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-, CF₃-, NO₂-, CN-, CO₂H- or CH₃O- groups on the aminoquinoline ring, and determined that all of the tested derivatives were very potent inhibitors of both cholinesterases, with inhibition constants (K_i) 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 Fe²⁺, Zn²⁺ and Cu²⁺ 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 5, the most potent AChE inhibitor with a CH₃O- on C(7) position, followed by 6 and 14, 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.

In this paper, we aimed to evaluate whether simple, low molecular mass benzoquinone derivatives, featuring different substituents in para- and meta-position relative to the tert-butyl group, possess biological activities against major targets associated with Alzheimer’s disease. The 1,4-benzoquinone derivatives studied herein inhibited both cholinesterases in the micromolar concentration range, generally showing a preference for butyrylcholinesterase over acetylcholinesterase; formed complexes with biometal ions Fe²⁺, Cu²⁺ and Zn²⁺; and displayed a certain BACE1 inhibition. Moreover, the tested compounds displayed certain antioxidant activity via either electron transfer or hydrogen atom transfer mechanisms. The antioxidant capacity of the unsubstituted tert-butyl-1,4-benzoquinone (compound 1) was three times lower than that of the standard antioxidant BHT, while 2,6-disubstituted derivatives (compounds 15 and 7) exhibited peroxyl radical scavenging activity comparable to that of Trolox. Taken together with in silico-predicted low toxicity, good intestinal absorption and favorable oral bioavailability, the presented 1,4-benzoquinone derivatives are promising scaffolds for the design of more complex molecules with enhanced cholinesterase and BACE1 inhibitory activity. Furthermore, they could serve as functional substituents in other structural scaffolds to combine and enhance their biological activities.

One of the major hallmarks of Alzheimer’s disease (AD), deposition of amyloid plaques in the brain, arises from the proteolytic processing of the amyloid precursor protein (APP), a process in which the rate-limiting step is carried by β-secretase (BACE1). Due to this essential role in the development of AD, BACE1 has become a widely studied drug target for the development of new drugs aimed at blocking amyloid β peptide formation and aggregation through inhibition of BACE1 activity. The development of the first BACE1 inhibitors allowed the determination of its crystal structure and description of its active site, confirming the existence of eleven well-defined subsites able to accommodate a range of substrates, which enabled BACE1 to participate in a number of biological processes. For this reason, the study of BACE1 structure and determination of specific structural motifs responsible for the accommodation of known substrates could enable defining drugs with very specific targets, as well as provide insight into the mode of action of BACE1 itself. This review will focus on the overall structure of BACE1 and its active site, as well as on the effect of genetic polymorphisms and isoforms on its activity.