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 μM and 3.19 μM on hAChE and hBuChE, respectively) and moderate CCB (30.4% at 1 μM) with no significant hepatotoxicity toward HepG2 cells and good predicted oral absorption and blood brain barrier permeability.

Chioua, M., Buzzi, E., Moraleda, I., Iriepa, I., Maj, M., Wnorowski, A., et al. (2018). Tacripyrimidines, the first tacrine-dihydropyrimidine hybrids, as multi-target-directed ligands for Alzheimer's disease. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 155, 839-846 [10.1016/j.ejmech.2018.06.044].

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

Giovannini, Catia;Tramarin, Anna;Bolognesi, Maria Laura
Membro del Collaboration Group
;
Bartolini, Manuela
2018

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 μM and 3.19 μM on hAChE and hBuChE, respectively) and moderate CCB (30.4% at 1 μM) with no significant hepatotoxicity toward HepG2 cells and good predicted oral absorption and blood brain barrier permeability.
2018
Chioua, M., Buzzi, E., Moraleda, I., Iriepa, I., Maj, M., Wnorowski, A., et al. (2018). Tacripyrimidines, the first tacrine-dihydropyrimidine hybrids, as multi-target-directed ligands for Alzheimer's disease. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 155, 839-846 [10.1016/j.ejmech.2018.06.044].
Chioua, Mourad; Buzzi, Eleonora; Moraleda, Ignacio; Iriepa, Isabel; Maj, Maciej; Wnorowski, Artur; Giovannini, Catia; Tramarin, Anna; Portali, Federic...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/644272
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