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
Bautista-Aguilera, Oscar M.. (Instituto de Química Orgánica General (IQOG-CSIC). Laboratorio de Química Médica)
Esteban, Gerard (Universitat Autònoma de Barcelona. Institut de Neurociències)
Chioua, Mourad (Instituto de Química Orgánica General (IQOG-CSIC). Laboratorio de Química Médica)
Nikolic, Katarina (University of Belgrade. Institute of Pharmaceutical Chemistry)
Agbaba, Danica (University of Belgrade. Institute of Pharmaceutical Chemistry)
Moraleda, Ignacio (Universidad de Alcalá. Departamento de Química Orgánica)
Iriepa, Isabel (Universidad de Alcalá. Departamento de Química Orgánica)
Soriano, Elena (Instituto de Química Orgánica General (IQOG-CSIC). Síntesis y estructura de compuestos orgánicos (SEPCO))
Samadi, Abdelouahid (Instituto de Química Orgánica General (IQOG-CSIC). Laboratorio de Química Médica)
Unzeta López, Mercedes (Universitat Autònoma de Barcelona. Institut de Neurociències)
Marco-Contelles, José (Instituto de Química Orgánica General (IQOG-CSIC). Laboratorio de Química Médica)
Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular

Data:	2014
Resum:	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 [IC] =1. 1±0. 3 nM; equine butyrylcholinesterase [eqBuChE]: IC =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 (IC [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 (IC [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.
Ajuts:	Ministerio de Economía y Competitividad SAF2009-07271 Ministerio de Economía y Competitividad SAF2012-33304
Nota:	Altres ajuts: COST action CM1103
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Donepezil-pyridyl hybrids ; ChE ; MAO ; 3D-QSAR ; Molecular modeling ; ADMET
Publicat a:	Drug Design, Development and Therapy, Vol. 8 (October 2014) , p. 1893-1910, ISSN 1177-8881

DOI: 10.2147/DDDT.S69258
PMID: 25378907

18 p, 2.9 MB

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