Tacripyrimidines, the first tacrine-dihydropyrimidine hybrids, as multi-target-directed ligands for Alzheimer's disease

Autor: Artur Wnorowski, Anna Tramarin, Krzysztof Jóźwiak, Catia Giovannini, Isabel Iriepa, Maria Laura Bolognesi, José Marco-Contelles, Federica Portali, Maciej Maj, Eleonora Buzzi, Pilar López-Alvarado, Ignacio Moraleda, J. Carlos Menéndez, Lhassane Ismaili, Mourad Chioua, Manuela Bartolini
Přispěvatelé: Chioua, Mourad, Buzzi, Eleonora, Moraleda, Ignacio, Iriepa, Isabel, Maj, Maciej, Wnorowski, Artur, Giovannini, Catia, Tramarin, Anna, Portali, Federica, Ismaili, Lhassane, López-Alvarado, Pilar, Bolognesi, Maria Laura, Jóźwiak, Krzysztof, Menéndez, J. Carlo, Marco-Contelles, José, Bartolini, Manuela, Ministerio de Economía, Industria y Competitividad (España), European Commission
Rok vydání: 2018
Předmět:
0301 basic medicine
Pharmacology
Ligands
01 natural sciences
MultiTarget-directed ligand
chemistry.chemical_compound
Drug Discovery
Cholinesterase Inhibitor
Butyrylcholinesterase
biology
Molecular Structure
Chemistry
General Medicine
Hep G2 Cells
Alzheimer's disease
Acetylcholinesterase
Calcium channel blockade
Tacrine
MultiTarget-directed ligands
medicine.drug
Human
Cell Survival
Tacripyrimidines
Molecular modeling
Hep G2 Cell
Ligand
03 medical and health sciences
Structure-Activity Relationship
Alzheimer Disease
medicine
Structure–activity relationship
Humans
Nimodipine
Cholinesterase
Dose-Response Relationship
Drug
010405 organic chemistry
Calcium channel
Drug Discovery3003 Pharmaceutical Science
Organic Chemistry
medicine.disease
Tacripyrimidine
0104 chemical sciences
030104 developmental biology
ChE inhibition
Pyrimidines
Pyrimidine
Drug Design
biology.protein
Cholinesterase Inhibitors
Zdroj: Digital.CSIC. Repositorio Institucional del CSIC
instname
ISSN: 1768-3254
Popis: 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 30-methoxy derivative (4e) emerged as the first well balanced ChEI/CCB agent, acting as low micromolar hChEI (3.05 mM and 3.19 mM on hAChE and hBuChE, respectively) and moderate CCB (30.4% at 1 mM) with no significant hepatotoxicity toward HepG2 cells and good predicted oral absorption and blood brain barrier permeability
EB and FP thank Erasmus for support. JMC thanks MINECO (Government of Spain) for grants SAF2012-33304 and CTQ-68380- R. JMC and MLB thank EU (COST Action 15135). MB and MLB gratefully acknowledges the University of Bologna and the Italian Ministry of Education, Universities and Research (MIUR)
Databáze: OpenAIRE
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