Multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of Alzheimer's disease: design, synthesis, biochemical evaluation, ADMET, molecular modeling, and QSAR analysis of novel donepezil-pyridyl hybrids.

Abstract

The design, synthesis, and biochemical evaluation of donepezil-pyridyl hybrids (DPHs) as multipotent cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors for the potential treatment of Alzheimer's disease (AD) is reported. The 3D-quantitative structure-activity relationship study was used to define 3D-pharmacophores for inhibition of MAO A/B, acetylcholinesterase (AChE), and butyrylcholinesterase (BuChE) enzymes and to design DPHs as novel multi-target drug candidates with potential impact in the therapy of AD. DPH14 (Electrophorus electricus AChE [EeAChE]: half maximal inhibitory concentration [IC50] =1.1±0.3 nM; equine butyrylcholinesterase [eqBuChE]: IC50 =600±80 nM) was 318-fold more potent for the inhibition of AChE, and 1.3-fold less potent for the inhibition of BuChE than the reference compound ASS234. DPH14 is a potent human recombinant BuChE (hBuChE) inhibitor, in the same range as DPH12 or DPH16, but 13.1-fold less potent than DPH15 for the inhibition of human recombinant AChE (hAChE). Compared with donepezil, DPH14 is almost equipotent for the inhibition of hAChE, and 8.8-fold more potent for hBuChE. Concerning human monoamine oxidase (hMAO) A inhibition, only DPH9 and 5 proved active, compound DPH9 being the most potent (IC50 [MAO A] =5,700±2,100 nM). For hMAO B, only DPHs 13 and 14 were moderate inhibitors, and compound DPH14 was the most potent (IC50 [MAO B] =3,950±940 nM). Molecular modeling of inhibitor DPH14 within EeAChE showed a binding mode with an extended conformation, interacting simultaneously with both catalytic and peripheral sites of EeAChE thanks to a linker of appropriate length. Absortion, distribution, metabolism, excretion and toxicity analysis showed that structures lacking phenyl-substituent show better druglikeness profiles; in particular, DPHs13-15 showed the most suitable absortion, distribution, metabolism, excretion and toxicity properties. Novel donepezil-pyridyl hybrid DPH14 is a potent, moderately selective hAChE and selective irreversible hMAO B inhibitor which might be considered as a promising compound for further development for the treatment of AD.

• Authors: Oscar M Bautista-Aguilera, Gerard Esteban, Mourad Chioua, Katarina Nikolic, Danica Agbaba, Ignacio Moraleda, Isabel Iriepa, Elena Soriano, Abdelouahid Samadi, Mercedes Unzeta, José Marco-Contelles
• Journal: Drug design, development and therapy (Drug Des Devel Ther) Vol. 8 Pg. 1893-910 ( 2014) ISSN: 1177-8881 [Electronic] New Zealand
• PMID: 25378907 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cholinesterase Inhibitors
• Indans
• Monoamine Oxidase Inhibitors
• Piperidines
• Pyridines
• Recombinant Proteins
• Donepezil
• Cholinesterases

Topics

• Alzheimer Disease (drug therapy)
• Cholinesterase Inhibitors (chemical synthesis, chemistry, metabolism, therapeutic use)
• Cholinesterases (metabolism)
• Donepezil
• Drug Design
• Humans
• Indans (chemistry, metabolism, therapeutic use)
• Models, Molecular
• Molecular Structure
• Monoamine Oxidase Inhibitors (chemical synthesis, chemistry, metabolism, therapeutic use)
• Piperidines (chemistry, metabolism, therapeutic use)
• Pyridines (chemistry, metabolism, therapeutic use)
• Quantitative Structure-Activity Relationship
• Recombinant Proteins (metabolism)