Tacripyrimidines, the first tacrine-dihydropyrimidine hybrids, as multi-target-directed ligands for Alzheimer's disease.
Eur J Med Chem
; 155: 839-846, 2018 Jul 15.
Article
en En
| MEDLINE
| ID: mdl-29958119
ABSTRACT
Notwithstanding the combination of cholinesterase (ChE) inhibition and calcium channel blockade within a multitarget therapeutic approach is envisaged as potentially beneficial to confront Alzheimer's disease (AD), this strategy has been scarcely investigated. To explore this promising line, a series of 5-amino-4-aryl-3,4,6,7,8,9-hexahydropyrimido [4,5-b]quinoline-2(1H)-thiones (tacripyrimidines) (4a-l) were designed by juxtaposition of tacrine, a ChE inhibitor (ChEI), and 3,4-dihydropyrimidin-2(1H)-thiones, as efficient calcium channel blockers (CCBs). In agreement with their design, all tacripyrimidines, except the unsubstituted parent compound and its p-methoxy derivative, acted as moderate to potent CCBs with activities generally similar or higher than the reference CCB drug nimodipine and were modest-to-good ChEIs. Most interestingly, the 3'-methoxy derivative (4e) emerged as the first well balanced ChEI/CCB agent, acting as low micromolar hChEI (3.05⯵M and 3.19⯵M on hAChE and hBuChE, respectively) and moderate CCB (30.4% at 1⯵M) with no significant hepatotoxicity toward HepG2 cells and good predicted oral absorption and blood brain barrier permeability.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Acetilcolinesterasa
/
Pirimidinas
/
Butirilcolinesterasa
/
Inhibidores de la Colinesterasa
/
Enfermedad de Alzheimer
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Eur J Med Chem
Año:
2018
Tipo del documento:
Article
País de afiliación:
España