Structural aspects of 4-aminoquinolines as reversible inhibitors of human acetylcholinesterase and butyrylcholinesterase. (1st August 2019)

• Record Type: Journal Article
• Authors: Bosak, Anita; Opsenica, Dejan M.; Šinko, Goran; Zlatar, Matija; Kovarik, Zrinka
• Is Part Of: Chemico-biological interactions. Volume 308(2019)
• Page Start: 101
• Page End: 109
• Publication Date: 2019-08-01
• Subjects: Cholinesterase -- Alzheimer's disease -- pKa value -- Quinoline-based compounds -- Selectivity; Biochemistry -- Periodicals; Toxicological chemistry -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biochimie -- Périodiques; Toxicologie biochimique -- Périodiques; 572
• DOI: 10.1016/j.cbi.2019.05.024
• Languages: English
• ISSNs: 0009-2797

Abstract

Abstract : Eight derivatives of 4-aminoquinolines differing in the substituents attached to the C(4)-amino group and C(7) were synthesised and tested as inhibitors of human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Both enzymes were inhibited by all of the compounds with inhibition constants ( K i ) ranging from 0.50 to 50 μM exhibiting slight selectivity toward AChE over BChE. The most potent inhibitors of AChE were compounds with an n -octylamino chain or adamantyl group. The shortening of the chain length resulted in a decrease in AChE inhibition by 5–20 times. Docking studies revealed that the quinoline group within the AChE active site was positioned in the choline binding site, while the C(4)-amino group substituents, depending on their lipophilicity, could establish hydrogen bonds or π-interactions with residues of the peripheral anionic site. The most potent inhibitors of BChE were compounds with the most voluminous substituent on C(4)-amino group (adamantyl) or those with a stronger electron withdrawing substituent on C(7) (trifluormethyl group). Based on AChE inhibition, compounds with an n -octylamino chain or adamantyl substituent were shown to possess the capacity for further development as potential drugs for treatment of neurodegenerative diseases. Highlights: Three derivatives were nanomolar selective AChE inhibitors. The quinoline group is primarily stabilised by the choline binding site residues. 4-aminoquinoline derivatives exhibit slight selectivity toward AChE over BChE. 4-aminoquinoline derivatives have potential to penetrate the blood brain barrier.