Serebryakova OG

References (21)

Title : Derivatives of 9-phosphorylated acridine as butyrylcholinesterase inhibitors with antioxidant activity and the ability to inhibit beta-amyloid self-aggregation: potential therapeutic agents for Alzheimer's disease - Makhaeva_2023_Front.Pharmacol_14_1219980
Author(s) : Makhaeva GF , Kovaleva NV , Rudakova EV , Boltneva NP , Lushchekina SV , Astakhova TY , Timokhina EN , Serebryakova OG , Shchepochkin AV , Averkov MA , Utepova IA , Demina NS , Radchenko EV , Palyulin VA , Fisenko VP , Bachurin SO , Chupakhin ON , Charushin VN , Richardson RJ
Ref : Front Pharmacol , 14 :1219980 , 2023
Abstract : We investigated the inhibitory activities of novel 9-phosphoryl-9,10-dihydroacridines and 9-phosphorylacridines against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and carboxylesterase (CES). We also studied the abilities of the new compounds to interfere with the self-aggregation of beta-amyloid (Abeta(42)) in the thioflavin test as well as their antioxidant activities in the ABTS and FRAP assays. We used molecular docking, molecular dynamics simulations, and quantum-chemical calculations to explain experimental results. All new compounds weakly inhibited AChE and off-target CES. Dihydroacridines with aryl substituents in the phosphoryl moiety inhibited BChE; the most active were the dibenzyloxy derivative 1d and its diphenethyl bioisostere 1e (IC(50) = 2.90 +/- 0.23 microM and 3.22 +/- 0.25 microM, respectively). Only one acridine, 2d, an analog of dihydroacridine, 1d, was an effective BChE inhibitor (IC(50) = 6.90 +/- 0.55 microM), consistent with docking results. Dihydroacridines inhibited Abeta(42) self-aggregation; 1d and 1e were the most active (58.9% +/- 4.7% and 46.9% +/- 4.2%, respectively). All dihydroacridines 1 demonstrated high ABTS(+)-scavenging and iron-reducing activities comparable to Trolox, but acridines 2 were almost inactive. Observed features were well explained by quantum-chemical calculations. ADMET parameters calculated for all compounds predicted favorable intestinal absorption, good blood-brain barrier permeability, and low cardiac toxicity. Overall, the best results were obtained for two dihydroacridine derivatives 1d and 1e with dibenzyloxy and diphenethyl substituents in the phosphoryl moiety. These compounds displayed high inhibition of BChE activity and Abeta(42) self-aggregation, high antioxidant activity, and favorable predicted ADMET profiles. Therefore, we consider 1d and 1e as lead compounds for further in-depth studies as potential anti-AD preparations.
ESTHER : Makhaeva_2023_Front.Pharmacol_14_1219980
PubMedSearch : Makhaeva_2023_Front.Pharmacol_14_1219980
PubMedID: 37654616

Title : Conjugates of Tacrine and Salicylic Acid Derivatives as New Promising Multitarget Agents for Alzheimer's Disease - Makhaeva_2023_Int.J.Mol.Sci_24_2285
Author(s) : Makhaeva GF , Kovaleva NV , Rudakova EV , Boltneva NP , Grishchenko MV , Lushchekina SV , Astakhova TY , Serebryakova OG , Timokhina EN , Zhilina EF , Shchegolkov EV , Ulitko MV , Radchenko EV , Palyulin VA , Burgart YV , Saloutin VI , Bachurin SO , Richardson RJ
Ref : Int J Mol Sci , 24 :2285 , 2023
Abstract : A series of previously synthesized conjugates of tacrine and salicylamide was extended by varying the structure of the salicylamide fragment and using salicylic aldehyde to synthesize salicylimine derivatives. The hybrids exhibited broad-spectrum biological activity. All new conjugates were potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity toward BChE. The structure of the salicylamide moiety exerted little effect on anticholinesterase activity, but AChE inhibition increased with spacer elongation. The most active conjugates were salicylimine derivatives: IC(50) values of the lead compound 10c were 0.0826 microM (AChE) and 0.0156 microM (BChE), with weak inhibition of the off-target carboxylesterase. The hybrids were mixed-type reversible inhibitors of both cholinesterases and displayed dual binding to the catalytic and peripheral anionic sites of AChE in molecular docking, which, along with experimental results on propidium iodide displacement, suggested their potential to block AChE-induced beta-amyloid aggregation. All conjugates inhibited Abeta(42) self-aggregation in the thioflavin test, and inhibition increased with spacer elongation. Salicylimine 10c and salicylamide 5c with (CH(2))(8) spacers were the lead compounds for inhibiting Abeta(42) self-aggregation, which was corroborated by molecular docking to Abeta(42). ABTS(+)-scavenging activity was highest for salicylamides 5a-c, intermediate for salicylimines 10a-c, low for F-containing salicylamides 7, and non-existent for methoxybenzoylamides 6 and difluoromethoxybenzoylamides 8. In the FRAP antioxidant (AO) assay, the test compounds displayed little or no activity. Quantum chemical analysis and molecular dynamics (MD) simulations with QM/MM potentials explained the AO structure-activity relationships. All conjugates were effective chelators of Cu(2+), Fe(2+), and Zn(2+), with molar compound/metal (Cu(2+)) ratios of 2:1 (5b) and ~1:1 (10b). Conjugates exerted comparable or lower cytotoxicity than tacrine on mouse hepatocytes and had favorable predicted intestinal absorption and blood-brain barrier permeability. The overall results indicate that the synthesized conjugates are promising new multifunctional agents for the potential treatment of AD.
ESTHER : Makhaeva_2023_Int.J.Mol.Sci_24_2285
PubMedSearch : Makhaeva_2023_Int.J.Mol.Sci_24_2285
PubMedID: 36768608

Title : Conjugates of Tacrine with Salicylamide as Promising Multitarget Agents for Alzheimer's Disease - Grishchenko_2022_ChemMedChem__e202200080
Author(s) : Grishchenko MV , Makhaeva GF , Burgart YV , Rudakova EV , Boltneva NP , Kovaleva NV , Serebryakova OG , Lushchekina SV , Astakhova TY , Zhilina EF , Shchegolkov EV , Richardson RJ , Saloutin VI
Ref : ChemMedChem , :e202200080 , 2022
Abstract : New conjugates of tacrine and salicylamide with alkylene spacers were synthesized and evaluated as potential multifunctional agents for Alzheimer's disease (AD). The compounds exhibited high acetylcholinesterase (AChE, IC(50) to 0.224microM) and butyrylcholinesterase (BChE, IC(50) to 0.0104microM) inhibitory activities. They were also rather poor inhibitors of carboxylesterase, suggesting a low tendency to exert potential unwanted drug-drug interactions in clinical use. The conjugates were mixed-type reversible inhibitors of both cholinesterases and demonstrated dual binding to the catalytic and peripheral anionic sites of AChE in molecular docking that, along with experimental results on propidium iodide displacement, suggest their potential to block AChE-induced beta-amyloid aggregation. The new conjugates exhibited high ABTS(.+) -scavenging activity. N-(6-(1,2,3,4-Tetrahydroacridin-9-ylamino)hexyl)salicylamide is a lead compound that also demonstrates metal chelating ability toward Cu(2+) , Fe(2+) and Zn(2+) . Thus, the new conjugates have displayed the potential to be multifunctional anti-AD agents for further development.
ESTHER : Grishchenko_2022_ChemMedChem__e202200080
PubMedSearch : Grishchenko_2022_ChemMedChem__e202200080
PubMedID: 35322571

Title : Powerful Potential of Polyfluoroalkyl-Containing 4-Arylhydrazinylidenepyrazol-3-ones for Pharmaceuticals - Burgart_2022_Molecules_28_
Author(s) : Burgart YV , Elkina NA , Shchegolkov EV , Krasnykh OP , Makhaeva GF , Triandafilova GA , Solodnikov SY , Boltneva NP , Rudakova EV , Kovaleva NV , Serebryakova OG , Ulitko MV , Borisevich SS , Gerasimova NA , Evstigneeva NP , Kozlov SA , Korolkova YV , Minin AS , Belousova AV , Mozhaitsev ES , Klabukov AM , Saloutin VI
Ref : Molecules , 28 : , 2022
Abstract : 4-Arylhydrazinylidene-5-(polyfluoroalkyl)pyrazol-3-ones (4-AHPs) were found to be obtained by the regiospecific cyclization of 2-arylhydrazinylidene-3-(polyfluoroalkyl)-3-oxoesters with hydrazines, by the azo coupling of 4-nonsubstituted pyrazol-5-oles with aryldiazonium chlorides or by the firstly discovered acid-promoted self-condensation of 2-arylhydrazinylidene-3-oxoesters. All the 4-AHPs had an acceptable ADME profile. Varying the substituents in 4-AHPs promoted the switching or combining of their biological activity. The polyfluoroalkyl residue in 4-AHPs led to the appearance of an anticarboxylesterase action in the micromolar range. An NH-fragment and/or methyl group instead of the polyfluoroalkyl one in the 4-AHPs promoted antioxidant properties in the ABTS, FRAP and ORAC tests, as well as anti-cancer activity against HeLa that was at the Doxorubicin level coupled with lower cytotoxicity against normal human fibroblasts. Some Ph-N-substituted 4-AHPs could inhibit the growth of N. gonorrhoeae bacteria at MIC 0.9 microg/mL. The possibility of using 4-AHPs for cell visualization was shown. Most of the 4-AHPs exhibited a pronounced analgesic effect in a hot plate test in vivo at and above the diclofenac and metamizole levels except for the ones with two chlorine atoms in the aryl group. The methylsulfonyl residue was proved to raise the anti-inflammatory effect also. A mechanism of the antinociceptive action of the 4-AHPs through blocking the TRPV1 receptor was proposed and confirmed using in vitro experiment and molecular docking.
ESTHER : Burgart_2022_Molecules_28_
PubMedSearch : Burgart_2022_Molecules_28_
PubMedID: 36615256

Title : Amiridine-piperazine hybrids as cholinesterase inhibitors and potential multitarget agents for Alzheimer's disease treatment - Makhaeva_2021_Bioorg.Chem_112_104974
Author(s) : Makhaeva GF , Lushchekina SV , Kovaleva NV , Yu Astakhova T , Boltneva NP , Rudakova EV , Serebryakova OG , Proshin AN , Serkov IV , Trofimova TP , Tafeenko VA , Radchenko EV , Palyulin VA , Fisenko VP , Korabecny J , Soukup O , Richardson RJ
Ref : Bioorg Chem , 112 :104974 , 2021
Abstract : We synthesized eleven new amiridine-piperazine hybrids 5a-j and 7 as potential multifunctional agents for Alzheimer's disease (AD) treatment by reacting N-chloroacetylamiridine with piperazines. The compounds displayed mixed-type reversible inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Conjugates were moderate inhibitors of equine and human BChE with negligible fluctuation in anti-BChE activity, whereas anti-AChE activity was substantially dependent on N4-substitution of the piperazine ring. Compounds with para-substituted aromatic moieties (5g, 5h, and bis-amiridine 7) had the highest anti-AChE activity in the low micromolar range. Top-ranked compound 5h, N-(2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinolin-9-yl)-2-[4-(4-nitro-phenyl)-piperazin-1-yl]-acetamide, had an IC(50) for AChE = 1.83 +/- 0.03 microM (K(i) = 1.50 +/- 0.12 and alphaK(i) = 2.58 +/- 0.23 microM). The conjugates possessed low activity against carboxylesterase, indicating a likely absence of unwanted drug-drug interactions in clinical use. In agreement with analysis of inhibition kinetics and molecular modeling studies, the lead compounds were found to bind effectively to the peripheral anionic site of AChE and displace propidium, indicating their potential to block AChE-induced beta-amyloid aggregation. Similar propidium displacement activity was first shown for amiridine. Two compounds, 5c (R = cyclohexyl) and 5e (R = 2-MeO-Ph), exhibited appreciable antioxidant capability with Trolox equivalent antioxidant capacity values of 0.47 +/- 0.03 and 0.39 +/- 0.02, respectively. Molecular docking and molecular dynamics simulations provided insights into the structure-activity relationships for AChE and BChE inhibition, including the observation that inhibitory potencies and computed pK(a) values of hybrids were generally lower than those of the parent molecules. Predicted ADMET and physicochemical properties of conjugates indicated good CNS bioavailability and safety parameters comparable to those of amiridine and therefore acceptable for potential lead compounds at the early stages of anti-AD drug development.
ESTHER : Makhaeva_2021_Bioorg.Chem_112_104974
PubMedSearch : Makhaeva_2021_Bioorg.Chem_112_104974
PubMedID: 34029971

Title : Novel potent bifunctional carboxylesterase inhibitors based on a polyfluoroalkyl-2-imino-1,3-dione scaffold - Makhaeva_2021_Eur.J.Med.Chem_218_113385
Author(s) : Makhaeva GF , Lushchekina SV , Boltneva NP , Serebryakova OG , Kovaleva NV , Rudakova EV , Elkina NA , Shchegolkov EV , Burgart YV , Stupina TS , Terentiev AA , Radchenko EV , Palyulin VA , Saloutin VI , Bachurin SO , Richardson RJ
Ref : Eur Journal of Medicinal Chemistry , 218 :113385 , 2021
Abstract : An expanded series of alkyl 2-arylhydrazinylidene-3-oxo-3-polyfluoroalkylpropionates (HOPs) 3 was obtained via Cu(OAc)(2)-catalyzed azo coupling. All were nanomolar inhibitors of carboxylesterase (CES), while moderate or weak inhibitors of acetylcholinesterase and butyrylcholinesterase. Steady-state kinetics studies showed that HOPs 3 are mixed type inhibitors of the three esterases. Molecular docking studies demonstrated that two functional groups in the structure of HOPs, trifluoromethyl ketone (TFK) and ester groups, bind to the CES active site suggesting subsequent reactions: formation of a tetrahedral adduct, and a slow hydrolysis reaction. The results of molecular modeling allowed us to explain some structure-activity relationships of CES inhibition by HOPs 3: their selectivity toward CES in comparison with cholinesterases and the high selectivity of pentafluoroethyl-substituted HOP 3p to hCES1 compared to hCES2. All compounds were predicted to have good intestinal absorption and blood-brain barrier permeability, low cardiac toxicity, good lipophilicity and aqueous solubility, and reasonable overall drug-likeness. HOPs with a TFK group and electron-donor substituents in the arylhydrazone moiety were potent antioxidants. All compounds possessed low cytotoxicity and low acute toxicity. Overall, a new promising type of bifunctional CES inhibitors has been found that are able to interact with the active site of the enzyme with the participation of two functional groups. The results indicate that HOPs have the potential to be good candidates as human CES inhibitors for biomedicinal applications.
ESTHER : Makhaeva_2021_Eur.J.Med.Chem_218_113385
PubMedSearch : Makhaeva_2021_Eur.J.Med.Chem_218_113385
PubMedID: 33831780

Title : Arachidonoylcholine and Other Unsaturated Long-Chain Acylcholines Are Endogenous Modulators of the Acetylcholine Signaling System - Akimov_2020_Biomolecules_10_
Author(s) : Akimov MG , Kudryavtsev DS , Kryukova EV , Fomina-Ageeva EV , Zakharov SS , Gretskaya NM , Zinchenko GN , Serkov IV , Makhaeva GF , Boltneva NP , Kovaleva NV , Serebryakova OG , Lushchekina SV , Palikov VA , Palikova Y , Dyachenko IA , Kasheverov IE , Tsetlin VI , Bezuglov VV
Ref : Biomolecules , 10 : , 2020
Abstract : Cholines acylated with unsaturated fatty acids are a recently discovered family of endogenous lipids. However, the data on the biological activity of acylcholines remain very limited. We hypothesized that acylcholines containing residues of arachidonic (AA-CHOL), oleic (Ol-CHOL), linoleic (Ln-CHOL), and docosahexaenoic (DHA-CHOL) acids act as modulators of the acetylcholine signaling system. In the radioligand binding assay, acylcholines showed inhibition in the micromolar range of both alpha7 neuronal nAChR overexpressed in GH4C1 cells and muscle type nAChR from Torpedo californica, as well as Lymnaea stagnalis acetylcholine binding protein. Functional response was checked in two cell lines endogenously expressing alpha7 nAChR. In SH-SY5Y cells, these compounds did not induce Ca(2+) rise, but inhibited the acetylcholine-evoked Ca(2+) rise with IC50 9 to 12 muM. In the A549 lung cancer cells, where alpha7 nAChR activation stimulates proliferation, Ol-CHOL, Ln-CHOL, and AA-CHOL dose-dependently decreased cell viability by up to 45%. AA-CHOL inhibited human erythrocyte acetylcholinesterase (AChE) and horse serum butyrylcholinesterase (BChE) by a mixed type mechanism with Ki = 16.7 +/- 1.5 muM and alphaKi = 51.4 +/- 4.1 muM for AChE and Ki = 70.5 +/- 6.3 muM and alphaKi = 214 +/- 17 muM for BChE, being a weak substrate of the last enzyme only, agrees with molecular docking results. Thus, long-chain unsaturated acylcholines could be viewed as endogenous modulators of the acetylcholine signaling system.
ESTHER : Akimov_2020_Biomolecules_10_
PubMedSearch : Akimov_2020_Biomolecules_10_
PubMedID: 32059521

Title : 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 - Makhaeva_2019_Bioorg.Chem_91_103097
Author(s) : Makhaeva GF , Elkina NA , Shchegolkov EV , Boltneva NP , Lushchekina SV , Serebryakova OG , Rudakova EV , Kovaleva NV , Radchenko EV , Palyulin VA , Burgart YV , Saloutin VI , Bachurin SO , Richardson RJ
Ref : Bioorg Chem , 91 :103097 , 2019
Abstract : To search for effective and selective inhibitors of carboxylesterase (CES), a series of 3-oxo-2-tolylhydrazinylidene-4,4,4-trifluorobutanoates bearing higher or natural alcohol moieties was synthesized via pre-transesterification of ethyl trifluoroacetylacetate with alcohols to isolate transesterificated oxoesters as lithium salts, which were then subjected to azo coupling with tolyldiazonium chloride. Inhibitory activity against porcine liver CES, along with two structurally related serine hydrolases, acetylcholinesterase and butyrylcholinesterase, were investigated using enzyme kinetics and molecular docking. Kinetics studies demonstrated that the tested keto-esters are reversible and selective mixed-type CES inhibitors. Analysis of X-ray crystallographic data together with our IR and NMR spectra and QM calculations indicated that the Z-isomers were the most stable. The kinetic data were well explained by the molecular docking results of the Z-isomers, which showed specific binding of the compounds in the CES catalytic active site with carbonyl oxygen atoms in the oxyanion hole and non-specific binding outside it. Some compounds were studied as inhibitors of the main human isozymes involved in biotransformation of ester-containing drugs, hCES1 and hCES2. Esters of geraniol (3d) and adamantol (3e) proved to be highly active and selective inhibitors of hCES2, inhibiting the enzyme in the nanomolar range, whereas esters of borneol (3f) and isoborneol (3g) were more active and selective against hCES1. Computational ADMET studies revealed that all test compounds had excellent intestinal absorption, medium blood-brain barrier permeability, and low hERG liability risks. Moreover, all test compounds possessed radical-scavenging properties and low acute toxicity. Overall, the results indicate that members of this novel series of esters have the potential to be good candidates as hCES1 or hCES2 inhibitors for biomedicinal applications.
ESTHER : Makhaeva_2019_Bioorg.Chem_91_103097
PubMedSearch : Makhaeva_2019_Bioorg.Chem_91_103097
PubMedID: 31323527

Title : Synthesis of 2-arylhydrazinylidene-3-oxo-4,4,4-trifluorobutanoic acids as new selective carboxylesterase inhibitors and radical scavengers - Khudina_2019_Bioorg.Med.Chem.Lett__126716
Author(s) : Khudina OG , Makhaeva GF , Elkina NA , Boltneva NP , Serebryakova OG , Shchegolkov EV , Rudakova EV , Lushchekina SV , Burgart YV , Bachurin SO , Richardson RJ , Saloutin VI
Ref : Bioorganic & Medicinal Chemistry Lett , :126716 , 2019
Abstract : A series of 2-arylhydrazinylidene-3-oxo-4,4,4-trifluorobutanoic acids was synthesized via dealkylation of ethyl 2-arylhydrazinylidene-3-oxo-4,4,4-trifluorobutanoates under the action of a Lewis acid. Under the same conditions, ethyl 2-arylhydrazinylidene-3-oxobutanoates were also found to undergo dealkylation rather than the previously described cyclization into cinnolones. Study of the esterase profile of these compounds showed that trifluoromethyl-containing acids, in contrast to non-fluorinated analogs, were effective and selective inhibitors of carboxylesterase (CES), without substantially inhibiting structurally related cholinesterases (acetylcholinesterase and butyrylcholinesterase). Moreover, both 3-oxo-4,4,4-trifluorobutanoic and 3-oxobutanoic acids having methyl or methoxy substituent in the arylhydrazinylidene fragment showed high antioxidant activity in the ABTS test. Thus, 2-arylhydrazinylidene-3-oxo-4,4,4-trifluorobutanoic acids were found to constitute a new class of effective and selective CES inhibitors that also possess high radical-scavenging activity.
ESTHER : Khudina_2019_Bioorg.Med.Chem.Lett__126716
PubMedSearch : Khudina_2019_Bioorg.Med.Chem.Lett__126716
PubMedID: 31640885

Title : Synthesis, molecular docking, and biological activity of 2-vinyl chromones: Toward selective butyrylcholinesterase inhibitors for potential Alzheimer's disease therapeutics - Makhaeva_2018_Bioorg.Med.Chem_26_4716
Author(s) : Makhaeva GF , Boltneva NP , Lushchekina SV , Rudakova EV , Serebryakova OG , Kulikova LN , Beloglazkin AA , Borisov RS , Richardson RJ
Ref : Bioorganic & Medicinal Chemistry , 26 :4716 , 2018
Abstract : We investigated the biological activity of a series of substituted chromeno[3,2-c]pyridines, including compounds previously synthesized by our group and novel compounds whose syntheses are reported here. Tandem transformation of their tetrahydropyridine ring under the action of activated alkynes yielding 2-vinylsubstituted chromones was used to prepare nitrogen-containing derivatives of a biologically active chromone system. The inhibitory activity of these chromone derivatives against acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and carboxylesterase (CaE) was investigated using the methods of enzyme kinetics and molecular docking. Antioxidant (antiradical) activity of the compounds was assessed in the ABTS assay. The results demonstrated that a subset of the studied chromone derivatives selectively inhibit BChE but do not exhibit antiradical activity. In addition, the results of molecular docking effectively explained the observed features in the efficacy, selectivity, and mechanism of BChE inhibition by the chromone derivatives.
ESTHER : Makhaeva_2018_Bioorg.Med.Chem_26_4716
PubMedSearch : Makhaeva_2018_Bioorg.Med.Chem_26_4716
PubMedID: 30104121

Title : Synthesis, molecular docking, and biological activity of polyfluoroalkyl dihydroazolo[5,1-c][1,2,4]triazines as selective carboxylesterase inhibitors - Shchegol'kov_2017_Bioorg.Med.Chem_25_3997
Author(s) : Shchegol'kov EV , Makhaeva GF , Boltneva NP , Lushchekina SV , Serebryakova OG , Rudakova EV , Kovaleva NV , Burgart YV , Saloutin VI , Chupakhin ON , Bachurin SO , Richardson RJ
Ref : Bioorganic & Medicinal Chemistry , 25 :3997 , 2017
Abstract : To search for effective and selective inhibitors of carboxylesterase (CaE), a series of 7-hydroxy-7-polyfluoroalkyl-4,7-dihydroazolo[5,1-c][1,2,4]triazines has been synthesized. Their inhibitory activity against acetylcholinesterase, butyrylcholinesterase, and CaE were investigated using the methods of enzyme kinetics and molecular docking. It was shown that the tested compounds are reversible selective CaE inhibitors of mixed type. Elongation of the polyfluoroalkyl substituent and the presence of an ester, preferably the ethoxycarbonyl group, enhance inhibitory activity toward CaE. Furthermore, the compounds with a tetrazole ring are more active against CaE than their triazole analogues. The obtained kinetic data are well explained by the results of molecular docking, according to which there is a similar orientation of triazolo- and tetrazolotriazines in the active site of CaE and the opposite one for pyrazolotriazines. In the 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) assay, all of the studied tetrazolotriazines and some pyrazolotriazines demonstrated good antiradical activity comparable with a standard antioxidant, Trolox. The leading compounds were nonafluorobutyl substituted tetrazolo- and 7-phenylpyrazolotriazines, which possess effective and selective CaE inhibitory activity as well as additional useful radical-scavenging properties.
ESTHER : Shchegol'kov_2017_Bioorg.Med.Chem_25_3997
PubMedSearch : Shchegol'kov_2017_Bioorg.Med.Chem_25_3997
PubMedID: 28578994

Title : 9-Substituted acridine derivatives as acetylcholinesterase and butyrylcholinesterase inhibitors possessing antioxidant activity for Alzheimer's disease treatment - Makhaeva_2017_Bioorg.Med.Chem_25_5981
Author(s) : Makhaeva GF , Lushchekina SV , Boltneva NP , Serebryakova OG , Rudakova EV , Ustyugov AA , Bachurin SO , Shchepochkin AV , Chupakhin ON , Charushin VN , Richardson RJ
Ref : Bioorganic & Medicinal Chemistry , 25 :5981 , 2017
Abstract : 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.
ESTHER : Makhaeva_2017_Bioorg.Med.Chem_25_5981
PubMedSearch : Makhaeva_2017_Bioorg.Med.Chem_25_5981
PubMedID: 28986116

Title : Esterase profiles of organophosphorus compounds in vitro predict their behavior in vivo - Makhaeva_2016_Chem.Biol.Interact_259_332
Author(s) : Makhaeva GF , Rudakova EV , Serebryakova OG , Aksinenko AY , Lushchekina SV , Bachurin SO , Richardson RJ
Ref : Chemico-Biological Interactions , 259 :332 , 2016
Abstract : We studied 4 serine esterases (EOHs) that are associated with the following consequences from their inhibition by organophosphorus compounds (OPCs): acetylcholinesterase (AChE: acute neurotoxicity; cognition enhancement), butyrylcholinesterase (BChE: inhibition of drug metabolism and/or stoichiometric scavenging of EOH inhibitors; cognition enhancement), carboxylesterase (CaE; inhibition of drug metabolism and/or stoichiometric scavenging of EOH inhibitors), and neuropathy target esterase (NTE: delayed neurotoxicity, OPIDN). The relative degree of inhibition of these EOHs constitutes the "esterase profile" of an OPC, which we hypothesize can serve as a predictor of its overall physiological effects. To test this hypothesis, we selected 3 OPCs known from previous work on reference enzymes to span a wide range of esterase profiles, neuropathic potential, and acute cholinergic toxicity. For each compound, we determined in vitro IC50 and in vivo ED50 values for inhibition of AChE, BChE, CaE, and NTE in mouse brain and blood. The results showed good correlations between in vitro and in vivo measures of potency and selectivity except for brain CaE, a tissue-specific isoform of the enzyme that was less sensitive to the test compounds than expected. Thus, this synthesis of new and previously published results indicates that the concept of the esterase profile of OPCs is useful for the prediction of therapeutic and toxic effects in vivo.
ESTHER : Makhaeva_2016_Chem.Biol.Interact_259_332
PubMedSearch : Makhaeva_2016_Chem.Biol.Interact_259_332
PubMedID: 27154493

Title : Synthesis, molecular docking and biological evaluation of N,N-disubstituted 2-aminothiazolines as a new class of butyrylcholinesterase and carboxylesterase inhibitors - Makhaeva_2016_Bioorg.Med.Chem_24_1050
Author(s) : Makhaeva GF , Boltneva NP , Lushchekina SV , Serebryakova OG , Stupina TS , Terentiev AA , Serkov IV , Proshin AN , Bachurin SO , Richardson RJ
Ref : Bioorganic & Medicinal Chemistry , 24 :1050 , 2016
Abstract : A series of 31 N,N-disubstituted 2-amino-5-halomethyl-2-thiazolines was designed, synthesized, and evaluated for inhibitory potential against acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and carboxylesterase (CaE). The compounds did not inhibit AChE; the most active compounds inhibited BChE and CaE with IC50 values of 0.22-2.3muM. Pyridine-containing compounds were more selective toward BChE; compounds with the para-OMe substituent in one of the two dibenzyl fragments were more selective toward CaE. Iodinated derivatives were more effective BChE inhibitors than brominated ones, while there was no influence of halogen type on CaE inhibition. Inhibition kinetics for the 9 most active compounds indicated non-competitive inhibition of CaE and varied mechanisms (competitive, non-competitive, or mixed-type) for inhibition of BChE. Docking simulations predicted key binding interactions of compounds with BChE and CaE and revealed that the best docked positions in BChE were at the bottom of the gorge in close proximity to the catalytic residues in the active site. In contrast, the best binding positions for CaE were clustered rather far from the active site at the top of the gorge. Thus, the docking results provided insight into differences in kinetic mechanisms and inhibitor activities of the tested compounds. A cytotoxicity test using the MTT assay showed that within solubility limits (<30muM), none of the tested compounds significantly affected viability of human fetal mesenchymal stem cells. The results indicate that a new series of N,N-disubstituted 2-aminothiazolines could serve as BChE and CaE inhibitors for potential medicinal applications.
ESTHER : Makhaeva_2016_Bioorg.Med.Chem_24_1050
PubMedSearch : Makhaeva_2016_Bioorg.Med.Chem_24_1050
PubMedID: 26827140

Title : Conjugates of gamma-Carbolines and Phenothiazine as new selective inhibitors of butyrylcholinesterase and blockers of NMDA receptors for Alzheimer Disease - Makhaeva_2015_Sci.Rep_5_13164
Author(s) : Makhaeva GF , Lushchekina SV , Boltneva NP , Sokolov VB , Grigoriev VV , Serebryakova OG , Vikhareva EA , Aksinenko AY , Barreto GE , Aliev G , Bachurin SO
Ref : Sci Rep , 5 :13164 , 2015
Abstract : Alzheimer disease is a multifactorial pathology and the development of new multitarget neuroprotective drugs is promising and attractive. We synthesized a group of original compounds, which combine in one molecule gamma-carboline fragment of dimebon and phenothiazine core of methylene blue (MB) linked by 1-oxo- and 2-hydroxypropylene spacers. Inhibitory activity of the conjugates toward acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and structurally close to them carboxylesterase (CaE), as well their binding to NMDA-receptors were evaluated in vitro and in silico. These newly synthesized compounds showed significantly higher inhibitory activity toward BChE with IC50 values in submicromolar and micromolar range and exhibited selective inhibitory action against BChE over AChE and CaE. Kinetic studies for the 9 most active compounds indicated that majority of them were mixed-type BChE inhibitors. The main specific protein-ligand interaction is pi-pi stacking of phenothiazine ring with indole group of Trp82. These compounds emerge as promising safe multitarget ligands for the further development of a therapeutic approach against aging-related neurodegenerative disorders such as Alzheimer and/or other pathological conditions.
ESTHER : Makhaeva_2015_Sci.Rep_5_13164
PubMedSearch : Makhaeva_2015_Sci.Rep_5_13164
PubMedID: 26281952

Title : Further studies toward a mouse model for biochemical assessment of neuropathic potential of organophosphorus compounds - Makhaeva_2014_J.Appl.Toxicol_34_1426
Author(s) : Makhaeva GF , Rudakova EV , Hein ND , Serebryakova OG , Kovaleva NV , Boltneva NP , Fink JK , Richardson RJ
Ref : J Appl Toxicol , 34 :1426 , 2014
Abstract : Inhibition and aging of neuropathy target esterase (NTE) by neuropathic organophosphorus (OP) compounds triggers OP compound-induced delayed neuropathy (OPIDN), whereas inhibition of acetylcholinesterase (AChE) produces cholinergic toxicity. The neuropathic potential of an OP compound is defined by its relative inhibitory potency toward NTE vs. AChE assessed by enzyme assays following dosing in vivo or after incubations of direct-acting compounds or active metabolites with enzymes in vitro. The standard animal model of OPIDN is the adult hen, but its large size and high husbandry costs make this species a burdensome model for assessing neuropathic potential. Although the mouse does not readily exhibit clinical signs of OPIDN, it displays axonal lesions and expresses brain AChE and NTE. Therefore, the present research was performed as a further test of the hypothesis that inhibition of mouse brain AChE and NTE could be used to assess neuropathic potential using mouse brain preparations in vitro or employing mouse brain assays following dosing of OP compounds in vivo. Excellent correlations were obtained for inhibition kinetics in vitro of mouse brain enzymes vs. hen brain and human recombinant enzymes. Furthermore, inhibition of mouse brain AChE and NTE after dosing with OP compounds afforded ED50 ratios that agreed with relative inhibitory potencies assessed in vitro. Taken together, results with mouse brain enzymes demonstrated consistent correspondence between in vitro and in vivo predictors of neuropathic potential, thus adding to previous studies supporting the validity of a mouse model for biochemical assessment of the ability of OP compounds to produce OPIDN. Copyright (c) 2014 John Wiley & Sons, Ltd.
ESTHER : Makhaeva_2014_J.Appl.Toxicol_34_1426
PubMedSearch : Makhaeva_2014_J.Appl.Toxicol_34_1426
PubMedID: 24395470

Title : N,N-disubstituted 2-aminothiazolines as new inhibitors of serine esterases -
Author(s) : Boltneva NP , Serebryakova OG , Makhaeva GF , Serkov IV , Proshin AN , Bachurin SO
Ref : Dokl Biochem Biophys , 451 :209 , 2013
PubMedID: 23975403

Title : Kinetics and mechanism of inhibition of serine esterases by fluorinated carbethoxy 1-aminophosphonates -
Author(s) : Makhaeva GF , Lushchekina SV , Serebryakova OG , Aksinenko AY , Goreva TV , Richardson RJ , Martynov IV
Ref : Dokl Biochem Biophys , 451 :203 , 2013
PubMedID: 23975401

Title : Synthesis and testing of trifluoromethyl-containing phosphonate-peptide conjugates as inhibitors of serine hydrolases - Sokolova_2011_Bioorg.Med.Chem.Lett_21_7216
Author(s) : Sokolova NV , Nenajdenko VG , Sokolov VB , Serebryakova OG , Makhaeva GF
Ref : Bioorganic & Medicinal Chemistry Lett , 21 :7216 , 2011
Abstract : A modification of novel fluorinated organophosphorous compounds containing terminal alkyne group by different azidopeptides via Cu(I)-catalyzed click chemistry has been described. The inhibitor activity of trifluoromethyl-containing methylphosphonates and their peptide-conjugates towards acetylcholinesterase, butyrylcholinesterase, and carboxylesterase has been investigated. It was shown that the incorporation of peptide fragments significantly modulates the esterase profile of starting methylphosphonates.
ESTHER : Sokolova_2011_Bioorg.Med.Chem.Lett_21_7216
PubMedSearch : Sokolova_2011_Bioorg.Med.Chem.Lett_21_7216
PubMedID: 22001085

Title : Synthesis of organophosphates with fluorine-containing leaving groups as serine esterase inhibitors with potential for Alzheimer disease therapeutics - Makhaeva_2009_Bioorg.Med.Chem.Lett_19_5528
Author(s) : Makhaeva GF , Aksinenko AY , Sokolov VB , Serebryakova OG , Richardson RJ
Ref : Bioorganic & Medicinal Chemistry Lett , 19 :5528 , 2009
Abstract : Acetylcholinesterase and butyrylcholinesterase inhibitors are potential cognition enhancers in Alzheimer disease. O,O-Dialkylphosphate inhibitors with 1-substituted 2,2,2-trifluoroethoxy leaving groups were synthesized by phosphonate-phosphate rearrangement. Substituents in the 1-position of the leaving group along with the O-alkyl groups modulated potency and selectivity against acetylcholinesterase, butyrylcholinesterase, and carboxylesterase.
ESTHER : Makhaeva_2009_Bioorg.Med.Chem.Lett_19_5528
PubMedSearch : Makhaeva_2009_Bioorg.Med.Chem.Lett_19_5528
PubMedID: 19717305

Title : Esterase profile and analysis of structure-inhibitor selectivity relationships for homologous phosphorylated 1-hydroperfluoroisopropanols -
Author(s) : Makhaeva GF , Serebryakova OG , Boltneva NP , Galenko TG , Aksinenko AY , Sokolov VB , Martynov IV
Ref : Dokl Biochem Biophys , 423 :352 , 2008
PubMedID: 19230387