Synthesis and Biological Evaluation of (−)- and (+)-Debromoflustramine B and Its Analogues as Selective Butyrylcholinesterase Inhibitors

Rivera-Becerril, Ernesto; Joseph‐Nathan, Pedro; Pérez-Álvarez, Víctor; Morales‐Ríos, Martha S.

doi:10.1021/jm800277g

Cited by 58 publications

(28 citation statements)

References 53 publications

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“…It also showed potent inhibitory activity against AChE with the IC 50 value of 2.61 ± 0.13 μM. This result was similar to the Rivera-Becerril’s report [38], confirming the double bond of the prenyl group is interacting as a specific π-hydrogen bond acceptor with the enzyme. The influence order is prenylated oxyl > allyloxy > methoxyl > hydroxyl.…”

Section: Resultssupporting

confidence: 89%

Synthesis and biological evaluation of 1, 3-dihydroxyxanthone mannich base derivatives as anticholinesterase agents

Qin

Lan

Zhong

et al. 2013

Chemistry Central Journal

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BackgroundAlzheimer’s disease (AD), a progressive and degenerative disorder, has become one of the severe problems among the aged population all over the world. To use cholinesterase inhibitor drugs has become the most predominant treatment strategy for AD.ResultsA series of novel 1, 3-dihydroxyxanthone Mannich bases derivatives (1a ~ 4e) were synthesized, structure elucidated and evaluated for anti-cholinesterase activity. The result showed that most of the target compounds exhibited moderate to good inhibitory activities with the IC50 values at micromole level concentration against both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The preliminary structure-activity indicated that: (i) The alkoxy or alkenoxy substituents in the position 3 of xanthone have a positive influence on the inhibition potency; (ii) types of dialkylamine methyl in position 2 of xanthone affected cholinesterase activities and AChE/BuChE selectivity. Among them, 2-((diethylamino)methyl)-1-hydroxy-3-(3-methylbut-2-enyloxy)-9H-xanthen-9-one showed potent inhibitory activity against AChE with the IC50 value of 2.61 ± 0.13 μM and the best inhibitory activity against BuChE with the IC50 value of 0.51 ± 0.01 μM. The results of a mixed-type manner in enzyme kinetic experiment and molecular docking study for 2-((diethylamino)methyl)-1-hydroxy-3-(3-methylbut-2-enyloxy)-9H-xanthen-9-one demonstrated that the Mannich base derivatives were likely to bind to the active site (AS) and the peripheral anionic site (PAS) of cholinesterases.ConclusionsThis study suggested that 1, 3-dihydroxyxanthone Mannich base derivatives were potential dual inhibitors of both AChE and BuChE, which may be considered as a kind of novel drug candidates for treatment of AD.

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Section: Resultssupporting

confidence: 89%

Synthesis and biological evaluation of 1, 3-dihydroxyxanthone mannich base derivatives as anticholinesterase agents

Qin

Lan

Zhong

et al. 2013

Chemistry Central Journal

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“…The flustraminef amily comprises over 20 prenylated indole al- [19] whereas debromoflustramine Ba nd its analogues have been evaluated for their butyrylcholinesterase inhibitory activity: (À)-debromoflustramine Bi so ver 7500times more potent than its (+ +)-enantiomer. [20] Amides 13 and 22 were previously reported as intermediates in the total syntheses of flustramides A [21] and B [22] and flustramines Aa nd B. [23] Reductive cyclization with alane-dimethylethylamine complex (Scheme 6) was carriedo ut on (+ +)-13 (prepared using (R,R)-L 2 )a nd (+ +)-22 (prepared using (S,S)-L 1 )t o obtain the unnatural (+ +)-isomers of all four natural products, spectrald ata of which was in agreement with literature reports.…”

Section: Total Syntheses Of Flustra Alkaloids and Determination Of Thmentioning

confidence: 99%

Development of the Regiodivergent Asymmetric Prenylation of 3‐Substituted Oxindoles

Trost

Chan

Malhotra

2017

Chemistry A European J

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This paper fully describes our efforts to design a Pd-catalyzed asymmetric prenylation of 3-substituted oxindoles that affords access to both the linear and reverse-prenylated products. Both 3-alkyl- and 3-aryloxindoles performed well under our optimized reaction conditions. The regiodivergent alkylation of monoterpene-derived electrophiles using this methodology was also investigated. The utility of this methodology in natural product synthesis was demonstrated through the efficient total syntheses of four Flustra alkaloids, which also allowed the absolute stereochemistry of the prenylated oxindole products to be assigned. Surprisingly, the same enantiomer of ligand produced linear and branched regioisomers of opposite chirality.

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“…[17][18][19][20] It is suggested that BuChE is a key player in brain areas that influence the aggregation of neuritic Aβ plaques due to the correlation between BuChE polymorphisms and the progression of cognitive impairment in dementia with Lewy bodies (DLB) and AD. [21][22][23] It is also believed that BuChE is particularly important in individuals with more severe dementia, since its activity is increased with disease development. Therefore, compounds that can interact specifically with PAS or CAS residues are important in ChE inhibition and may help in prevention of Aβ aggregation facilitated by AChE.…”

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confidence: 99%

Chiral Bistacrine Analogues: Synthesis, Cholinesterase Inhibitory Activity and a Molecular Modeling Approach

Lopes¹,

Costa²,

Ceschi³

et al. 2017

J. Braz. Chem. Soc.

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Cholinesterase enzymes are important targets for the therapy of Alzheimer's disease. Tacrine-based dual binding site cholinesterases inhibitors are potential disease-modifying anti-Alzheimer drug candidates. In the present work, we described the synthesis of a series of chiral homo-and heterodimers of bis (7)-tacrine connected by a heptylene chain as a spacer with the methyl substituent at the C-3 position of the alicyclic region of tacrine nucleus and/or a chlorine atom attached to the C-6. Friedländer cyclocondensation between (R) or (S) 3-methylcyclohexanone prepared from monoterpene pulegone and o-aminobenzoic acids in the presence of POCl 3 afford 9-chloroacridines as intermediates, which were used to the synthesis of homo-and heterodimers. All compounds demonstrated to be potent inhibitors of acetylcholinesterase (AChE) at low nanomolar concentration and showed selectivity for AChE over butyrylcholinesterase (BuChE). Furthermore, the affinity difference between enantiomeric bis(7)-tacrine analogues series indicated some degree of stereoselectivity in the active site of AChE for chiral bis-cognitin compounds. Keywords: bistacrine, chiral, cholinesterases, synthesis, molecular docking IntroductionAlzheimer's disease (AD) is one of the leading causes of death among elderly people in the World, and its treatment remains a challenge for the pharmaceutical community. Nearly a million new cases per year it is expected to emerge by 2050.1,2 The proposed cholinergic hypothesis of cognitive impairment has been accepted for decades to explain AD and is characterized by the loss of cholinergic basal forebrain, and their projections to the cerebral cortices. 2,3 According to this hypothesis, the memory and cognitive decline well-marked in AD result from a deficit of the important neurotransmitter acetylcholine (ACh). In this context, the inhibition of cholinesterase enzymes (ChEs) that are responsible for the hydrolyses of ACh emerge as a symptomatic treatment to relieve these symptoms. [4][5][6] The current therapeutic options for AD are limited to three inhibitors of acetylcholinesterase (AChEI):4-8 donepezil (Aricept ® ), rivastigmine (Exelon ® ) and galantamine (Razadyne ® , Reminyl ® ). In addition, the N-methyl-D-aspartate (NMDA) receptor antagonist memantine (Namenda ® ) is also used. [9][10][11] However, none of these therapeutic options represent a real cure.The cholinesterase enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are enzymes which are found in the central nervous system (CNS) and catalyze the hydrolysis of ACh efficiently but at different rates. [9][10][11][12] However, as AD progresses, the activity of AChE decreases, while that of BuChE significantly increases and may even surpass the AChE activity. 13,14 The acetylcholine binding site of AChE is located at the base of a deep hydrophobic channel measuring Lopes et al. 2219 Vol. 28, No. 11, 2017 approximately 20 Å in length. It is formed by a catalytic anionic site (CAS) composed by the catalytic triad Ser200, His440 and Gl...

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Synthesis and Biological Evaluation of (−)- and (+)-Debromoflustramine B and Its Analogues as Selective Butyrylcholinesterase Inhibitors

Cited by 58 publications

References 53 publications

Synthesis and biological evaluation of 1, 3-dihydroxyxanthone mannich base derivatives as anticholinesterase agents

Synthesis and biological evaluation of 1, 3-dihydroxyxanthone mannich base derivatives as anticholinesterase agents

Development of the Regiodivergent Asymmetric Prenylation of 3‐Substituted Oxindoles

Chiral Bistacrine Analogues: Synthesis, Cholinesterase Inhibitory Activity and a Molecular Modeling Approach

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