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

Basic Information

ID: ALA4152325

Journal: Eur J Med Chem

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

Authors: Chioua M, Buzzi E, Moraleda I, Iriepa I, Maj M, Wnorowski A, Giovannini C, Tramarin A, Portali F, Ismaili L, López-Alvarado P, Bolognesi ML, Jóźwiak K, Menéndez JC, Marco-Contelles J, Bartolini M.

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.

CiteXplore: 29958119

DOI: 10.1016/j.ejmech.2018.06.044

Patent ID: ┄