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.
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.
Laboratory of Medicinal Chemistry (Institute of General Organic Chemistry [IQOG], National Research Council [CSIC]), Madrid, Spain.
Oscar M
OM
Bautista-Aguilera
Department of Biochemistry and Molecular Biology, Institute of Neurosciences, Autonomous Barcelona University, Barcelona, Spain.
Gerard
G
Esteban
Laboratory of Medicinal Chemistry (Institute of General Organic Chemistry [IQOG], National Research Council [CSIC]), Madrid, Spain.
Mourad
M
Chioua
Institute of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia.
Katarina
K
Nikolic
Institute of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia.
Danica
D
Agbaba
Department of Organic Chemistry, Faculty of Pharmacy, University of Alcalá, Ctra Barcelona, Alcalá de Henares, Spain.
Ignacio
I
Moraleda
Department of Organic Chemistry, Faculty of Pharmacy, University of Alcalá, Ctra Barcelona, Alcalá de Henares, Spain.
Isabel
I
Iriepa
Synthesis, and Structure of Organic Compounds (SEPCO) (IQOG, CSIC), Madrid, Spain.
Elena
E
Soriano
Laboratory of Medicinal Chemistry (Institute of General Organic Chemistry [IQOG], National Research Council [CSIC]), Madrid, Spain.
Abdelouahid
A
Samadi
Department of Biochemistry and Molecular Biology, Institute of Neurosciences, Autonomous Barcelona University, Barcelona, Spain.
Mercedes
M
Unzeta
Laboratory of Medicinal Chemistry (Institute of General Organic Chemistry [IQOG], National Research Council [CSIC]), Madrid, Spain.
José
J
Marco-Contelles
D000544:Alzheimer Disease / Q000188:drug therapy*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D002802:Cholinesterases / Q000378:metabolism; D000077265:Donepezil; D015195:Drug Design; D006801:Humans; D007189:Indans / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D008958:Models, Molecular; D015394:Molecular Structure; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D021281:Quantitative Structure-Activity Relationship; D011994:Recombinant Proteins / Q000378:metabolism
D002800:Cholinesterase Inhibitors; D007189:Indans; D008996:Monoamine Oxidase Inhibitors; D010880:Piperidines; D011725:Pyridines; D011994:Recombinant Proteins; D000077265:Donepezil; D002802:Cholinesterases
3D-QSAR; ADMET; ChE; MAO; donepezil-pyridyl hybrids; molecular modeling