Tackling neuroinflammation and cholinergic deficit in Alzheimer's disease: Multi-target inhibitors of cholinesterases, cyclooxygenase-2 and 15-lipoxygenase
“…Tacrine is the first drug approved for AD treatment. It has a high affinity for the AChE CAS and is widely employed as a pharmacophore to create multifunctional cholinesterase inhibitors possessing additional neuroprotective and disease-modifying properties [46,[51][52][53][54][55][56][57].…”
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.
“…Tacrine is the first drug approved for AD treatment. It has a high affinity for the AChE CAS and is widely employed as a pharmacophore to create multifunctional cholinesterase inhibitors possessing additional neuroprotective and disease-modifying properties [46,[51][52][53][54][55][56][57].…”
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.
“…The result exhibited that Ki value for compound 5c was 0.053 µM. This value of Ki outperforms many highly potent mixed-type inhibitors discovered recently 13,31,32 .Figure 3Kinetic study on the mechanism of eeAChE inhibition by compounds 5c . ( A ) Overlaid Lineweavere-Burk reciprocal plot of eeAChE initial velocity at increasing ATCI concentration in the absence of inhibitors and in the presence of 5c is shown.…”
Acetylcholinesterase (AChE) catalyzes the conversion of Aβ peptide to its aggregated form and the peripheral anionic site (PAS) of AChE is mainly involved in this phenomenon. Also catalytic active site (CAS) of donepezil stimulates the break-down of acetylcholine (ACh) and depletion of ACh in cholinergic synapses are well established in brains of patients with AD. In this study, a set of compounds bearing phenoxyethyl amines were synthesized and their inhibitory activity toward electric eel AChE (eeAChE) and equine butyrylcholinesterase (eqBuChE) were evaluated. Molecular dynamics (MD) was employed to record the binding interactions of best compounds against human cholinesterases (hAChE and hBuChE) as well as donepezil as reference drug. In vitro results revealed that compound 5c is capable of inhibiting eeAChE activity at IC50 of 0.50 µM while no inhibitory activity was found for eqBuChE for up to 100 µM concentrations. Compound 5c, also due to its facile synthesis, small structure and high selectivity for eeAChE would be very interesting candidate in forthcoming studies. The main interacting parts of compound 5c and compound 7c (most potent eeAChE and eqBuChE inhibitors respectively) with receptors which confer selectivity for AChE and BuChE inhibition were identified, discussed, and compared with donepezil’s interactions. Also during MD simulation it was discovered for the first time that binding of substrates like donepezil to dual CAS and PAS or solely CAS region might have a suppressive impact on 4-α-helical bundles near the tryptophan amphiphilic tetramerization (WAT) domain of AChE and residues which are far away from AChE active site. The results proposed that residues involved in donepezil interactions (Trp86 and Phe295) which are located in CAS and mid-gorge are the mediator of conformational changes in whole protein structure.
“…Cholinergic deficits, as well as neuroinflammation, are known to be involved in the progression of neurodegenerative diseases such as Alzheimer's disease [34], suggesting that acetylcholine is vital in maintaining synaptic plasticity and mediating learning and memory [35]. In this study, we showed that there was an increase in the acetylcholine content in the brain of okara-fed mice compared to the control group, suggesting that this increase was caused by an increase in the expression of acetylcholine-synthesizing enzyme, ChAT.…”
The microbiota–gut–brain axis has attracted increasing attention in the last decade. Here, we investigated whether okara, a soybean by-product rich in dietary fiber, can attenuate cognitive impairment in senescence-accelerated mouse prone 8 (SAMP8) mice by altering gut microbial composition. Mice were fed either a standard diet, or a diet containing okara (7.5% or 15%, w/w) for 26 weeks. In the memory test, the 7.5% okara-fed mice showed a longer step-through latency and the 15% okara-fed mice had a short escape latency compared with control mice. The 15% okara-fed mice displayed decreased body weight, increased fecal weight, and altered cecal microbiota composition compared with the control group; however, there was no significant difference in the serum lactic acid and butyric acid levels among these mice groups. The 7.5% okara-fed mice had significantly higher NeuN intensity in the hippocampus compared with control mice. Furthermore, a decrease in inflammatory cytokine TNF-α and an increase in brain-derived neurotrophic factor (BDNF) was observed in the 7.5% okara-fed group. The expression of synthesizing enzyme of acetylcholine was increased by the okara diets, and the acetylcholine level in the brain was higher in the 7.5% okara-fed group than in the control. These suggest that oral administration of okara could delay cognitive decline without drastically changing gut microbiota.
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