Makhaeva_2023_Int.J.Mol.Sci_24_2285

Reference

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

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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 (2023)
Conjugates of Tacrine and Salicylic Acid Derivatives as New Promising Multitarget Agents for Alzheimer's Disease
Int J Mol Sci 24 :2285

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 (2023)
Int J Mol Sci 24 :2285

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    [id] => 37303
    [paper] => Makhaeva_2023_Int.J.Mol.Sci_24_2285
    [author] => 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
    [year] => 2023
    [title] => Conjugates of Tacrine and Salicylic Acid Derivatives as New Promising Multitarget Agents for Alzheimer's Disease
    [journal] => Int J Mol Sci
    [volume] => 24
    [page] => 2285
    [medline] => 36768608
    [abstract] => Makhaeva_2023_Int.J.Mol.Sci_24_2285
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            [content] => 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.
        )

)