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Notwithstanding the clinical use of tacrine was hampered by severe hepatotoxicity, tacrine still remains a reference scaffold in the search for new efficient drugs for Alzheimer's disease therapy. In this account we summarize the efforts toward the development and characterization of non‐hepatotoxic tacripyrines and related tacrine analogues resulting from the substitution of the benzene ring by a 1,4‐dihydropyridine, a 1,2,3,4‐tetrahydropyrimidine or a pyridone nucleus. These efforts have successfully led to the identification of a number of promising hits endowed with interesting multifunctional profiles. These include the 4′‐metoxytacripyrine (S)‐ITH122, able to target cholinesterases (ChEs), beta‐amyloid (Aβ) and Ca2+ channels, the racemic 3′‐methoxytacripyrimidine EB65F2, the first fully balanced micromolar inhibitor of ChEs and Ca2+ channels, and tacripyrine (−)‐SCR1693 a GSK‐3β (enzyme involved in tau phosphorylation) inhibitor able to also lower Aβ production in N2a cells. [ABSTRACT FROM AUTHOR]

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(1 H )-thiones (tacripyrimidines) ( 4a - l ) were designed by juxtaposition of tacrine, a ChE inhibitor (ChEI), and 3,4-dihydropyrimidin-2(1 H )-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. [ABSTRACT FROM AUTHOR]