Chalcones Acting as Inhibitors of Cholinesterases, ß-Secretase and ß- Amyloid Aggregation and other Targets for Alzheimer's Disease: A Critical Review.

BACKGROUND: Alzheimer's disease (AD) involves an irreversible and progressive neurodegeneration, with multifactorial pathophysiology, including the cholinergic deficit, amyloid plaques, neurofibrillary tangles, oxidative stress, and neurodegeneration. Despite the severity of the disease, the therapeutic arsenal is limited, arousing the interest of researchers to search for substances that can act on these markers. OBJECTIVE: In this review, we highlight some relevant points, such as the ability of chalcones to act on different targets related to the pathophysiology of Alzheimer's disease; cholinesterases, amyloid peptide, beta-secretase and other biomarkers. METHOD: This mini-review covered the literature concerning chalcones bioactivity from 2010 until now. In addition to the theoretical review, we included the prediction of physicochemical properties using SwissADME software. RESULTS: We found that the majority of the chalcones have been tested against cholinesterases, with moderate to good potencies, but in recent years, the number of publications related to targets of the amyloid hypothesis has been growing. Regarding the physicochemical properties, chalcones have a good profile, except for the water solubility, which is not favorable. CONCLUSION: The most important characteristic of these molecules is that many of the examples mentioned here act on more than one target, characterizing them as multi-target compounds. Regarding predicted properties, solubility stands out as the most problematic one; however, these structures can incorporate functional groups that circumvent this problem of solubility without interfering in the biological activity.

Synthesis and biological evaluation of 2'-Aminochalcone: A multi-target approach to find drug candidates to treat Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative process that compromises cognitive functions. The physiopathology of AD is multifactorial and is mainly supported by the cholinergic and amyloid hypotheses, which allows the identification the fundamental role of some markers, such as the enzymes acetylcholinesterase (AChE) and ß-secretase (BACE-1), and the ß-amyloid peptide (Aß). In this work, we prepared a series of chalcones and 2'-aminochalcones, which were tested against AChE and BACE-1 enzymes and on the aggregation of Aß. All compounds inhibited AChE activity with different potencies. We have found that the majority of chalcones having the amino group are able to inhibit BACE-1, which was not observed for chalcones without this group. The most active compound is the one derived from 2,3-dichlorobenzaldeyde, having an IC50 value of 2.71 µM. A molecular docking study supported this result, showing a good interaction of the amino group with aspartic acid residues of the catalytic diade of BACE-1. Thioflavin-T fluorescence emission is reduced in 30 - 40%, when Aß42 is incubated in the presence of some chalcones under aggregation conditions. In vitro cytotoxicity and in silico prediction of pharmacokinetic properties were also conducted in this study.