Synthesis, molecular docking, and biological evaluation of 3-oxo-2-tolylhydrazinylidene-4,4,4-trifluorobutanoates bearing higher and natural alcohol moieties as new selective carboxylesterase inhibitors

Махаева, Галина Ф.; Elkina, Natalia А.; Shchegolkov, Evgeny V.; Boltneva, Natalia P.; Lushchekina, Sofya V.; Serebryakova, Olga G.; Рудакова, Е. В.; Kovaleva, N. V.; Radchenko, Eugene V.; Palyulin, Vladimir A.; Burgart, Yanina V.; Салоутин, В. И.; Бачурин, С. О.; Richardson, Rudy J.

doi:10.1016/j.bioorg.2019.103097

Cited by 30 publications

(16 citation statements)

References 77 publications

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“…QM/MM optimization of non-covalent complex of hAChE with TFK in the active site obtained by molecular docking leads to size expansion of the active site necessary to accommodate the inhibitor and lower energy barrier for formation of covalent adduct. Traditionally, resulting hemiketals are called "transition state analogs", though practically they are rather analogs of tetrahedral intermediate of AChE-catalyzed ester hydrolysis [55,56]. Hemiketal configuration is very close for TFK and TMTFA, with the only difference that trimethyl ammonium group of TMTFA is 0.6 Å closer to Glu202 than tert-butyl moiety of TMTFA.…”

Section: Molecular Modeling Of Interaction Between Tfk and Achementioning

confidence: 99%

1-(3-Tert-Butylphenyl)-2,2,2-Trifluoroethanone as a Potent Transition-State Analogue Slow-Binding Inhibitor of Human Acetylcholinesterase: Kinetic, MD and QM/MM Studies

et al. 2020

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Kinetic studies and molecular modeling of human acetylcholinesterase (AChE) inhibition by a fluorinated acetophenone derivative, 1-(3-tert-butylphenyl)-2,2,2-trifluoroethanone (TFK), were performed. Fast reversible inhibition of AChE by TFK is of competitive type with Ki = 5.15 nM. However, steady state of inhibition is reached slowly. Kinetic analysis showed that TFK is a slow-binding inhibitor (SBI) of type B with Ki* = 0.53 nM. Reversible binding of TFK provides a long residence time, τ = 20 min, on AChE. After binding, TFK acylates the active serine, forming an hemiketal. Then, disruption of hemiketal (deacylation) is slow. AChE recovers full activity in approximately 40 min. Molecular docking and MD simulations depicted the different steps. It was shown that TFK binds first to the peripheral anionic site. Then, subsequent slow induced-fit step enlarged the gorge, allowing tight adjustment into the catalytic active site. Modeling of interactions between TFK and AChE active site by QM/MM showed that the “isomerization” step of enzyme-inhibitor complex leads to a complex similar to substrate tetrahedral intermediate, a so-called “transition state analog”, followed by a labile covalent intermediate. SBIs of AChE show prolonged pharmacological efficacy. Thus, this fluoroalkylketone intended for neuroimaging, could be of interest in palliative therapy of Alzheimer’s disease and protection of central AChE against organophosphorus compounds.

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Section: Molecular Modeling Of Interaction Between Tfk and Achementioning

confidence: 99%

1-(3-Tert-Butylphenyl)-2,2,2-Trifluoroethanone as a Potent Transition-State Analogue Slow-Binding Inhibitor of Human Acetylcholinesterase: Kinetic, MD and QM/MM Studies

et al. 2020

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“…Radical scavenging activity of the compounds was evaluated by the ABTS radical cation (ABTS •+ ) scavenging assay showing the ability of the compounds to decolorize the ABTS •+ solution [ 86 ] with some modifications [ 87 ]. Trolox was used as the antioxidant standard; ascorbic acid was used as the comparison compound.…”

Section: Methodsmentioning

confidence: 99%

New Multifunctional Agents for Potential Alzheimer’s Disease Treatment Based on Tacrine Conjugates with 2-Arylhydrazinylidene-1,3-Diketones

et al. 2022

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Alzheimer’s disease (AD) is considered a modern epidemic because of its increasing prevalence worldwide and serious medico-social consequences, including the economic burden of treatment and patient care. The development of new effective therapeutic agents for AD is one of the most urgent and challenging tasks. To address this need, we used an aminoalkylene linker to combine the well-known anticholinesterase drug tacrine with antioxidant 2-tolylhydrazinylidene-1,3-diketones to create 3 groups of hybrid compounds as new multifunctional agents with the potential for AD treatment. Lead compounds of the new conjugates effectively inhibited acetylcholinesterase (AChE, IC50 0.24–0.34 µM) and butyrylcholinesterase (BChE, IC50 0.036–0.0745 µM), with weak inhibition of off-target carboxylesterase. Anti-AChE activity increased with elongation of the alkylene spacer, in agreement with molecular docking, which showed compounds binding to both the catalytic active site and peripheral anionic site (PAS) of AChE, consistent with mixed type reversible inhibition. PAS binding along with effective propidium displacement suggest the potential of the hybrids to block AChE-induced β-amyloid aggregation, a disease-modifying effect. All of the conjugates demonstrated metal chelating ability for Cu2+, Fe2+, and Zn2+, as well as high antiradical activity in the ABTS test. Non-fluorinated hybrid compounds 6 and 7 also showed Fe3+ reducing activity in the FRAP test. Predicted ADMET and physicochemical properties of conjugates indicated good CNS bioavailability and safety parameters acceptable for potential lead compounds at the early stages of anti-AD drug development.

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“…A series of 3-oxo-2-tolylhydrazinylidene-4,4,4-trifluorobutanoates containing higher or natural alcohol moieties in their structures were designed and synthesized in response to the need for effective and selective inhibitors of carboxylesterase (CES) [ 10 ]. The ester derivative of naturally occurring geraniol is one of them and it proved to be a highly active and selective inhibitor of hCES2, blocking the enzyme within the nanomolar range (IC 50 to ca.…”

Section: Acyclic Monoterpene Derivativesmentioning

confidence: 99%

“…Another (–)-borneol derivative with an ester group, namely bornyl (2 Z )-4,4,4-trifluoro-2-[2-(4-methylphenyl)hydrazinylidene]-3-oxobutanoate 132 ( Figure 36 ), was studied as an inhibitor of the main human isoenzymes involved in the biotransformation of ester-containing drugs: hCES1 and hCES2 [ 10 ]. The tested ester derivative of natural occurring (–)-borneol with the hydrazinylidene group is more active and selective against hCES1 than against hCES2.…”

Section: Monoterpene Bicyclic Derivativesmentioning

confidence: 99%

Monoterpenes and Their Derivatives—Recent Development in Biological and Medical Applications

Zielińska-Błajet

Feder‐Kubis

2020

IJMS

220

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Monoterpenes, comprising hydrocarbons, are the largest class of plant secondary metabolites and are commonly found in essential oils. Monoterpenes and their derivatives are key ingredients in the design and production of new biologically active compounds. This review focuses on selected aliphatic, monocyclic, and bicyclic monoterpenes like geraniol, thymol, myrtenal, pinene, camphor, borneol, and their modified structures. The compounds in question play a pivotal role in biological and medical applications. The review also discusses anti-inflammatory, antimicrobial, anticonvulsant, analgesic, antiviral, anticancer, antituberculosis, and antioxidant biological activities exhibited by monoterpenes and their derivatives. Particular attention is paid to the link between biological activity and the effect of structural modification of monoterpenes and monoterpenoids, as well as the introduction of various functionalized moieties into the molecules in question.

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Synthesis, molecular docking, and biological evaluation of 3-oxo-2-tolylhydrazinylidene-4,4,4-trifluorobutanoates bearing higher and natural alcohol moieties as new selective carboxylesterase inhibitors

Cited by 30 publications

References 77 publications

1-(3-Tert-Butylphenyl)-2,2,2-Trifluoroethanone as a Potent Transition-State Analogue Slow-Binding Inhibitor of Human Acetylcholinesterase: Kinetic, MD and QM/MM Studies

1-(3-Tert-Butylphenyl)-2,2,2-Trifluoroethanone as a Potent Transition-State Analogue Slow-Binding Inhibitor of Human Acetylcholinesterase: Kinetic, MD and QM/MM Studies

New Multifunctional Agents for Potential Alzheimer’s Disease Treatment Based on Tacrine Conjugates with 2-Arylhydrazinylidene-1,3-Diketones

Monoterpenes and Their Derivatives—Recent Development in Biological and Medical Applications

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