New Tetrahydroacridine Hybrids with Dichlorobenzoic Acid Moiety Demonstrating Multifunctional Potential for the Treatment of Alzheimer’s Disease

• Main Authors: Kamila Czarnecka, Małgorzata Girek, Przemysław Wójtowicz, Paweł Kręcisz, Robert Skibiński, Jakub Jończyk, Kamil Łątka, Marek Bajda, Anna Walczak, Grzegorz Galita, Jacek Kabziński, Ireneusz Majsterek, Piotr Szymczyk, Paweł Szymański
• Format: Article
• Language: English
• Published: MDPI AG 2020-05-01
• Series: International Journal of Molecular Sciences
• Subjects: acetylcholinesterase inhibitors; Alzheimer’s disease; molecular modeling; Ellman’s method
• Online Access: https://www.mdpi.com/1422-0067/21/11/3765
• ISSN: 1661-6596; 1422-0067

A series of new tetrahydroacridine and 3,5-dichlorobenzoic acid hybrids with different spacers were designed, synthesized, and evaluated for their ability to inhibit both cholinesterase enzymes. Compounds <b>3a</b>, <b>3b</b>, <b>3f</b>, and <b>3g</b> exhibited selective butyrylcholinesterase (<i>Eq</i>BuChE) inhibition with IC₅₀ values ranging from 24 to 607 nM. Among them, compound 3b was the most active (IC₅₀ = 24 nM). Additionally, 3c (IC₅₀ for <i>Ee</i>AChE = 25 nM and IC₅₀ for <i>Eq</i>BuChE = 123 nM) displayed dual cholinesterase inhibitory activity and was the most active compound against acetylcholinesterase (AChE). Active compound 3c was also tested for the ability to inhibit Aβ aggregation. Theoretical physicochemical properties of the compounds were calculated using ACD Labs Percepta and Chemaxon. A Lineweaver–Burk plot and docking study showed that 3c targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Moreover, 3c appears to possess neuroprotective activity and could be considered a free-radical scavenger. In addition, 3c did not cause DNA damage and was found to be less toxic than tacrine after oral administration; it also demonstrated little inhibitory activity towards hyaluronidase (HYAL), which may indicate that it possesses anti-inflammatory properties. The screening for new in vivo interactions between 3c and known receptors was realized by yeast three-hybrid technology (Y3H).