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•Seven alkaloids were isolated from the roots of Berberis parkeriana Schneid.•Nine new derivatives of jatrorrhizine were chemically synthesized.•Compounds showed selective inhibition ...against butyrylcholinesterase enzyme (IC50 = 5.5 ± 0.3 – 124.5 ± 0.4 µM).•Enzyme inhibition interactions were studied by molecular docking and kinetics.
Seven known isoquinoline alkaloids 1–7 were isolated from the root extracts of Berberis parkeriana Schneid. Nine new derivatives 8–16 of one of the isolated compounds, jatrorrhizine (7), were synthesized. All the isolated as well as derivatized compounds were evaluated for their in-vitro acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) inhibitory activity. Functionalized compounds selectively exhibited a potent-to-moderate activity with IC50 = 5.5 ± 0.3–124.5 ± 0.4 μM against butyrylcholinesterase enzyme. Among them, compound 15 was a potent BChE inhibitor (IC50 = 5.5 ± 0.3 μM), as compared to the standard drug galantamine hydrobromide (IC50 = 40.83 ± 0.37 μM). Active compounds were further subjected to kinetic, and molecular docking studies to predict their modes of inhibition, and interactions with the receptor (BChE), respectively. Enzyme kinetics studies showed that compounds 9 (IC50 = 25.3 ± 0.5 μM), and 14 (IC50 = 23.9 ± 0.5 μM) were non-competitive inhibitors, while compound 15 exhibited a competitive inhibition. In addition, these compounds were found to be non-cytotoxic against human fibroblast (BJ) cell line, except 9 (IC50 = 17.1 ± 1.0 μM), and 10 (IC50 = 18.4 ± 0.3 μM). Inhibition of cholinesterases is an important approach for development of drugs against Alzheimer’s disease, and thus discoveries presented here deserve further investigation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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•9-Aryl-N-methyl-9,10-dihydroacridines (9-aryl-NMDHAs) are radical scavengers.•9-Aryl-N-methyl-acridinium tetrafluoroborates are cholinesterase inhibitors.•9-Heterocyclic amino-NMDHAs ...are radical scavengers and cholinesterase inhibitors.
We investigated the inhibitory activity of 4 groups of novel acridine derivatives against acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and carboxylesterase (CaE) using the methods of enzyme kinetics and molecular docking. Antioxidant activity of the compounds was determined using the 2,2′-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS+) radical decolorization assay as their ability to scavenge free radicals. Analysis of the esterase profiles and antiradical activities of the acridine derivatives showed that 9-aryl(heteroaryl)-N-methyl-9,10-dihydroacridines have a high radical-scavenging activity but low potency as AChE and BChE inhibitors, whereas 9-aryl(heteroaryl)-N-methyl-acridinium tetrafluoroborates effectively inhibit cholinesterases but do not exhibit antiradical activity. In contrast, a group of derivatives of 9-heterocyclic amino-N-methyl-9,10-dihydroacridine has been found that combine effective inhibition of AChE and BChE with rather high radical-scavenging activity. The results of molecular docking well explain the observed features in the efficacy, selectivity, and mechanism of cholinesterase inhibition by the acridine derivatives. Thus, in a series of acridine derivatives we have found compounds possessing dual properties of effective and selective cholinesterase inhibition together with free radical scavenging, which makes promising the use of the acridine scaffold to create multifunctional drugs for the therapy of neurodegenerative diseases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
In the present work, we use a merger of computational and biochemical techniques as a rational guideline for structural modification of benzofuran derivatives to find pertinent structural features ...for the butyrylcholinesterase inhibitory activity and selectivity. Previously, we revealed a series of 2-phenylbenzofuran compounds that displayed a selective inhibitory activity for BChE. Here, in an effort to discover novel selective BChE inhibitors with favorable physicochemical and pharmacokinetic profiles, 2-benzylbenzofurans were designed, synthesized, and evaluated as BChE inhibitors. The 2-phenylbenzofuran scaffold structure is modified by introducing one methylene spacer between the benzofuran core and the 2-phenyl ring with a hydroxyl substituent in the para or meta position. Either position 5 or 7 of the benzofuran scaffold was substituted with a bromine or chlorine atom. Further assessment of the selected list of compounds indicated that the substituent's nature and position determined their activity and selectivity. 5-bromo-2-(4-hydroxybenzyl)benzofuran
proved to be the most potent butyrylcholinesterase inhibitor (IC
= 2.93 µM) of the studied series. Computational studies were carried out to correlate the theoretical and experimental binding affinity of the compounds to the BChE protein.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The development of multitarget compounds against multifactorial diseases, such as Alzheimer's disease, is an area of very intensive research, due to the expected superior therapeutic efficacy that ...should arise from the simultaneous modulation of several key targets of the complex pathological network. Here we describe the synthesis and multitarget biological profiling of a new class of compounds designed by molecular hybridization of an NMDA receptor antagonist fluorobenzohomoadamantanamine with the potent acetylcholinesterase (AChE) inhibitor 6-chlorotacrine, using two different linker lengths and linkage positions, to preserve or not the memantine-like polycyclic unsubstituted primary amine. The best hybrids exhibit greater potencies than parent compounds against AChE (IC50 0.33 nM in the best case, 44-fold increased potency over 6-chlorotacrine), butyrylcholinesterase (IC50 21 nM in the best case, 24-fold increased potency over 6-chlorotacrine), and NMDA receptors (IC50 0.89 μM in the best case, 2-fold increased potency over the parent benzohomoadamantanamine and memantine), which suggests an additive effect of both pharmacophoric moieties in the interaction with the primary targets. Moreover, most of these compounds have been predicted to be brain permeable. This set of biological properties makes them promising leads for further anti-Alzheimer drug development.
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•A novel class of fluorobenzohomoadamantanamine‒chlorotacrine hybrids was synthesized.•The hybrids are up to 44-fold more potent than 6-chlorotacrine for hAChE inhibition.•The hybrids are up to 24-fold more potent than 6-chlorotacrine for hBChE inhibition.•The hybrids are up to 2-fold more potent than memantine for NMDA antagonism.•Most of the hybrids are brain permeable, according to the PAMPA-BBB assay.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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•Synthesis of cholinesterase inhibitors, fusing tacrine and the alkaloid solanocapsine.•Inhibition against AChE and BuChE enzymes at nM range was achieved.•Improved inhibition of ...BuChE was achieved since it could better allocate big compounds.•Docking and molecular dynamic studies suggest that they could act as dual inhibitors.
To date, Alzheimer's disease is the most alarming neurodegenerative disorder worldwide. This illness is multifactorial in nature and cholinesterase inhibitors have been the ones used in clinical treatments. In this context, many of these drugs selectively inhibit the acetylcholinesterase enzyme interacting in both the active site and the peripheric anionic site. Besides, some agents have exhibited extensive benefits being able to co-inhibit butyrylcholinesterase.
In this contribution, a strategy previously explored by numerous authors is reported; the synthesis of hybrid cholinesterase inhibitors. This strategy uses a molecule of recognized high inhibitory activity (tacrine) together with a steroidal alkaloid of natural origin using different connectors. The biological assays demonstrated the improvement in the inhibitory activity compared to the alkaloidal precursor, together with the reinforcement of the interactions in multiple sites of the enzymatic cavity. This strategy should be explored and exploited in this area.
Docking and molecular dynamic studies were performed to explain enzyme-ligand interactions, assisting a structure–activity relationship analysis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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Butyrylcholinesterase (BuChE) is considered a promising drug target as it plays an important role in the progression of late stage Alzheimer’s disease (AD). Two compound libraries ...were selected and 64 124 amine containing moieties were screened using a hierarchical virtual screening protocol to discover new selective BuChE inhibitors. From these and subsequent docking experiments, 9-phenylacridinedione (9-PAD) was identified as a promising scaffold for selective inhibition of BuChE. Selected top dock scored 9-PADs were assayed and compounds 3 and 6 exhibited potent and highly selective human BuChE inhibition (IC50: 98 nM and 142 nM, respectively). Both molecules were also predicted to show sufficient brain permeability, not have any substantial toxicities, especially hepatotoxicity, and no significant in vitro cytotoxicity against SH-SY5Y neuroblastoma cells at concentrations up to 100 µM. These findings indicate that 9-PAD is a promising lead structure for the development of agents able to treat late stage AD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
For the potential therapy of Alzheimer’s disease (AD), butyrylcholinesterase (BChE) has gradually gained worldwide interest in the progression of AD. This study used a pharmacophore-based virtual ...screening (VS) approach to identify Z32439948 as a new BChE inhibitor. Aiding by molecular docking and molecular dynamics, essential binding information was disclosed. Specifically, a subpocket was found and structure-guided design of a series of novel compounds was conducted. Derivatives were evaluated in vitro for cholinesterase inhibition and physicochemical properties (BBB, log P, and solubility). The investigation involved docking, molecular dynamics, enzyme kinetics, and surface plasmon resonance as well. The study highlighted compounds 27a (hBChE IC50 = 0.078 ± 0.03 μM) and (R)-37a (hBChE IC50 = 0.005 ± 0.001 μM) as the top-ranked BChE inhibitors. These compounds showed anti-inflammatory activity and no apparent cytotoxicity against the human neuroblastoma (SH-SY5Y) and mouse microglia (BV2) cell lines. The most active compounds exhibited the ability to improve cognition in both scopolamine- and Aβ1–42 peptide-induced cognitive deficit models. They can be promising lead compounds with potential implications for treating the late stage of AD.
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IJS, KILJ, NUK, PNG, UL, UM
A series of 4-aminomethyl-7-benzyloxy-2H-chromen-2-ones was investigated with the aim of identifying multiple inhibitors of cholinesterases (acetyl- and butyryl-, AChE and BChE) and monoamine oxidase ...B (MAO B) as potential anti-Alzheimer molecules. Starting from a previously reported potent MAO B inhibitor (3), we studied single-point modifications at the benzyloxy or at the basic moiety. The in vitro screening highlighted triple-acting compounds (6, 8, 9, 16, 20) showing nanomolar and selective MAO B inhibition along with IC50 against ChEs at the low micromolar level. Enzyme kinetics analysis toward AChE and docking simulations on the target enzymes were run in order to get insight into the mechanism of action and plausible binding modes.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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•New multifunctional propargylamines were synthesized and evaluated biologically.•All compounds selectively inhibit human butyrylcholinesterase.•All compounds cross the blood-brain ...barrier in an in vitro assay.•Three compounds also inhibit monamine oxidase B.•The crystal structure of human butyrylcholinesterase in complex with 3 was solved.
In the brains of patients with Alzheimer’s disease, the enzymatic activities of butyrylcholinesterase (BChE) and monoamine oxidase B (MAO-B) are increased. While BChE is a viable therapeutic target for alleviation of symptoms caused by cholinergic hypofunction, MAO-B is a potential therapeutic target for prevention of neurodegeneration in Alzheimer’s disease. Starting with piperidine-based selective human (h)BChE inhibitors and propargylamine-based MAO inhibitors, we have designed, synthesized and biochemically evaluated a series of N-propargylpiperidines. All of these compounds inhibited hBChE with good selectivity over the related enzyme, acetylcholinesterase, and crossed the blood-brain barrier in a parallel artificial membrane permeation assay. The crystal structure of one of the inhibitors (compound 3) in complex with hBChE revealed its binding mode. Three compounds (4, 5, 6) showed concomitant inhibition of MAO-B. Additionally, the most potent hBChE inhibitor 7 and dual BChE and MAO-B inhibitor 6 were non-cytotoxic and protected neuronal SH-SY5Y cells from toxic amyloid β-peptide species.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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•Novel 3-substitue-6-oxopyridazin-1(6H)-ylmethyl carbamate derivatives were synthesized.•Compounds 7c, 14c, and 16c showed significant inhibitory activity against eqBuChE.•Compound 7c ...displayed a competitive inhibition while 14c and 16c showed a mixed-type inhibition.•Molecular docking study was performed for the selected compounds.
In the current study, forty-four new 3-(2/3/4-methoxyphenyl)-6-oxopyridazin-1(6H)-ylmethyl carbamate derivatives were synthesized and evaluated for their ability to inhibit electric eel acetylcholinesterase (EeAChE) and equine butyrylcholinesterase (eqBuChE) enzymes. According to the inhibitory activity results, 3-(2-methoxyphenyl)-6-oxopyridazin-1(6H)-ylmethyl heptylcarbamate (16c, eqBuChE, IC50 = 12.8 μM; EeAChE, no inhibition at 100 μM) was the most potent eqBuChE inhibitor among the synthesized compounds and was found to be a moderate inhibitor compared to donepezil (eqBuChE, IC50 = 3.25 μM; EeAChE, IC50 = 0.11 μM). Kinetic and molecular docking studies indicated that compounds 16c and 14c (hexylcarbamate derivative, eqBuChE, IC50 = 35 μM; EeAChE, no inhibition at 100 μM) were mixed-type inhibitors which accommodated within the catalytic active site (CAS) and peripheral anionic site (PAS) of hBuChE through stable hydrogen bonding and π-π stacking. Furthermore, it was determined that 3-(2-methoxyphenyl)-6-oxopyridazin-1(6H)-ylmethyl (4-methylphenyl)carbamate 7c (eqBuChE, IC50 = 34.5 μM; EeAChE, 38.9% inhibition at 100 μM) was the most active derivative against EeAChE and a competitive inhibitor binding to the CAS of hBuChE. As a result, 6-(2-methoxyphenyl)pyridazin-3(2H)-one scaffold is important for the inhibitory activity and compounds 7c, 14c and 16c might be considered as promising lead candidates for the design and development of selective BuChE inhibitors for Alzheimer’s disease treatment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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