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Title

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

AuthorsChioua, Mourad ; Buzzi, Eleonora; Moraleda, Ignacio; Iriepa, Isabel; Maj, Maciej; Wnorowski, Artur; Giovannini, Catia; Tamarin, Anna; Portali, Federica; Ismaili, Lhassane; López-Alvarado, Pilar; Bolognesi, Maria Laura; Jozwiak, Krzysztof; Menéndez, J. Carlos; Marco-Contelles, José ; Bartolini, Manuela
KeywordsTacripyrimidines
MultiTarget-directed ligands
ChE inhibition
Molecular modeling
Alzheimer's disease
Calcium channel blockade
Issue Date2018
PublisherElsevier
CitationEuropean Journal of Medicinal Chemistry 155: 839-846 (2018)
AbstractNotwithstanding 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
Publisher version (URL)http://dx.doi.org/10.1016/j.ejmech.2018.06.044
URIhttp://hdl.handle.net/10261/171174
Identifiersdoi: 10.1016/j.ejmech.2018.06.044
issn: 0223-5234
e-issn: 1768-3254
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