Derivatives of Amodiaquine as Potent Human Cholinesterases Inhibitors: Implication for Treatment of Alzheimer's Disease.

As some previously reported studies have proven that amodiaquine, in addition to its primary antimalarial activity, also has potential for new applications such as the inhibition of cholinesterases, in our study we focused on the evaluation of the influence of different substituents in the aminoquinoline part of the amodiaquine structure on the inhibition of human acetylcholinesterase and butyrylcholinesterase to investigate the possibility for their use as drugs for the treatment of AD. We synthesized a series of amodiaquine derivatives bearing H-, F-, CF-, NO-, CN-, COH- or CHO- groups on the aminoquinoline ring, and determined that all of the tested derivatives were very potent inhibitors of both cholinesterases, with inhibition constants () in the nM and low μM range and with prominent selectivity (up to 300 times) for the inhibition of acetylcholinesterase. All compounds displayed an ability to chelate biometal ions Fe, Zn and Cu and an antioxidant power comparable to that of standard antioxidants. Most of the compounds were estimated to be able to cross the blood-brain barrier by passive transport and were nontoxic toward cells that represent the models of individual organs. Considering all these beneficial features, our study has singled out compound , the most potent AChE inhibitor with a CHO- on C(7) position, followed by and , compounds without substituent or hydroxyl groups in the C(17) position, respectively, as the most promising compounds from the series which could be considered as potential multi-target drugs for the treatment of AD.