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

Abstract

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.

Therapeutic potential of ferulic acid and its derivatives in Alzheimer’s disease—A systematic review

“…Inspired by the utility of phenolics in this challenging area, several small molecule inhibitors have also been reported in the literature. (Makhaeva et al, 2020) (Samanta et al 2019) Thus, it can be observed that there is a growing interest in exploring phenolics and phenolic based small molecules against a challenging disease like AD where there is a complicated interplay and interconnectivity of several biochemical pathways, which are involved in its progression and pathology. We can only hope that these potential phenolic molecules, with their multifunctional activities, would provide some therapeutic relief in an area such as AD therapy where there is an immense need for newer avenues of therapeutic modalities.…”

“…Inspired by the utility of phenolics in this challenging area, several small molecule inhibitors have also been reported in the literature. (Makhaeva et al., 2020) (Samanta et al. 2019) Thus, it can be observed that there is a growing interest in exploring phenolics and phenolic based small molecules against a challenging disease like AD where there is a complicated interplay and interconnectivity of several biochemical pathways, which are involved in its progression and pathology.…”

Amaryllidaceae Alkaloids of Norbelladine-Type as Inspiration for Development of Highly Selective Butyrylcholinesterase Inhibitors: Synthesis, Biological Activity Evaluation, and Docking Studies

“…Moreover, some studies have shown that BuChE may contribute to the pathogenesis of type 2 diabetes mellitus (T2DM) by causing insulin resistance; the latter is considered as one of the major risk factors contributing to AD onset [ 15 , 16 ]. Recently, several new structural scaffolds have been designed, synthesized, and studied as new cholinesterase inhibitors [ 17 , 18 , 19 ].…”

Bis-Amiridines as Acetylcholinesterase and Butyrylcholinesterase Inhibitors: N-Functionalization Determines the Multitarget Anti-Alzheimer’s Activity Profile

“…We now know that AChE can mediate functions that have a bearing on AD pathogenesis, namely, its peripheral anionic site (PAS) can bring about the aggregation of Aβ [ 24 , 25 , 26 ]. This finding has prompted a new research direction aimed at discovering drug candidates capable of both inhibiting AChE activity and its capacity to facilitate the formation of Aβ aggregates [ 27 , 28 , 29 , 30 , 31 , 32 ]. Agents possessing both these abilities could perform dual functions as cognition enhancers and disease modifiers [ 33 , 34 , 35 ].…”

“…These pathogenic features of ROS justify the incorporation of antioxidants in AD therapeutics [ 40 , 42 , 43 , 44 ]. Accordingly, in the search for potential therapeutic agents for AD, it could be beneficial to discover anticholinesterase compounds that could perform a double duty as antioxidants [ 32 , 44 , 45 , 46 , 47 , 48 ].…”