Timokhina EN

References (3)

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