) demonstrated significant memory‐enhancing effects in AD mouse model (Mao et al, ). However, compound ( 42 ) was nearly insoluble in water and was then further optimized to produce a series of more water‐soluble analogues ( 43 ) (Ni et al, ).…”

When nature’s robots go rogue: exploring protein homeostasis dysfunction and the implications for understanding human aging disease pathologies

“…A recent study of healthy post-mortem brains investigated the role of proteostasis factors in disease progression and found that regions of the brain with protein expression profiles that suggested a likelihood for aggregate formation, as well as those involved in proteostasis, were particularly susceptible to neurodegeneration in AD [145]. Efforts to combat or prevent AD onset have focused on acetylcholinesterase inhibitors [146] and targets of the cholinergic system [147], N -methyl-D-aspartate (NMDA) receptor antagonism to reduces neural A levels [148], exercise to prevent hippocampal mitochondria dysfunction [149], and erythrocyte membrane-encapsulated celecoxib to promote neurogenesis via prostaglandins [150]. In contrast, attempts to inhibit secretase have not proven clinically effective [151].…”