Esterase profiles of organophosphorus compounds in vitro predict their behavior in vivo

Махаева, Галина Ф.; Рудакова, Е. В.; Serebryakova, Olga G.; Aksinenko, А. Yu.; Lushchekina, Sofya V.; Бачурин, С. О.; Richardson, Rudy J.

doi:10.1016/j.cbi.2016.05.002

Cited by 60 publications

(21 citation statements)

References 61 publications

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“…AChE from human erythrocytes, BChE from equine serum, and CaE from porcine liver were used. It was previously shown that the two last-mentioned enzymes have high levels of identity with the corresponding human enzymes 63,64 .…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, CaE inhibition by anticholinesterase drugs may induce undesirable drug-drug interactions 63,81 . Thus, the esterase profile approach, employed here, i.e., the comparative evaluation of a compound’s inhibitory activity against several esterases 63,64,82,83 , contributes to the early detection of possible adverse effects connected with CaE inhibition.…”

Section: Discussionmentioning

confidence: 99%

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Conjugates of methylene blue with γ-carboline derivatives as new multifunctional agents for the treatment of neurodegenerative diseases

Бачурин

Махаева

Shevtsova

et al. 2019

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We studied the inhibitory activity of methylene blue (MB) γ-carbolines (gC) conjugates (MB-gCs) against human erythrocyte acetylcholinesterase (AChE), equine serum butyrylcholinesterase (BChE), and a structurally related enzyme, porcine liver carboxylesterase (CaE). In addition, we determined the ability of MB-gCs to bind to the peripheral anionic site (PAS) of Electrophorus electricus AChE (EeAChE) and competitively displace propidium iodide from this site. Moreover, we examined the ability of MB-gCs to scavenge free radicals as well as their influence on mitochondrial potential and iron-induced lipid peroxidation. We found that MB-gCs effectively inhibited AChE and BChE with IC50 values in the range 1.73–10.5 μM and exhibited low potencies against CaE (9.8–26% inhibition at 20 μM). Kinetic studies showed that MB-gCs were mixed-type reversible inhibitors of both cholinesterases. Molecular docking results showed that the MB-gCs could bind both to the catalytic active site and to the PAS of human AChE and BChE. Accordingly, MB-gCs effectively displaced propidium from the peripheral anionic site of EeAChE. In addition, MB-gCs were extremely active in both radical scavenging tests. Quantum mechanical DFT calculations suggested that free radical scavenging was likely mediated by the sulfur atom in the MB fragment. Furthermore, the MB-gCs, in like manner to MB, can restore mitochondrial membrane potential after depolarization with rotenone. Moreover, MB-gCs possess strong antioxidant properties, preventing iron-induced lipid peroxidation in mitochondria. Overall, the results indicate that MB-gCs are promising candidates for further optimization as multitarget therapeutic agents for neurodegenerative diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Conjugates of methylene blue with γ-carboline derivatives as new multifunctional agents for the treatment of neurodegenerative diseases

Бачурин

Махаева

Shevtsova

et al. 2019

Sci Rep

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“…We used human erythrocyte AChE, equine serum BChE, and porcine liver CaE. It was shown previously that the two last-mentioned enzymes have a high identity to the human enzymes4041. The inhibitory activity was characterized as the percentage of inhibition at 20 μM or as the IC 50 value, i.e., the inhibitor concentration required to reduce the enzyme activity by 50%.…”

Section: Resultsmentioning

confidence: 99%

Novel conjugates of aminoadamantanes with carbazole derivatives as potential multitarget agents for AD treatment

Бачурин¹,

Shevtsova²,

Махаева³

et al. 2017

Sci Rep

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A new group of compounds, promising for the design of original multitarget therapeutic agents for treating neurodegenerative diseases, based on conjugates of aminoadamantane and carbazole derivatives was synthesized and investigated. Compounds of these series were found to interact with a group of targets that play an important role in the development of this type of diseases. First of all, these compounds selectively inhibit butyrylcholinesterase, block NMDA receptors containing NR2B subunits while maintaining the properties of MK-801 binding site blockers, exert microtubules stabilizing properties, and possess the ability to protect nerve cells from death at the calcium overload conditions. The leading compound C-2h has been shown the most promising effects on all analyzed parameters. Thus, these compounds can be regarded as promising candidates for the design of multi-target disease-modifying drugs for treatment of AD and/or similar neuropathologies.

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“…For all conjugates 7, we determined their esterase profile, i.e., the relative ability to inhibit several related serine esterases -AChE, BChE, and CES. This approach makes it possible to estimate both the primary pharmacological effects of the tested compounds (the inhibition of AChE and BChE) and their possible unwanted side effects (the inhibition of CES that hydrolyzes numerous ester-containing drugs) [73][74][75][76][77]. AChE from human erythrocytes was used along with two enzymes of non-human origin: equine serum BChE and porcine liver CES.…”

Section: Inhibition Studies Of Ache Bche and Ces Structure-activitymentioning

confidence: 99%

“…AChE from human erythrocytes was used along with two enzymes of non-human origin: equine serum BChE and porcine liver CES. These sources of BChE and CES were used because of their relatively low cost, high sequence identity to human enzymes [73,74,76], and the exploratory character of this work.…”

Section: Inhibition Studies Of Ache Bche and Ces Structure-activitymentioning

confidence: 99%

New Hybrids of 4-Amino-2,3-polymethylene-quinoline and p-Tolylsulfonamide as Dual Inhibitors of Acetyl- and Butyrylcholinesterase and Potential Multifunctional Agents for Alzheimer’s Disease Treatment

et al. 2020

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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.

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Esterase profiles of organophosphorus compounds in vitro predict their behavior in vivo

Cited by 60 publications

References 61 publications

Conjugates of methylene blue with γ-carboline derivatives as new multifunctional agents for the treatment of neurodegenerative diseases

Conjugates of methylene blue with γ-carboline derivatives as new multifunctional agents for the treatment of neurodegenerative diseases

Novel conjugates of aminoadamantanes with carbazole derivatives as potential multitarget agents for AD treatment

New Hybrids of 4-Amino-2,3-polymethylene-quinoline and p-Tolylsulfonamide as Dual Inhibitors of Acetyl- and Butyrylcholinesterase and Potential Multifunctional Agents for Alzheimer’s Disease Treatment

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