Structural insights into cholinesterases inhibition by harmane β-carbolinium derivatives: A kinetics – molecular modeling approach

Torres, Juliana Maia; Lira, Aline F.; Silva, Daniel R.; Guzzo, Lucas M.; Sant’Anna, Carlos Maurício R.; Kümmerle, Arthur Eugen; Rumjanek, Víctor Marcos

doi:10.1016/j.phytochem.2012.05.004

Cited by 15 publications

(21 citation statements)

References 43 publications

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“…Moreover, stacking interactions between Trp‐84 and the terminal aromatic ring of the two compounds are also established. These interactions are similar to those described in earlier sections for Cortinarius infractus alkaloids and for some synthetic quaternary β‐carbolines . Docking simulations of prunifoleine and 14‐oxoprunifoleine in hBChE revealed that these compounds bind to the enzyme with different orientation, which can help to explain their different potencies for eqBChE inhibition.…”

Section: Classes Of Anticholinesterase Alkaloidssupporting

confidence: 82%

“…These interactions are similar to those described in earlier sections for Cortinarius infractus alkaloids [144] and for some synthetic quaternary b-carbolines. [146] Docking simulations of prunifoleine and 14-oxoprunifoleine in hBChE revealed that these compounds bind to the enzyme with different orientation, which can help to explain their different potencies for eqBChE inhibition. In addition to hydrophobic interactions, prunifoleine, which is about 10-fold more potent than 14-oxoprunifoleine, may establish polar contacts with Ser-198 and His-438 residues of the hBChE catalytic site.…”

Section: Monoterpene Indole Alkaloidsmentioning

confidence: 99%

“…The Author(s) declare(s) that they have no conflicts of interest to disclose. [143,146,148] AChE IC50~10 -6 -10 -5 M BChE IC50~10 -5 -10 -4 M [142][143][144][145][146][147][148] a Despite some steroid and triterpene alkaloids displaying selectivity for AChE inhibition, most of compounds belonging to these classes present some capacity for BChE inhibition. b Results refer to Huperzine A. c Results referd to galantamine.…”

Section: Conflict Of Interestmentioning

confidence: 99%

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Alkaloids as a source of potential anticholinesterase inhibitors for the treatment of Alzheimer's disease

Konrath

Passos

Klein‐Júnior

et al. 2013

Journal of Pharmacy and Pharmacology

181

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Objectives The inhibition of acetylcholinesterase (AChE), the key enzyme in the breakdown of acetylcholine, is currently the main pharmacological strategy available for Alzheimer's disease (AD). In this sense, many alkaloids isolated from natural sources, such as physostigmine, have been long recognized as acetyl-and butyrylcholinesterase (BChE) inhibitors. Since the approval of galantamine for the treatment of AD patients, the search for new anticholinesterase alkaloids has escalated, leading to promising candidates such as huperzine A. This review aims to summarize recent advances in current knowledge on alkaloids as AChE and BChE inhibitors, highlighting structure-activity relationship (SAR) and docking studies. Key findings Natural alkaloids belonging to the steroidal/triterpenoidal, quinolizidine, isoquinoline and indole classes, mainly distributed within Buxaceae, Amaryllidaceae and Lycopodiaceae, are considered important sources of alkaloids with anti-enzymatic properties. Investigations into the possible SARs for some active compounds are based on molecular modelling studies, predicting the mode of interaction of the molecules with amino acid residues in the active site of the enzymes. Following this view, an increasing interest in achieving more potent and effective analogues makes alkaloids good chemical templates for the development of new cholinesterase inhibitors. Summary The anticholinesterase activity of alkaloids, together with their structural diversity and physicochemical properties, makes them good candidate agents for the treatment of AD.

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Section: Classes Of Anticholinesterase Alkaloidssupporting

confidence: 82%

Section: Monoterpene Indole Alkaloidsmentioning

confidence: 99%

Section: Conflict Of Interestmentioning

confidence: 99%

See 1 more Smart Citation

Alkaloids as a source of potential anticholinesterase inhibitors for the treatment of Alzheimer's disease

Konrath

Passos

Klein‐Júnior

et al. 2013

Journal of Pharmacy and Pharmacology

181

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“…Energy quantities of the species harmane β-carboliniums derivatives, that are involved in the inhibition of cholinesterases were calculated by RM1 method. 141 In this article, Torres et al 141 stated: "All calculations were carried out with the RM1 method, which was shown to have a better performance than earlier hamiltonians for the determination of ΔH f (Rocha et al, 2006); we also observed that the RM1-calculated geometries of sp2 N-containing groups (such as the side chains of histidine, tryptophan and arginine residues) are more planar than those obtained with the older hamiltonians".…”

Section: Physical Chemistrymentioning

confidence: 75%

RM1 Semiempirical Model: Chemistry, Pharmaceutical Research, Molecular Biology and Materials Science

Lima¹,

Rocha²,

Freire³

et al. 2018

J. Braz. Chem. Soc.

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In this review, we show improvements to the semiempirical quantum chemical method RM1 and present a wide range of its applications as reported by researchers of various areas, such as theoretical, organic, physical, analytical, and inorganic chemistry, as well as their interfaces with medicinal chemistry, biology, and materials science. Success of RM1 is seemingly due to its ability to predict structural, energetic, electronic and wave function dependent properties of the investigated systems, coupled with its low computational demand required to perform calculations when compared to ab initio and density functional methods. Moreover, RM1 is widely available in several computational chemistry softwares, such as MOPAC, GAMESS, Amber, Spartan, HyperChem, and AMPAC. This review describes various case studies that perhaps can be of interest to researchers who might need a more solid basis from which to expand the frontier of applicability of RM1 to even more complex problems on larger systems.

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“…It is well known that β-carbolines inhibit cholinesterases 7 , 12 , 13 and that β-carbolinium salts are better inhibitors than their nonionic counterparts. 7 , 14 The most recent example is a chlorinated nostocarboline ( 8 ) ( Figure 3 ) isolated from the cyanobacterial strain of Nostoc 78-12A, which was shown to inhibit AChE at an IC 50 value of 5.3 μM. 15 Nevertheless, our finding added new information to the structure–activity relationship of β-carbolinium AChE inhibitors in that the bromine substituent on the benzene ring and an alkyl substituent at C-1 of the pyridine ring positively contributed to the activity, whereas the carboxyl group at C-3 reduced the activity.…”

Section: Resultsmentioning

confidence: 99%

N-Methyl-β-carbolinium Salts and an N-Methylated 8-Oxoisoguanine as Acetylcholinesterase Inhibitors from a Solitary Ascidian, Cnemidocarpa irene

et al. 2017

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New brominated β-carbolines irenecarbolines A (1) and B (4) along with known β-carbolines 2 and 3 and a new 8-oxoisoguanine derivative, 5, were isolated from a solitary ascidian, Cnemidocarpa irene. The structures of these compounds were determined on the basis of their spectral data. All, except for 3, inhibited the action of acetylcholinesterase (AchE). The activities of 1 and 5 were comparable to those of galantamine, a clinically used AchE inhibitor. Compounds 1 and 2 were found to be present in high concentrations in blood, and fluorescence was observed in certain types of cells found in the blood of the tunicate.

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Structural insights into cholinesterases inhibition by harmane β-carbolinium derivatives: A kinetics – molecular modeling approach

Cited by 15 publications

References 43 publications

Alkaloids as a source of potential anticholinesterase inhibitors for the treatment of Alzheimer's disease

Alkaloids as a source of potential anticholinesterase inhibitors for the treatment of Alzheimer's disease

RM1 Semiempirical Model: Chemistry, Pharmaceutical Research, Molecular Biology and Materials Science

N-Methyl-β-carbolinium Salts and an N-Methylated 8-Oxoisoguanine as Acetylcholinesterase Inhibitors from a Solitary Ascidian, Cnemidocarpa irene

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