New hybrids of 4-amino-2,3-polymethylenequinoline with different sizes of the aliphatic ring linked to butylated hydroxytoluene (BHT) by enaminoalkyl (7) or aminoalkyl (8) 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 8c, 2,6-di-tert-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 8 with amine-containing spacers were better antioxidants than those with enamine spacers 7. 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 8 appear promising as candidates for AD therapeutics.

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Patterns of the interaction between water soluble polysubstituted fullerene derivatives (PFDs) and the lipid bilayer of phosphatidylcholine liposomes were investigated by applying triplet and fluorescent probes. Objective quantitative criteria have been proposed for the evaluation of membranotropic action of chemical substances, notably, fullerene derivatives that quench fluorescent probes with different localizations within the membrane. Thus, the defined criteria are the rate constants for the quenching of the fluorescence of triplet probes and the equilibrium constants for PFD probe complexes, which characterize their stability. The localization of PFDs in the membrane was determined by comparing rate constants for the quenching of eosin phosphorescence and equilibrium constants for PFD-chromophore complexes. In addition, the effi ciency of the interaction of PFDs with various sites of the phospholipid membrane has been seen to depend on the charge of addends that are attached to the polysubstituted derivatives. N Br NH 2 H 2 N Br O COO Br O Br Br − O Br Eosin Y 2,7 Br proflavine Pyrene Fig. 1. Luminescent probes used in the study.

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