Boltneva NP

General

Full name : Boltneva Natalya P

First name : Natalya P

Mail : Institute of Physiologically Active Compounds Russian Acad Sci\; Molecular Toxicology\; 1 Severny proezd\; Chernogolovka\; 142432

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Country : Russia

Email : boltneva@ipac.ac.ru

Phone : +74965242597

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References (37)

Title : Combining Experimental and Computational Methods to Produce Conjugates of Anticholinesterase and Antioxidant Pharmacophores with Linker Chemistries Affecting Biological Activities Related to Treatment of Alzheimer's Disease - Makhaeva_2024_Molecules_29_321
Author(s) : Makhaeva GF , Kovaleva NV , Rudakova EV , Boltneva NP , Lushchekina SV , Astakhova TY , Timokhina EN , Serkov IV , Proshin AN , Soldatova YV , Poletaeva DA , Faingold, II , Mumyatova VA , Terentiev AA , Radchenko EV , Palyulin VA , Bachurin SO , Richardson RJ
Ref : Molecules , 29 :321 , 2024
Abstract : Effective therapeutics for Alzheimer's disease (AD) are in great demand worldwide. In our previous work, we responded to this need by synthesizing novel drug candidates consisting of 4-amino-2,3-polymethylenequinolines conjugated with butylated hydroxytoluene via fixed-length alkylimine or alkylamine linkers (spacers) and studying their bioactivities pertaining to AD treatment. Here, we report significant extensions of these studies, including the use of variable-length spacers and more detailed biological characterizations. Conjugates were potent inhibitors of acetylcholinesterase (AChE, the most active was 17d IC(50) 15.1 +/- 0.2 nM) and butyrylcholinesterase (BChE, the most active was 18d: IC(50) 5.96 +/- 0.58 nM), with weak inhibition of off-target carboxylesterase. Conjugates with alkylamine spacers were more effective cholinesterase inhibitors than alkylimine analogs. Optimal inhibition for AChE was exhibited by cyclohexaquinoline and for BChE by cycloheptaquinoline. Increasing spacer length elevated the potency against both cholinesterases. Structure-activity relationships agreed with docking results. Mixed-type reversible AChE inhibition, dual docking to catalytic and peripheral anionic sites, and propidium iodide displacement suggested the potential of hybrids to block AChE-induced beta-amyloid (Abeta) aggregation. Hybrids also exhibited the inhibition of Abeta self-aggregation in the thioflavin test; those with a hexaquinoline ring and C8 spacer were the most active. Conjugates demonstrated high antioxidant activity in ABTS and FRAP assays as well as the inhibition of luminol chemiluminescence and lipid peroxidation in mouse brain homogenates. Quantum-chemical calculations explained antioxidant results. Computed ADMET profiles indicated favorable blood-brain barrier permeability, suggesting the CNS activity potential. Thus, the conjugates could be considered promising multifunctional agents for the potential treatment of AD.
ESTHER : Makhaeva_2024_Molecules_29_321
PubMedSearch : Makhaeva_2024_Molecules_29_321
PubMedID: 38257233

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 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 Methylene Blue with Cycloalkaneindoles as New Multifunctional Agents for Potential Treatment of Neurodegenerative Disease - Bachurin_2022_Int.J.Mol.Sci_23_
Author(s) : Bachurin SO , Shevtsova EF , Makhaeva GF , Aksinenko AY , Grigoriev VV , Goreva TV , Epishina TA , Kovaleva NV , Boltneva NP , Lushchekina SV , Rudakova EV , Vinogradova DV , Shevtsov PN , Pushkareva EA , Dubova LG , Serkova TP , Veselov IM , Fisenko VP , Richardson RJ
Ref : Int J Mol Sci , 23 : , 2022
Abstract : The development of multi-target-directed ligands (MTDLs) would provide effective therapy of neurodegenerative diseases (ND) with complex and nonclear pathogenesis. A promising method to create such potential drugs is combining neuroactive pharmacophoric groups acting on different biotargets involved in the pathogenesis of ND. We developed a synthetic algorithm for the conjugation of indole derivatives and methylene blue (MB), which are pharmacophoric ligands that act on the key stages of pathogenesis. We synthesized hybrid structures and performed a comprehensive screening for a specific set of biotargets participating in the pathogenesis of ND (i.e., cholinesterases, NMDA receptor, mitochondria, and microtubules assembly). The results of the screening study enabled us to find two lead compounds (4h and 4i) which effectively inhibited cholinesterases and bound to the AChE PAS, possessed antioxidant activity, and stimulated the assembly of microtubules. One of them (4i) exhibited activity as a ligand for the ifenprodil-specific site of the NMDA receptor. In addition, this lead compound was able to bypass the inhibition of complex I and prevent calcium-induced mitochondrial depolarization, suggesting a neuroprotective property that was confirmed using a cellular calcium overload model of neurodegeneration. Thus, these new MB-cycloalkaneindole conjugates constitute a promising class of compounds for the development of multitarget neuroprotective drugs which simultaneously act on several targets, thereby providing cognitive stimulating, neuroprotective, and disease-modifying effects.
ESTHER : Bachurin_2022_Int.J.Mol.Sci_23_
PubMedSearch : Bachurin_2022_Int.J.Mol.Sci_23_
PubMedID: 36430413

Title : Bis-Amiridines as Acetylcholinesterase and Butyrylcholinesterase Inhibitors: N-Functionalization Determines the Multitarget Anti-Alzheimer's Activity Profile - Makhaeva_2022_Molecules_27_
Author(s) : Makhaeva GF , Kovaleva NV , Boltneva NP , Rudakova EV , Lushchekina SV , Astakhova TY , Serkov IV , Proshin AN , Radchenko EV , Palyulin VA , Korabecny J , Soukup O , Bachurin SO , Richardson RJ
Ref : Molecules , 27 : , 2022
Abstract : Using two ways of functionalizing amiridine-acylation with chloroacetic acid chloride and reaction with thiophosgene-we have synthesized new homobivalent bis-amiridines joined by two different spacers-bis-N-acyl-alkylene (3) and bis-N-thiourea-alkylene (5) -as potential multifunctional agents for the treatment of Alzheimer's disease (AD). All compounds exhibited high inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity for BChE. These new agents displayed negligible carboxylesterase inhibition, suggesting a probable lack of untoward drug-drug interactions arising from hydrolytic biotransformation. Compounds 3 with bis-N-acyl-alkylene spacers were more potent inhibitors of both cholinesterases compared to compounds 5 and the parent amiridine. The lead compounds 3a-c exhibited an IC(50)(AChE) = 2.9-1.4 microM, IC(50)(BChE) = 0.13-0.067 microM, and 14-18% propidium displacement at 20 microM. Kinetic studies of compounds 3a and 5d indicated mixed-type reversible inhibition. Molecular docking revealed favorable poses in both catalytic and peripheral AChE sites. Propidium displacement from the peripheral site by the hybrids suggests their potential to hinder AChE-assisted Abeta(42) aggregation. Conjugates 3 had no effect on Abeta(42) self-aggregation, whereas compounds 5c-e (m = 4, 5, 6) showed mild (13-17%) inhibition. The greatest difference between conjugates 3 and 5 was their antioxidant activity. Bis-amiridines 3 with N-acylalkylene spacers were nearly inactive in ABTS and FRAP tests, whereas compounds 5 with thiourea in the spacers demonstrated high antioxidant activity, especially in the ABTS test (TEAC = 1.2-2.1), in agreement with their significantly lower HOMO-LUMO gap values. Calculated ADMET parameters for all conjugates predicted favorable blood-brain barrier permeability and intestinal absorption, as well as a low propensity for cardiac toxicity. Thus, it was possible to obtain amiridine derivatives whose potencies against AChE and BChE equaled (5) or exceeded (3) that of the parent compound, amiridine. Overall, based on their expanded and balanced pharmacological profiles, conjugates 5c-e appear promising for future optimization and development as multitarget anti-AD agents.
ESTHER : Makhaeva_2022_Molecules_27_
PubMedSearch : Makhaeva_2022_Molecules_27_
PubMedID: 35164325

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 : Conjugation of Aminoadamantane and gamma-Carboline Pharmacophores Gives Rise to Unexpected Properties of Multifunctional Ligands - Bachurin_2021_Molecules_26_
Author(s) : Bachurin SO , Makhaeva GF , Shevtsova EF , Aksinenko AY , Grigoriev VV , Shevtsov PN , Goreva TV , Epishina TA , Kovaleva NV , Pushkareva EA , Boltneva NP , Lushchekina SV , Gabrelyan AV , Zamoyski VL , Dubova LG , Rudakova EV , Fisenko VP , Bovina EV , Richardson RJ
Ref : Molecules , 26 : , 2021
Abstract : A new series of conjugates of aminoadamantane and gamma-carboline, which are basic scaffolds of the known neuroactive agents, memantine and dimebon (Latrepirdine) was synthesized and characterized. Conjugates act simultaneously on several biological structures and processes involved in the pathogenesis of Alzheimer's disease and some other neurodegenerative disorders. In particular, these compounds inhibit enzymes of the cholinesterase family, exhibiting higher inhibitory activity against butyrylcholinesterase (BChE), but having almost no effect on the activity of carboxylesterase (anti-target). The compounds serve as NMDA-subtype glutamate receptor ligands, show mitoprotective properties by preventing opening of the mitochondrial permeability transition (MPT) pore, and act as microtubule stabilizers, stimulating the polymerization of tubulin and microtubule-associated proteins. Structure-activity relationships were studied, with particular attention to the effect of the spacer on biological activity. The synthesized conjugates showed new properties compared to their prototypes (memantine and dimebon), including the ability to bind to the ifenprodil-binding site of the NMDA receptor and to occupy the peripheral anionic site of acetylcholinesterase (AChE), which indicates that these compounds can act as blockers of AChE-induced beta-amyloid aggregation. These new attributes of the conjugates represent improvements to the pharmacological profiles of the separate components by conferring the potential to act as neuroprotectants and cognition enhancers with a multifunctional mode of action.
ESTHER : Bachurin_2021_Molecules_26_
PubMedSearch : Bachurin_2021_Molecules_26_
PubMedID: 34576998

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 : New Multifunctional Agents Based on Conjugates of 4-Amino-2,3-polymethylenequinoline and Butylated Hydroxytoluene for Alzheimer's Disease Treatment - Makhaeva_2020_Molecules_25_5891
Author(s) : Makhaeva GF , Kovaleva NV , Rudakova EV , Boltneva NP , Lushchekina SV , Faingold, II , Poletaeva DA , Soldatova YV , Kotelnikova RA , Serkov IV , Ustinov AK , Proshin AN , Radchenko EV , Palyulin VA , Richardson RJ
Ref : Molecules , 25 :5891 , 2020
Abstract : New hybrids of 4-amino-2,3-polymethylenequinoline with different sizes of the aliphatic ring linked to butylated hydroxytoluene (BHT) by enaminoalkyl (7) or aminoalkyl (8) spacers were synthesized as potential multifunctional agents for Alzheimer's disease (AD) treatment. All compounds were potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity toward BChE. Lead compound 8c, 2,6-di-tert-butyl-4-{[2-(7,8,9,10- tetrahydro-6H-cyclohepta[b]quinolin-11-ylamino)-ethylimino]-methyl}-phenol exhibited an IC(50)(AChE) = 1.90 +/- 0.16 microM, IC(50)(BChE) = 0.084 +/- 0.008 microM, and 13.6 +/- 1.2% propidium displacement at 20 M. Compounds possessed low activity against carboxylesterase, indicating likely absence of clinically unwanted drug-drug interactions. Kinetics were consistent with mixed-type reversible inhibition of both cholinesterases. Docking indicated binding to catalytic and peripheral AChE sites; peripheral site binding along with propidium displacement suggest the potential of the hybrids to block AChE-induced beta-amyloid aggregation, a disease-modifying effect. Compounds demonstrated high antioxidant activity in ABTS and FRAP assays as well as inhibition of luminol chemiluminescence and lipid peroxidation in mouse brain homogenates. Conjugates 8 with amine-containing spacers were better antioxidants than those with enamine spacers 7. Computational ADMET profiles for all compounds predicted good blood-brain barrier distribution (permeability), good intestinal absorption, and medium cardiac toxicity risk. Overall, based on their favorable pharmacological and ADMET profiles, conjugates 8 appear promising as candidates for AD therapeutics.
ESTHER : Makhaeva_2020_Molecules_25_5891
PubMedSearch : Makhaeva_2020_Molecules_25_5891
PubMedID: 33322783

Title : 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 - Makhaeva_2020_Molecules_25_3915
Author(s) : Makhaeva GF , Kovaleva NV , Boltneva NP , Lushchekina SV , Astakhova TY , Rudakova EV , Proshin AN , Serkov IV , Radchenko EV , Palyulin VA , Bachurin SO , Richardson RJ
Ref : Molecules , 25 :3915 , 2020
Abstract : 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 IC(50) (AChE) = 0.131 +/- 0.01 muM (five times more potent than tacrine), IC(50)(BChE) = 0.0680 +/- 0.0014 muM, and 17.5 +/- 1.5% propidium displacement at 20 muM. 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 beta-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.
ESTHER : Makhaeva_2020_Molecules_25_3915
PubMedSearch : Makhaeva_2020_Molecules_25_3915
PubMedID: 32867324

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 : Conjugates of tacrine and 1,2,4-thiadiazole derivatives as new potential multifunctional agents for Alzheimer's disease treatment: Synthesis, quantum-chemical characterization, molecular docking, and biological evaluation - Makhaeva_2019_Bioorg.Chem__103387
Author(s) : Makhaeva GF , Kovaleva NV , Boltneva NP , Lushchekina SV , Rudakova EV , Stupina TS , Terentiev AA , Serkov IV , Proshin AN , Radchenko EV , Palyulin VV , Bachurin SO , Richardson RJ
Ref : Bioorg Chem , :103387 , 2019
Abstract : We synthesized conjugates of tacrine with 1,2,4-thiadiazole derivatives linked by two different spacers, pentylaminopropene (compounds 4) and pentylaminopropane (compounds 5), as potential drugs for the treatment of Alzheimer's disease (AD). The conjugates effectively inhibited cholinesterases with a predominant effect on butyrylcholinesterase (BChE). They were also effective at displacing propidium from the peripheral anionic site (PAS) of acetylcholinesterase (AChE), suggesting that they could block AChE-induced beta-amyloid aggregation. In addition, the compounds exhibited high radical-scavenging capacity. Conjugates 5 had higher anti-BChE activity and greater anti-aggregant potential as well relatively lower potency against carboxylesterase than compounds 4. Quantum-mechanical (QM) characterization agreed with NMR data to identify the most stable forms of conjugates for docking studies, which showed that the compounds bind to both CAS and PAS of AChE consistent with mixed reversible inhibition. Conjugates 4 were more potent radical scavengers, in agreement with HOMO localization in the enamine-thiadiazole system. Computational studies showed that all of the conjugates were expected to have good intestinal absorption, whereas conjugates 4 and 5 were predicted to have medium and high blood-brain barrier permeability, respectively. All conjugates were predicted to have medium cardiac toxicity risks. Overall, the results indicated that the conjugates are promising candidates for further development and optimization as multifunctional therapeutic agents for the treatment of AD.
ESTHER : Makhaeva_2019_Bioorg.Chem__103387
PubMedSearch : Makhaeva_2019_Bioorg.Chem__103387
PubMedID: 31735356

Title : Conjugates of methylene blue with gamma-carboline derivatives as new multifunctional agents for the treatment of neurodegenerative diseases - Bachurin_2019_Sci.Rep_9_4873
Author(s) : Bachurin SO , Makhaeva GF , Shevtsova EF , Boltneva NP , Kovaleva NV , Lushchekina SV , Rudakova EV , Dubova LG , Vinogradova DV , Sokolov VB , Aksinenko AY , Fisenko VP , Richardson RJ , Aliev G
Ref : Sci Rep , 9 :4873 , 2019
Abstract : We studied the inhibitory activity of methylene blue (MB) gamma-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 muM and exhibited low potencies against CaE (9.8-26% inhibition at 20 muM). 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.
ESTHER : Bachurin_2019_Sci.Rep_9_4873
PubMedSearch : Bachurin_2019_Sci.Rep_9_4873
PubMedID: 30890752

Title : Overview of novel multifunctional agents based on conjugates of gamma-carbolines, carbazoles, tetrahydrocarbazoles, phenothiazines, and aminoadamantanes for treatment of Alzheimer's disease - Makhaeva_2019_Chem.Biol.Interact_13ChEPon_308_224
Author(s) : Makhaeva GF , Shevtsova EF , Boltneva NP , Lushchekina SV , Kovaleva NV , Rudakova EV , Bachurin SO , Richardson RJ
Ref : Chemico-Biological Interactions , 308 :224 , 2019
Abstract : Alzheimer's disease (AD) is a multifactorial neurodegenerative process whose effective treatment will require drugs that can act simultaneously on multiple pathogenic targets. Here, we present an overview of our previous multitarget studies of five groups of novel hybrid structures that combine, through spacers, five pharmacophores that have been found promising for AD treatment: gamma-carbolines, carbazoles, tetrahydrocarbazoles, phenothiazines, and aminoadamantanes. Biological activity of the compounds was assessed by a battery of assays. These included inhibitory potency against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) as indicators of potential for cognition enhancement and against carboxylesterase (CaE) to exclude unwanted inhibition of this biotransformation pathway. Displacement of propidium from the peripheral anionic site of AChE was determined as a predictor of anti-aggregation activity. Binding to the two sites of the NMDA subtype of the glutamate receptor was conducted as an additional indicator of potential cognition enhancement and neuroprotection. Propensity to protect against mitochondrial triggers of cell death was evaluated by tests of mitochondrial potential and calcium-induced swelling as indicators of mitochondrial permeability transition. Antioxidant potential was measured to evaluate the tendency to prevent oxidative stress. Potential for disease modification was gauged by the ability to stimulate microtubule assembly. Finally, binding modes of conjugates to AChE and BChE were studied using quantum mechanical-assisted molecular docking. We found selective BChE inhibitors (conjugates of gamma-carbolines and phenothiazine I, gamma-carbolines and carbazoles II, and aminoadamantanes and carbazoles III) as well as inhibitors of both cholinesterases (conjugates of gamma-carbolines and methylene blue IV and bis-gamma-carbolines with ditriazole-containing spacers V). These compounds combined potentials for cognition enhancement, neuroprotection, and disease modification. None of the conjugates exhibited high potency against CaE, thereby precluding potential drug-drug interactions from CaE inhibition. Thus, the studied compounds exhibited positive characteristics of multitarget drugs, indicating their potential for the next generation of AD therapeutics.
ESTHER : Makhaeva_2019_Chem.Biol.Interact_13ChEPon_308_224
PubMedSearch : Makhaeva_2019_Chem.Biol.Interact_13ChEPon_308_224
PubMedID: 31100279

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 : Anticholinesterase and Antioxidant Activity of New Binary Conjugates of gamma-Carbolines - Makhaeva_2019_Dokl.Biochem.Biophys_484_1
Author(s) : Makhaeva GF , Shevtsova EF , Boltneva NP , Kovaleva NV , Rudakova EV , Dubova LG , Shevtsov PN , Bachurin SO
Ref : Dokl Biochem Biophys , 484 :1 , 2019
Abstract : The synthesized new binary conjugates of tetrahydro-gamma-carbolines, which contained ditriazole spacers of different length, exhibited considerable anticholinesterase and antioxidant activity as well as the potential ability to block the acetylcholinesterase-induced aggregation of beta-amyloid in contrast to the original prototype Dimebon. This makes the compounds promising candidates for further investigation as drugs for the treatment of Alzheimer's disease. Special attention should be given to the conjugate containing the hexamethylene intertriazole spacer, which can be considered as a leader in this series of compounds.
ESTHER : Makhaeva_2019_Dokl.Biochem.Biophys_484_1
PubMedSearch : Makhaeva_2019_Dokl.Biochem.Biophys_484_1
PubMedID: 31012000

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
PubMedID:

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 : Conjugates of Tacrine and Its Cyclic Homologues with p-Toluenesulfonamide as Novel Acetylcholinesterase and Butyrylcholinesterase Inhibitors - Makhaeva_2018_Dokl.Biochem.Biophys_483_369
Author(s) : Makhaeva GF , Kovaleva NV , Lushchekina SV , Rudakova EV , Boltneva NP , Proshin AN , Lednev BV , Serkov IV , Bachurin SO
Ref : Dokl Biochem Biophys , 483 :369 , 2018
Abstract : Using the acylation reaction with tosyl chloride of N-aminopropyl analogues of tacrine and its cyclic homologues with different size of the aliphatic cycle (5-8), we synthesized a number of new derivatives of p-toluenesulfonamide. It is shown that the synthesized hybrid compounds of tacrine and p-toluenesulfonamide are effective inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with the preferential inhibition of BChE. They also displace propidium from the peripheral anionic site of the electric eel AChE (Electrophorus electricus). The characteristics of the efficiency and selectivity of cholinesterase inhibition by the test compounds were confirmed by the results of molecular docking.
ESTHER : Makhaeva_2018_Dokl.Biochem.Biophys_483_369
PubMedSearch : Makhaeva_2018_Dokl.Biochem.Biophys_483_369
PubMedID: 30607741

Title : Novel conjugates of tacrine with 1,2,4,-thiadiazole as highly effective cholinesterase inhibitors, blockers of NMDA receptors, and antioxidants - Makhaeva_2017_Dokl.Biochem.Biophys_477_405
Author(s) : Makhaeva GF , Grigoriev VV , Proshin AN , Kovaleva NV , Rudakova EV , Boltneva NP , Serkov IV , Bachurin SO
Ref : Dokl Biochem Biophys , 477 :405 , 2017
Abstract : Conjugates of tacrine with 1,2,4-thiadiazole derivatives were synthesized for the first time. Their esterase profile and effects on the key NMDA receptor-binding sites as well as antioxidant activity were investigated. The obtained compounds effectively inhibited cholinesterases (with a predominant effect on butyrylcholinesterase), simultaneously blocked two NMDA receptor-binding sites (allosteric and intrachannel sites, and exhibited a high radical-scavenging activity. Our study shows that the obtained compounds are promising to design drugs for the treatment of Alzheimer's disease and other multifactorial neurodegenerative diseases.
ESTHER : Makhaeva_2017_Dokl.Biochem.Biophys_477_405
PubMedSearch : Makhaeva_2017_Dokl.Biochem.Biophys_477_405
PubMedID: 29297118

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 : Novel conjugates of aminoadamantanes with carbazole derivatives as potential multitarget agents for AD treatment - Bachurin_2017_Sci.Rep_7_45627
Author(s) : Bachurin SO , Shevtsova EF , Makhaeva GF , Grigoriev VV , Boltneva NP , Kovaleva NV , Lushchekina SV , Shevtsov PN , Neganova ME , Redkozubova OM , Bovina EV , Gabrelyan AV , Fisenko VP , Sokolov VB , Aksinenko AY , Echeverria V , Barreto GE , Aliev G
Ref : Sci Rep , 7 :45627 , 2017
Abstract : 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.
ESTHER : Bachurin_2017_Sci.Rep_7_45627
PubMedSearch : Bachurin_2017_Sci.Rep_7_45627
PubMedID: 28358144

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 : 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 : 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 3.1.1.1), human erythrocyte acetylcholinesterase (AChE, EC 3.1.1.7), and horse serum butyrylcholinesterase (BChE, EC 3.1.1.8) 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

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 : Synthesis and biological activity of O-carbamoylated 1,1,1,3,3,3-hexafluoroisopropanols as new specific inhibitors of carboxylesterase - Mukhamadieva_2012_Pharm.Chem.J_46_461
Author(s) : Mukhamadieva GR , Boltneva NP , Galenko TG , Sokolov VB , Epishina TA , Makhaeva GF
Ref : Pharmaceutical Chemistry Journal , 46 :461 , 2012
Abstract : A series of O-carbamoylated 1,1,1,3,3,3-hexafluoroisopropanols of general formula RNHC(O)OCH(CF3)2, where R = CH3, n-C3H7, tert-C4H9, cyclo-C6H11, C6H5-CH2, C6H5, 4-Cl-C6H4, 3-Cl-C6H4, 3,4-Cl2-C6H3, and naphthylen-2-yl were synthesized. The reaction kinetics of the synthesized carbamates with human erythrocyte acetylcholinesterase (EC 3.1.1.7), horse serum butyrylcholinesterase (EC 3.1.1.8), and porcine liver carboxylesterase (EC 3.1.1.1) were studied. It was shown that the synthesized carbamates did not inhibit acetylcholinesterase, inhibited weakly butyrylcholinesterase, and inhibited selectively the activity of carboxylesterase. A new selective irreversible inhibitor of carboxylesterase, 2,2,2-trifluoro-1-trifluoromethylethyl cyclohexylcarbamate, which had low acute toxicity, was obtained.
ESTHER : Mukhamadieva_2012_Pharm.Chem.J_46_461
PubMedSearch : Mukhamadieva_2012_Pharm.Chem.J_46_461
PubMedID:

Title : Comparative analysis of esterase activities of human, mouse, and rat blood - Rudakova_2011_Bull.Exp.Biol.Med_152_73
Author(s) : Rudakova EV , Boltneva NP , Makhaeva GF
Ref : Bulletin of Experimental Biology & Medicine , 152 :73 , 2011
Abstract : Acetylcholinesterase, butyrylcholinesterase, carboxylesterase, and paraoxonase activities in human, mouse, and rat blood were measured. The proportions of these enzymes activities differed significantly. In humans, the most significant were cholinesterase activities, while in rats and mice the contribution of carboxylesterase activity was the greatest. High arylesterase activity of paraoxonase was observed in all cases. Species-specific differences should be taken into consideration when carrying out preclinical trials on rodents for optimization of the pharmacokinetic characteristics of drugs containing complex ester groups.
ESTHER : Rudakova_2011_Bull.Exp.Biol.Med_152_73
PubMedSearch : Rudakova_2011_Bull.Exp.Biol.Med_152_73
PubMedID: 22803044

Title : Biosensor analysis of blood esterases for organophosphorus compounds exposure assessment: approaches to simultaneous determination of several esterases - Sigolaeva_2010_Chem.Biol.Interact_187_312
Author(s) : Sigolaeva LV , Makhaeva GF , Rudakova EV , Boltneva NP , Porus M , Dubacheva G , Eremenko A , Kurochkin I , Richardson RJ
Ref : Chemico-Biological Interactions , 187 :312 , 2010
Abstract : This paper reviews our previously published data and presents new results on biosensor assay of blood esterases. Tyrosinase and choline oxidase biosensors based on nanostructured polyelectrolyte films were developed for these purposes. Experiments were performed on the quantitative determination of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), carboxylesterase (CaE), and neuropathy target esterase (NTE) in samples of whole blood of rats, mice, and humans. Good agreement was found between biosensor and spectrophotometric assays for AChE, BChE, and CaE. No direct comparison could be made for NTE because its activity cannot be measured spectrophotometrically in whole blood. A new method of simultaneous quantitative determination of AChE and BChE in test mixtures is also described. This method represents a bifunctional biosensor for the simultaneous analysis of choline and phenol based on integration of individual sensors. Algorithms for calculation of separate concentrations of AChE and BChE in the mixture were developed. The mean error of calculated component concentrations was approximately 6% for binary test mixtures. The present work provides a foundation for building multiplexed systems for the simultaneous determination of multiple esterases with applications to biomonitoring for exposures to organophosphorus compounds.
ESTHER : Sigolaeva_2010_Chem.Biol.Interact_187_312
PubMedSearch : Sigolaeva_2010_Chem.Biol.Interact_187_312
PubMedID: 20097186

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