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

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)