Burgart YV

References (11)

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 amiridine and thiouracil derivatives as effective inhibitors of butyrylcholinesterase with the potential to block beta-amyloid aggregation - Khudina_2023_Arch.Pharm.(Weinheim)__e2300447
Author(s) : Khudina OG , Grishchenko MV , Makhaeva GF , Kovaleva NV , Boltneva NP , Rudakova EV , Lushchekina SV , Shchegolkov EV , Borisevich SS , Burgart YV , Saloutin VI , Charushin VN
Ref : Arch Pharm (Weinheim) , :e2300447 , 2023
Abstract : New amiridine-thiouracil conjugates with different substituents in the pyrimidine fragment (R = CH(3) , CF(2) , CF(3) , (CF(2) )(2) H) and different spacer lengths (n = 1-3) were synthesized. The conjugates rather weakly inhibit acetylcholinesterase (AChE) and exhibit high inhibitory activity (IC(50) up to 0.752 +/- 0.021 microM) and selectivity to butyrylcholinesterase (BChE), which increases with spacer elongation; the lead compounds are 11c, 12c, and 13c. The conjugates are mixed-type reversible inhibitors of both cholinesterases and practically do not inhibit the structurally related off-target enzyme carboxylesterase. The results of molecular docking to AChE and BChE are consistent with the experiment on enzyme inhibition and explain the structure-activity relationships, including the rather low anti-AChE activity and the high anti-BChE activity of long-chain conjugates. The lead compounds displace propidium from the AChE peripheral anion site (PAS) at the level of the reference compound donepezil, which agrees with the mixed-type mechanism of AChE inhibition and the main mode of binding of conjugates in the active site of AChE due to the interaction of the pyrimidine moiety with the PAS. This indicates the ability of the studied conjugates to block AChE-induced aggregation of beta-amyloid, thereby exerting a disease-modifying effect. According to computer calculations, all synthesized conjugates have an ADME profile acceptable for drugs.
ESTHER : Khudina_2023_Arch.Pharm.(Weinheim)__e2300447
PubMedSearch : Khudina_2023_Arch.Pharm.(Weinheim)__e2300447
PubMedID: 38072670

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 : New Multifunctional Agents for Potential Alzheimer's Disease Treatment Based on Tacrine Conjugates with 2-Arylhydrazinylidene-1,3-Diketones - Elkina_2022_Biomolecules_12_
Author(s) : Elkina NA , Grishchenko MV , Shchegolkov EV , Makhaeva GF , Kovaleva NV , Rudakova EV , Boltneva NP , Lushchekina SV , Astakhova TY , Radchenko EV , Palyulin VA , Zhilina EF , Perminova AN , Lapshin LS , Burgart YV , Saloutin VI , Richardson RJ
Ref : Biomolecules , 12 : , 2022
Abstract : 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, IC(50) 0.24-0.34 M) and butyrylcholinesterase (BChE, IC(50) 0.036-0.0745 M), 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 beta-amyloid aggregation, a disease-modifying effect. All of the conjugates demonstrated metal chelating ability for Cu(2+), Fe(2+), and Zn(2+), as well as high antiradical activity in the ABTS test. Non-fluorinated hybrid compounds 6 and 7 also showed Fe(3+) 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.
ESTHER : Elkina_2022_Biomolecules_12_
PubMedSearch : Elkina_2022_Biomolecules_12_
PubMedID: 36358901

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 : 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 : 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 : Cholinesterase and carboxylesterase inhibitors as pharmacological agents - Makhaeva_2019_Russ Chem Bull_68_967
Author(s) : Makhaeva GF , Rudakova EV , Kovaleva NV , Lushchekina SV , Boltneva NP , Proshin AN , Shchegolkov EV , Burgart YV , Saloutin VI
Ref : Russ Chem Bull , 68 :967 , 2019
Abstract : Literature data and authors' own results on the role of serine hydrolases, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), as drug targets for treatment of neurodegenerative diseases and carboxylesterase (CaE) inhibitors as modulators of CaE-hydrolysis of ester-containing drugs are analyzed. Today, a promising approach is the development of cholinesterase inhibitors with additional neuroprotective and disease-modifying properties. The developed esterase profile approach, that is, comparative assessment of the inhibitory activity against AChE, BChE, and CaE, can be used to evaluate both the main potential pharmacological effect and possible side effects of a new compound. Analysis of the esterase profile, in combination with computer modeling and assessment of radical-scavenging ability of the synthesized compounds and their potential ability to block AChE-induced beta-amyloid aggregation revealed highly active multifunctional compounds for the treatment of Alzheimer's disease: selective inhibitors of BChE and inhibitors of both cholinesterases without potential side effects associated with CaE inhibition. A number of effective and selective inhibitors of CaE, free from cholinergic side effects, were also found for modulation of the rate of hydrolytic metabolism and for rational use of ester-containing drugs.
ESTHER : Makhaeva_2019_Russ Chem Bull_68_967
PubMedSearch : Makhaeva_2019_Russ Chem Bull_68_967

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 : Alkyl 2-arylhydrazinylidene-3-oxo-3-polyfluoroalkylpropionates as new effective and selective inhibitors of carboxylesterase - Boltneva_2015_Dokl.Biochem.Biophys_465_381
Author(s) : Boltneva NP , Makhaeva GF , Kovaleva NV , Lushchekina SV , Burgart YV , Shchegol'kov EV , Saloutin VI , Chupakhin ON
Ref : Dokl Biochem Biophys , 465 :381 , 2015
Abstract : A series of alkyl 2-Arylhydrazinylidene-3-oxo-3-polyfluoroalkylpropionates was synthesized and their inhibitory activity with respect to porcine liver carboxylesterase (CaE, EC, human erythrocyte acetylcholinesterase (AChE, EC, and horse serum butyrylcholinesterase (BChE, EC was studied. The molecular docking method was used to study the binding mode of the compounds in the active site of CaE. It was found that compounds containing the trifluoromethyl group in the third position of carbonyl chain are highly effective and selective inhibitors of CaE with nanomolar IC50 values, which agrees well with the results of molecular docking.
ESTHER : Boltneva_2015_Dokl.Biochem.Biophys_465_381
PubMedSearch : Boltneva_2015_Dokl.Biochem.Biophys_465_381
PubMedID: 26728730