New synthetic derivatives of isoindoline-dione: synthesis, neuroprotection assay and impact on the expression level of oxidative stress-related genes in neuronal-like cell line.

PURPOSE: Oxidative stress can damage cells and cause age-related illnesses such as Alzheimer's, Parkinson's, and Huntington's. This study looked at newly synthesized isoindole derivatives and their effects on SH-SY5Y as a neuroblastoma cell under oxidative stress through the NRF2 signaling pathway. NRF2 transcription factor plays a vital role in the oxidative stress response and cellular homeostasis. METHOD: Three isoindoline-dione derivatives were synthesized by reacting phthalic anhydrides with 4-(2-aminoethyl)-1-benzyl piperidine. Their structures were confirmed through FT-IR, NMR, and Mass spectroscopy. The derivatives were then tested on human SH-SY5Y cells under an oxidative stress model induced by hydrogen peroxide (H2O2). The cell viability, ROS levels, protein carbonyl content, and gene expression of NRF2 and phase II antioxidative enzymes were measured after 24 h. RESULTS: Three isoindoline derivatives (3a-3c) were observed to increase the viability of SH-SY5Y cells by protective against oxidative stress, reducing intracellular reactive oxygen species and carbonylated proteins, and increasing gene expression levels of NRF2 and associated genes such as NQO-1, and GSTK1. CONCLUSION: Isoindoline derivatives demonstrated a neuroprotective effect on SH-SY5Y cells through various neuroprotective mechanisms, although more studies are needed.

Novel 3-aminobenzofuran derivatives as multifunctional agents for the treatment of Alzheimer's disease.

A novel multifunctional series of 3-aminobenzofuran derivatives 5a-p were designed and synthesized as potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The target compounds 5a-p were prepared via a three-step reaction, starting from 2-hydroxy benzonitrile. In vitro anti-cholinesterase activity exhibited that most of the compounds had potent acetyl- and butyrylcholinesterase inhibitory activity. In particular, compound 5f containing 2-fluorobenzyl moiety showed the best inhibitory activity. Furthermore, this compound showed activity on self- and AChE-induced Aß-aggregation and MTT assay against PC12 cells. The kinetic study revealed that compound 5f showed mixed-type inhibition on AChE. Based on these results, compound 5f can be considered as a novel multifunctional structural unit against Alzheimer's disease.

Novel Coumarin-Pyridine Hybrids as Potent Multi-Target Directed Ligands Aiming at Symptoms of Alzheimer's Disease.

In this research, a series of coumarin-based scaffolds linked to pyridine derivatives via a flexible aliphatic linkage were synthesized and assessed as multifunctional anti-AD agents. All the compounds showed acceptable acetylcholinesterase (AChE) inhibition activity in the nanomolar range (IC50 = 2-144 nM) and remarkable butyrylcholinesterase (BuChE) inhibition property (IC50 = 9-123 nM) compared to donepezil as the standard drug (IC50 = 14 and 275 nM, respectively). Compound 3f as the best AChE inhibitor (IC50 = 2 nM) showed acceptable BuChE inhibition activity (IC50 = 24 nM), 100 times more active than the standard drug. Compound 3f could also significantly protect PC12 and SH-SY5Y cells against H2O2-induced cell death and amyloid toxicity, respectively, superior to the standard drugs. It could interestingly reduce ß-amyloid self and AChE-induced aggregation, more potent than the standard drug. All the results suggest that compound 3f could be considered as a promising multi-target-directed ligand (MTDL) against AD.

Design, synthesis, and bio-evaluation of new isoindoline-1,3-dione derivatives as possible inhibitors of acetylcholinesterase.

BACKGROUND AND PURPOSE: Alzheimer's disease is considered one of the lead causes of elderly death around the world. A significant decrease in acetylcholine level in the brain is common in most patients with Alzheimer's disease, therefore acetylcholinesterase (AChE) inhibitors such as donepezil and rivastigmine are widely used for patients with limited therapeutic results and major side effects. EXPERIMENTAL APPROACH: A series of isoindoline-1,3-dione -N-benzyl pyridinium hybrids were designed, synthesized and evaluated as anti-Alzheimer agents with cholinesterase inhibitory activities. The structure of the compounds were confirmed by various methods of analysis such as HNMR, CNMR, and FT-IR. Molecular modeling studies were also performed to identify the possible interactions between neprilysin and synthesized compounds. FINDINGS/RESULTS: The biological screening results indicated that all synthesized compounds displayed potent inhibitory activity with IC50 values ranging from 2.1 to 7.4 µM. Among synthesized compounds, para-fluoro substituted compounds 7a and 7f exhibited the highest inhibitory potency against AChE (IC50 = 2.1 µM). Molecular modeling studies indicated that the most potent compounds were able to interact with both catalytic and peripheral active sites of the enzyme. Also, some of the most potent compounds (7a, 7c, and 7f) demonstrated a neuroprotective effect against H2O2-induced cell death in PC12 neurons. CONCLUSION AND IMPLICATIONS: The synthesized compounds demonstrated moderate to good AChE inhibitory effect with results higher than rivastigmine.

Chromone derivatives bearing pyridinium moiety as multi-target-directed ligands against Alzheimer's disease.

A new serise of 7-hydroxy-chromone derivatives bearing pyridine moiety were synthesized, and evaluated as multifunctional agents against Alzheimer's disease (AD). Most of the compounds were good AChE inhibitors (IC50 = 9.8-0.71 µM) and showed remarkable BuChE inhibition activity (IC50 = 1.9-0.006 µM) compared with donepezil as the standard drug (IC50 = 0.023 and 3.4 µM). Compounds 14 and 10 showed the best inhibitory activity toward AChE (IC50 = 0.71 µM) and BuChE (IC50 = 0.006 µM), respectively. The ligand-protein docking simulations and kinetic studies revealed that compound 14 and 10 could bind effectively to the peripheral anionic binding site (PAS) of the AChE and BuChE through mixed-type inhibition. In addition, the most potent compounds showed acceptable neuroprotective activity on H2O2- and Aß-induced .neurotoxicity in PC12 cells, more than standard drugs. The compounds could block effectively self- and AChE-induced Aß aggregation. All the results suggest that compounds 14 and 10 could be considered as promising multi-target-directed ligands against AD.

Design and synthesis of new carbamates as inhibitors for fatty acid amide hydrolase and cholinesterases: Molecular dynamic, in vitro and in vivo studies.

As anandamide (N-arachidonoylethanolamine, AEA) shows neuroprotective effects, the inhibition of its degradative enzyme, fatty acid amide hydrolase (FAAH) has been considered as a hopeful avenue for the treatment of neurodegenerative diseases, like Alzheimer's disease (AD). Memory loss, cognitive impairment and diminution of the cholinergic tone, due to the dying cholinergic neurons in the basal forebrain, are common hallmarks in patients with AD. By taking advantage of cholinesterase inhibitors (ChEIs), the degradation of acetylcholine (ACh) is decreased leading to enhanced cholinergic neurotransmission in the aforementioned region and ultimately improves the clinical condition of AD patients. In this work, new carbamates were designed as inhibitors of FAAH and cholinestrases (ChEs) (acetylcholinestrase (AChE), butyrylcholinestrase (BuChE)) inspired by the structure of the native substrates, structure of active sites and the SARs of the well-known inhibitors of these enzymes. All the designed compounds were synthesized using different reactions. All the target compounds were tested for their inhibitory activity against FAAH and ChEs by employing the Cayman assay kit and Elman method respectively. Generally, compounds possessing aminomethyl phenyl linker was more potent compared to their corresponding compounds possessing piperazinyl ethyl linker. The inhibitory potential of the compounds 3a-q extended from 0.83 ± 0.03 µM (3i) to ˃100 µM (3a) for FAAH, 0.39 ± 0.02 µM (3i) to 24% inhibition in 113 ± 4.8 µM (3b) for AChE, and 1.8 ± 3.2 µM (3i) to 23.2 ± 0.2 µM (3b) for BuChE. Compound 3i a heptyl carbamate analog possessing 2-oxo-1,2-dihydroquinolin ring and aminomethyl phenyl linker showed the most inhibitory activity against three enzymes. Also, compound 3i was investigated for memory improvement using the Morris water maze test in which the compound showed better memory improvement at 10 mg/kg compared to reference drug rivastigmine at 2.5 mg/kg. Molecular docking and molecular dynamic studies of compound 3i into the enzymes displayed the possible interactions of key residues of the active sites with compound 3i. Finally, kinetic study indicated that 3i inhibits AChE through the mixed- mode mechanism and non-competitive inhibition mechanism was revealed for BuChE.

Chromone-lipoic acid conjugate: Neuroprotective agent having acceptable butyrylcholinesterase inhibition, antioxidant and copper-chelation activities.

PURPOSE: Alzheimer's disease (AD) is a multifaceted neurodegenerative disease. To target simultaneously multiple pathological processes involved in AD, natural-origin compounds with unique characteristics are promising scaffolds to develop novel multi-target compounds in the treatment of different neurodegenerative disease, especially AD. In this study, novel chromone-lipoic acid hybrids were prepared to find a new multifunctional lead structure for the treatment of AD. METHODS: Chromone-lipoic acid hybrids were prepared through click reaction and their neuroprotection and anticholinesterase activity were fully evaluated. The anti-amyloid aggregation, antioxidant and metal-chelation activities of the best compound were also investigated by standard methods to find a new multi-functional agent against AD. RESULTS: The primary biological screening demonstrated that all compounds had significant neuroprotection activity against H2O2-induced cell damage in PC12 cells. Compound 19 as the most potent butyrylcholinesterase (BuChE) inhibitor (IC50 = 7.55 µM) having significant neuroprotection activity as level as reference drug was selected for further biological evaluations. Docking and kinetic studies revealed non-competitive mixed-type inhibition of BuChE by compound 19. It could significantly reduce formation of the intracellular reactive oxygen species (ROS) and showed excellent reducing power (85.57 mM Fe+2), comparable with quercetin and lipoic acid. It could also moderately inhibit Aß aggregation and selectively chelate with copper ions in 2:1 M ratio. CONCLUSION: Compound 19 could be considered as a hopeful multifunctional agent for the further development gainst AD owing to the acceptable neuroprotective and anti-BuChE activity, moderate anti-Aß aggregation activity, outstanding antioxidant activity as well as selective copper chelation ability. A new chromone-lipoic acid hybrid was synthesized as anti-Alzheimer agent with BuChE inhibitory activity, anti-Aß aggregation, metal-chelation and antioxidant properties.

Synthesis of New 3-Arylcoumarins Bearing N-Benzyl Triazole Moiety: Dual Lipoxygenase and Butyrylcholinesterase Inhibitors With Anti-Amyloid Aggregation and Neuroprotective Properties Against Alzheimer's Disease.

A novel series of coumarin derivatives linked to the N-benzyl triazole group were synthesized and evaluated against 15-lipoxygenase (15-LOX), and acetyl- and butyrylcholinesterase (AChE and BuChE) to find the most potent derivative against Alzheimer's disease (AD). Most of the compounds showed weak to moderate activity against ChEs. Among the most active BuChE and 15-LOX inhibitors, 8l and 8n exhibited an excellent neuroprotective effect, higher than the standard drug (quercetin) on the PC12 cell model injured by H2O2 and significantly reduced aggregation of amyloid Aß1-42, with potencies of 1.44 and 1.79 times higher than donepezil, respectively. Compound 8l also showed more activity than butylated hydroxytoluene (BHT) as the reference antioxidant agent in reducing the levels of H2O2 activated by amyloid ß in BV2 microglial cells. Kinetic and ligand-enzyme docking studies were also performed for better understanding of the mode of interaction between the best BuChE inhibitor and the enzyme. Considering the acceptable BuChE and 15-LOX inhibition activities as well as significant neuroprotection, and anti-amyloid aggregation activities, 8l and 8n could be considered as potential MTDLs for further modification and studies against AD.

Isolation of HLA-G+ cells using MEM-G/9 antibody-conjugated magnetic nanoparticles for prenatal screening: a reliable, fast and efficient method.

The development of an effective and noninvasive early method for obtaining fetal cells is crucial to prenatal screening. Despite proving the presence of fetal cells in the reproductive tract, their use is limited due to their inability to properly isolate them from maternal cells. Magnetic-activated cell sorting (MACS) is a simple technique to separate cells. The present study aimed to develop a MACS-based platform for the isolation of the HLA-G expressing trophoblast cells. For this purpose, first, the triazine functionalized MNPs were synthesized and characterized. Then, MNPs were directly and indirectly conjugated by the MEM-G/9 antibodies targeting HLA-G+ cells. The antibody amount on the surface of the nanoparticles was determined with the Bradford assay. The cell capture efficiency was also investigated. Various characterization methods confirmed the successful nanoparticle synthesis and antibody conjugation. The optimal initial antibody amount for the immobilization was about 20 µg and the optimal time was 3 h. The antibody-nanoparticles by the indirect method had better targeting and capture efficiency than the direct method. The MNPs indirectly conjugated with antibodies are an efficient tool for cell isolation and present considerable potential to be applied in biomedical fields.

A review: Biologically active 3,4-heterocycle-fused coumarins.

The combination of heterocycles offers a new opportunity to create novel multicyclic compounds having improved biological activity. Coumarins are ubiquitous natural heterocycle widely adopted in the design of various biologically active compounds. Fusing different heterocycles with coumarin ring is one of the interesting approaches to generating novel hybrid molecules having highlighted biological activities. In the efforts to develop heterocyclic-fused coumarins, a wide range of 3,4-heterocycle-fused coumarins have been introduced bearing outstanding biological activity. The effect of heterocycles annulation at 3,4-positions of coumarin ring on the biological activity of the target structures were discussed. This review focuses on the important progress of 3,4-heterocycle-fused coumarins providing better insight for medicinal chemists on the design and preparation of biologically active heterocycle-fused coumarins with a significant therapeutic effect in the future.

Design, synthesis, and evaluation of novel cinnamic acid-tryptamine hybrid for inhibition of acetylcholinesterase and butyrylcholinesterase.

BACKGROUND: Acetylcholine deficiencies in hippocampus and cortex, aggregation of ß-amyloid, and ß-secretase over activity have been introduced as main reasons in pathogenesis of Alzheimer's disease. METHODS: Colorimetric Ellman's method was used for determination of IC50 value in AChE and BChE inhibitory activity. The kinetic studies, neuroprotective and ß-secretase inhibitory activities, evaluation of inhibitory potency on ß-amyloid (Aß) aggregations induced by AChE, and docking study were performed for prediction of the mechanism of action. RESULT AND DISCUSSION: A new series of cinnamic acids-tryptamine hybrid was designed, synthesized, and evaluated as dual cholinesterase inhibitors. These compounds demonstrated in-vitro inhibitory activities against acetyl cholinesterase (AChE) and butyryl cholinesterase (BChE). Among of these synthesized compounds, (E)-N-(2-(1H-indol-3-yl)ethyl)-3-(3,4-dimethoxyphenyl)acrylamide (5q) demonstrated the most potent AChE inhibitory activity (IC50 = 11.51 µM) and (E)-N-(2-(1H-indol-3-yl)ethyl)-3-(2-chlorophenyl)acrylamide (5b) were the best anti-BChE (IC50 = 1.95 µM) compounds. In addition, the molecular modeling and kinetic studies depicted 5q and 5b were mixed type inhibitor and bound with both the peripheral anionic site (PAS) and catalytic sites (CAS) of AChE and BChE. Moreover, compound 5q showed mild neuroprotective in PC12 cell line and weak ß-secretase inhibitory activities. This compound also inhibited aggregation of ß-amyloid (Aß) in self-induced peptide aggregation test at concentration of 10 µM. CONCLUSION: It is worth noting that both the kinetic study and the molecular modeling of 5q and 5b depicted that these compounds simultaneously interacted with both the catalytic active site and the peripheral anionic site of AChE and BChE. These findings match with those resulted data from the enzyme inhibition assay. Graphical abstract A new series of cinnamic-derived acids-tryptamine hybrid derivatives were designed, synthesized and evaluated as butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) inhibitors and neuroprotective agents. Compound 5b and 5q, as the more potent compounds, interacted with both the peripheral site and the choline binding site having mixed type inhibition. Results suggested that derivatives have a therapeutic potential for the treatment of AD.

Design, synthesis, in vivo and in vitro studies of 1,2,3,4-tetrahydro-9H-carbazole derivatives, highly selective and potent butyrylcholinesterase inhibitors.

Inhibition of butyrylcholinesterase (BChE) might be a useful therapeutic target for Alzheimer's disease (AD). A new series of 1,2,3,4-tetrahydro-9H-carbazole derivatives were designed synthesized and evaluated as BChE inhibitors. While all of the derivatives have shown for AChE IC50 values below the detectable limit (> 100 µM), they were selective potent BChE inhibitors. 1-(2-(6-fluoro-1,2,3,4-tetrahydro-9H-carbazole-9-yl)ethyl)piperidin-1-ium chloride (15 g) had the most potent anti-BChE activity (IC50 value = 0.11 µM), the highest BChE selectivity and mixed-type inhibition. Pharmacokinetic properties were accordant to Lipinski rule and compound 15g demonstrated neuroprotective and inhibition of ß-secretase (BACE1) activities. Furthermore, in vivo study of compound 15g in Morris water maze task has confirmed memory improvement in scopolamine-induced impairment. All results suggest that new sets of potent selective inhibitors of BChE have a therapeutic potential for the treatment of AD. A new series of 1,2,3,4-tetrahydro-9H-carbazole derivatives were designed synthesized and evaluated as BChE inhibitors. While all of the derivatives have shown for AChE IC50 values below the detectable limit, they were selective potent BChE inhibitors. Compound 15g had the most potent anti-BChE activity. All results suggest that new sets of potent selective inhibitors of BChE have a therapeutic potential for the treatment of AD.

Design and synthesis of benzodiazepine-1,2,3-triazole hybrid derivatives as selective butyrylcholinesterase inhibitors.

A new series of compounds based on benzodiazepine-1,2,3-triazole were synthesized and evaluated as cholinesterase inhibitors by Ellman's method. The compounds proved to be selective inhibitors of butyrylcholinesterase (BuChE) over acetylcholinesterase. The most potent compound was 3,3-dimethyl-11-(3-((1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one, identified as a submicromolar inhibitor of BuChE with IC50 value of 0.2 µM. In addition, the amyloid-ß self-aggregation evaluation studies for selected compounds showed potent inhibitory effects compared to donepezil. The docking and cell viability studies supported the potential of compound 9b-6 as significant BuChE inhibitor.

Molecular Characterization of Aquaglyceroporine: A Novel Mutation in LmAQP1 from Leishmania major (MRHO/IR/75/ER).

BACKGROUND: The first line treatment for cutaneous leishmaniasis is pentavalent antimony such as sodium stibogluconate (pentostam) and meglumine antimonite (glucantime). One of the most important ways to uptake the drug is by a trans-membrane protein, called aquaglyceroporin encoded by Aquaglyceroprotein1 (LmAQP1). In this study, molecular characterization of LmAQP1 was reported. METHODS: Leishmania major (MRHO/IR/75/ER) promastigotes were cultured, and then DNA extraction and RNA extraction were done and followed by cDNA synthesis. Amplicons resulted from PCR and RT-PCR using specific primers were purified and sequenced. Molecular characterization was done by bioinformatically software such as BLST, ClustalW2, and RMSD. RESULTS: Amplicons resulted from PCR and RT-PCR showed equal size in length. BLASTn analysis showed a point nucleotide change in LmAQP1 gene that encoded 282-amino-acid long protein with a mutation at position 154 including replacement of alanine by threonine. The observed mutation in the interested gene was assessed using the above-mentioned software. The mentioned gene was submitted at GenBank, NCBI with accession number of KU514052. CONCLUSION: The functional prediction of the protein encoded from LmAQP1 showed that the mentioned mutation could not affect the three-dimension structure, but it may modify the drug uptake potential of this important channel. Based on from LmAQP1 role, it seems to be an appropriate candidate for drug development. According to search through internet, this is the first report of LmAQP1 from L. major (MRHO/IR/75/ER).

Design, Synthesis, Molecular Docking, and Cholinesterase Inhibitory Potential of Phthalimide-Dithiocarbamate Hybrids as New Agents for Treatment of Alzheimer's Disease.

A novel series of phthalimide-dithiocarbamate hybrids was synthesized and evaluated for in vitro inhibitory potentials against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The anti-cholinesterase results indicated that among the synthesized compounds, the compounds 7g and 7h showed the most potent anti-AChE and anti-BuChE activities, respectively. Molecular docking and dynamic studies of the compounds 7g and 7h, respectively, in the active site of AChE and BuChE revealed that these compounds as well interacted with studied cholinesterases. These compounds also possessed drug-like properties and were able to cross the BBB.

New classes of carbazoles as potential multi-functional anti-Alzheimer's agents.

Multi-Target approach is particularly promising way to drug discovery against Alzheimer's disease. In the present study, we synthesized a series of compounds comprising the carbazole backbone linked to the benzyl piperazine, benzyl piperidine, pyridine, quinoline, or isoquinoline moiety through an aliphatic linker and evaluated as cholinesterase inhibitors. The synthesized compounds showed IC50 values of 0.11-36.5 µM and 0.02-98.6 µM against acetyl- and butyrylcholinesterase (AChE and BuChE), respectively. The ligand-protein docking simulations and kinetic studies revealed that compound 3s could bind effectively to the peripheral anionic binding site (PAS) and anionic site of the enzyme with mixed-type inhibition. Compound 3s was the most potent compound against AChE and BuChE and showed acceptable inhibition potency for self- and AChE-induced Aß1-42 aggregation. Moreover, compound 3s could significantly protect PC12 cells against H2O2-induced toxicity. The results suggested that the compounds 3s could be considered as a promising multi-functional agent for further drug discovery development against Alzheimer's disease.

Design, Synthesis, and Cholinesterase Inhibition Assay of Coumarin-3-carboxamide-N-morpholine Hybrids as New Anti-Alzheimer Agents.

A new series of coumarin-3-carboxamide-N-morpholine hybrids 5a-5l was designed and synthesized as cholinesterases inhibitors. The synthetic approach for title compounds was started from the reaction between 2-hydroxybenzaldehyde derivatives and Meldrum's acid to afford corresponding coumarin-3-carboxylic acids. Then, amidation of the latter compounds with 2-morpholinoethylamine or N-(3-aminopropyl)morpholine led to the formation of the compounds 5a-5l. The in vitro inhibition screen against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) revealed that most of the synthesized compounds had potent AChE inhibitory while their BuChE inhibitions are moderate to weak. Among them, propylmorpholine derivative 5g (N-[3-(morpholin-4-yl)propyl]-2-oxo-2H-chromene-3-carboxamide) bearing an unsubstituted coumarin moiety and ethylmorpholine derivative 5d (6-bromo-N-[2-(morpholin-4-yl)ethyl]-2-oxo-2H-chromene-3-carboxamide) bearing a 6-bromocoumarin moiety showed the most activity against AChE and BuChE, respectively. The inhibitory activity of compound 5g against AChE was 1.78 times more than that of rivastigmine and anti-BuChE activity of compound 5d is approximately same as rivastigmine. Kinetic and docking studies confirmed the dual binding site ability of compound 5g to inhibit AChE.

Design, synthesis, and biological evaluation of novel 4-oxobenzo[d]1,2,3-triazin-benzylpyridinum derivatives as potent anti-Alzheimer agents.

Novel 4-oxobenzo[d]1,2,3-triazin derivatives bearing pyridinium moiety 6a-q were synthesized and screened against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Most of the synthesized compounds showed good inhibitory activity against AChE. Among the synthesized compounds, the compound 6j exhibited the highest AChE inhibitory activity. It should be noted that these compounds displayed low anti-BuChE activity with the exception of the compound 6i, as it exhibited BuChE inhibitory activity more than donepezil. The kinetic study of the compound 6j revealed that this compound inhibited AChE in a mixed-type inhibition mode. This finding was also confirmed by the docking study. The latter study demonstrated that the compound 6j interacted with both the catalytic site and peripheral anionic site of the AChE active site. The compound 6j was also observed to have significant neuroprotective activity against H2O2-induced PC12 oxidative stress, but low activity against ß-secretase.

3-Aryl Coumarin Derivatives Bearing Aminoalkoxy Moiety as Multi-Target-Directed Ligands against Alzheimer's Disease.

Two series of novel coumarin derivatives, substituted at 3 and 7 positions with aminoalkoxy groups, are synthesized, characterized, and screened. The effect of amine substituents and the length of cross-linker are investigated in acetyl- and butyrylcholinesterase (AChE and BuChE) inhibition. Target compounds show moderate to potent inhibitory activities against AChE and BuChE. 3-(3,4-Dichlorophenyl)-7-[4-(diethylamino)butoxy]-2H-chromen-2-one (4y) is identified as the most potent compound against AChE (IC50 =0.27 µm). Kinetic and molecular modeling studies affirmed that compound 4y works in a mixed-type way and interacts simultaneously with the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. In addition, compound 4y blocks ß-amyloid (Aß) self-aggregation with a ratio of 44.11 % at 100 µm and significantly protects PC12 cells from H2 O2 -damage in a dose-dependent manner.

New benzyl pyridinium derivatives bearing 2,4-dioxochroman moiety as potent agents for treatment of Alzheimer's disease: Design, synthesis, biological evaluation, and docking study.

A new series of benzyl pyridinium-2,4-dioxochroman derivatives 7a-o was synthesized and evaluated as new anti-Alzheimer agents. Among the synthesized compounds, the compounds 7f and 7i exhibited the most potent anti-AChE and anti-BuChE activities, respectively. The kinetic study of the compound 7f revealed that this compound inhibited AChE in a mixed-type inhibition mode. Furthermore, the docking study of the compounds 7f and 7i showed that these compounds bound to both the catalytic site (CS) and peripheral anionic site (PAS) of AChE and BuChE, respectively. The compound 7f also exhibited a greater self-induced Aß peptide aggregation inhibitory activity in compare to donepezil. Furthermore, the neuroprotective activity of this compound at 20 µM was comparable to that of the standard neuroprotective agent (quercetin).