New Hybrids of 4-Amino-2,3-polymethylene-quinoline and p-Tolylsulfonamide as Dual Inhibitors of Acetyl- and Butyrylcholinesterase and Potential Multifunctional Agents for Alzheimer’s Disease Treatment

Abstract

New hybrid compounds of 4-amino-2,3-polymethylene-quinoline containing different sizes of the aliphatic ring and linked to p-tolylsulfonamide with alkylene spacers of increasing length were synthesized as potential drugs for treatment of Alzheimer’s disease (AD). All compounds were potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity toward BChE. The lead compound 4-methyl-N-(5-(1,2,3,4-tetrahydro-acridin-9-ylamino)-pentyl)-benzenesulfonamide (7h) exhibited an IC50 (AChE) = 0.131 ± 0.01 µM (five times more potent than tacrine), IC50(BChE) = 0.0680 ± 0.0014 µM, and 17.5 ± 1.5% propidium displacement at 20 µM. The compounds possessed low activity against carboxylesterase, indicating a likely absence of unwanted drug-drug interactions in clinical use. Kinetics studies were consistent with mixed-type reversible inhibition of both cholinesterases. Molecular docking demonstrated dual binding sites of the conjugates in AChE and clarified the differences in the structure-activity relationships for AChE and BChE inhibition. The conjugates could bind to the AChE peripheral anionic site and displace propidium, indicating their potential to block AChE-induced β-amyloid aggregation, thereby exerting a disease-modifying effect. All compounds demonstrated low antioxidant activity. Computational ADMET profiles predicted that all compounds would have good intestinal absorption, medium blood-brain barrier permeability, and medium cardiac toxicity risk. Overall, the results indicate that the novel conjugates show promise for further development and optimization as multitarget anti-AD agents.

Towards Deep Neural Network Models for the Prediction of the Blood–Brain Barrier Permeability for Diverse Organic Compounds

“…Previously, this approach was successfully used by us to model the effects of structure on a number of physico-chemical, pharmacokinetic, and toxicity endpoints such as lipophilicity [ 56 ], blood–brain barrier permeability (preliminary model [ 57 ]), human intestinal absorption [ 58 ], hERG-mediated cardiac toxicity [ 59 ], etc. Some of these models are available online at our ADMET Prediction Service page ( accessed 01 November 2020) and have been successfully used to evaluate the key absorption, distribution, metabolism, excretion, toxicity (ADMET) properties of potential drug compounds in the virtual screening and molecular design studies [ 60 , 61 , 62 , 63 ]. A secondary goal was to refine the modeling procedures suitable for deep neural networks as well as to evaluate their applicability.…”

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

“…Human erythrocyte AChE, equine serum BChE, porcine liver CES, acetylthiocholine iodide (ATCh), butyrylthiocholine iodide (BTCh), 5,5’-dithio-bis-(2-nitrobenzoic acid) (DTNB), 4-nitrophenol acetate (4-NPA), tacrine, and BNPP were purchased from Sigma-Aldrich (Saint Louis, MO, USA). The activity of AChE and BChE was determined by the method of Ellman (λ = 412 nm) as described in detail in [ 52 ]. The activity of CES was determined spectrophotometrically (λ = 405 nm) by the release of 4-nitrophenol using 4-NPA as a substrate as described in [ 52 ].…”

“…The activity of AChE and BChE was determined by the method of Ellman (λ = 412 nm) as described in detail in [ 52 ]. The activity of CES was determined spectrophotometrically (λ = 405 nm) by the release of 4-nitrophenol using 4-NPA as a substrate as described in [ 52 ]. Measurements were performed with a FLUOStar Optima microplate reader (BMG Labtech, Ortenberg, Germany).…”

“…Linking two active molecules together through a spacer, resulting in a multifunctional hybrid molecule, is one of the ways to create such multi-target ligands [ 47 ]. Tacrine, which was the first FDA-approved drug for AD treatment, is widely employed as an anticholinesterase pharmacophore to create multifunctional cholinesterase inhibitors possessing additional neuroprotective and disease-modifying properties [ 42 , 45 , 48 , 49 , 50 , 51 , 52 , 53 ].…”

Novel Donepezil–Arylsulfonamide Hybrids as Multitarget-Directed Ligands for Potential Treatment of Alzheimer’s Disease

“…The option for aromatic sulfonamides, as second pharmacophore, is due to their wide clinical applications, namely as antibacterial, antifungal, anti-cancer and anti-depressant [ 17 ]. Furthermore, a number of sulfonamide-containing hybrids, enclosing tacrine/quinoline moieties, have been recently developed as promising anti-AD drugs, exhibiting good capacity for the inhibition of cholinesterases and self-induced A β aggregation, as well as antioxidant activity [ 18 , 19 , 20 ].…”