New Multifunctional Agents Based on Conjugates of 4-Amino-2,3-polymethylenequinoline and Butylated Hydroxytoluene for Alzheimer’s Disease Treatment

• Main Authors: Galina F. Makhaeva, Nadezhda V. Kovaleva, Elena V. Rudakova, Natalia P. Boltneva, Sofya V. Lushchekina, Irina I. Faingold, Darya A. Poletaeva, Yuliya V. Soldatova, Raisa A. Kotelnikova, Igor V. Serkov, Anatoly K. Ustinov, Alexey N. Proshin, Eugene V. Radchenko, Vladimir A. Palyulin, Rudy J. Richardson
• Format: Article
• Language: English
• Published: MDPI AG 2020-12-01
• Series: Molecules
• Subjects: 4-amino-2,3-polymethylenequinolines; butylated hydroxytoluene (BHT); acetylcholinesterase (AChE); butyrylcholinesterase (BChE); antioxidants; neuroprotection
• Online Access: https://www.mdpi.com/1420-3049/25/24/5891

New hybrids of 4-amino-2,3-polymethylenequinoline with different sizes of the aliphatic ring linked to butylated hydroxytoluene (BHT) by enaminoalkyl (<b>7</b>) or aminoalkyl (<b>8</b>) spacers were synthesized as potential multifunctional agents for Alzheimer’s disease (AD) treatment. All compounds were potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity toward BChE. Lead compound <b>8c,</b> 2,6-di-<i>tert</i>-butyl-4-{[2-(7,8,9,10- tetrahydro-6H-cyclohepta[b]quinolin-11-ylamino)-ethylimino]-methyl}-phenol exhibited an IC₅₀(AChE) = 1.90 ± 0.16 µM, IC₅₀(BChE) = 0.084 ± 0.008 µM, and 13.6 ± 1.2% propidium displacement at 20 μM. Compounds possessed low activity against carboxylesterase, indicating likely absence of clinically unwanted drug-drug interactions. Kinetics were consistent with mixed-type reversible inhibition of both cholinesterases. Docking indicated binding to catalytic and peripheral AChE sites; peripheral site binding along with propidium displacement suggest the potential of the hybrids to block AChE-induced β-amyloid aggregation, a disease-modifying effect. Compounds demonstrated high antioxidant activity in ABTS and FRAP assays as well as inhibition of luminol chemiluminescence and lipid peroxidation in mouse brain homogenates. Conjugates <b>8</b> with amine-containing spacers were better antioxidants than those with enamine spacers <b>7</b>. Computational ADMET profiles for all compounds predicted good blood-brain barrier distribution (permeability), good intestinal absorption, and medium cardiac toxicity risk. Overall, based on their favorable pharmacological and ADMET profiles, conjugates <b>8</b> appear promising as candidates for AD therapeutics.