Conjugates of Tacrine with Salicylamide as Promising Multitarget Agents for Alzheimer's Disease

Grishchenko, Maria V.; Makhaeva, G. F.; Burgart, Yanina V.; Рудакова, Е. В.; Boltneva, Natalia P.; Kovaleva, N. V.; Serebryakova, Olga G.; Lushchekina, Sofya V.; Astakhova, T. Yu.; Zhilina, Ekaterina F.; Shchegolkov, Evgeny V.; Richardson, Rudy J.; Салоутин, В. И.

doi:10.1002/cmdc.202200080

Cited by 16 publications

(10 citation statements)

References 42 publications

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“…It was found that all compounds bind to the hAChE in a uniform way, occupying both the CAS and PAS. In the CAS, the protonated tacrine fragment binds forming π-π stacking interactions with the Trp86 side chain and a hydrogen bond with its main chain hydrogen oxygen ( Figure 4 A–C), as was observed previously for tacrine-containing conjugates [ 116 , 117 ]. Compounds 6a-c also form a few hydrogen bonds between Tyr124 phenolic hydroxyl group and the linker nitrogen atoms or carbonyl atom of the acetyl group ( Figure 4 A).…”

Section: Resultssupporting

confidence: 65%

New Multifunctional Agents for Potential Alzheimer’s Disease Treatment Based on Tacrine Conjugates with 2-Arylhydrazinylidene-1,3-Diketones

et al. 2022

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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, IC50 0.24–0.34 µM) and butyrylcholinesterase (BChE, IC50 0.036–0.0745 µM), 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 β-amyloid aggregation, a disease-modifying effect. All of the conjugates demonstrated metal chelating ability for Cu2+, Fe2+, and Zn2+, as well as high antiradical activity in the ABTS test. Non-fluorinated hybrid compounds 6 and 7 also showed Fe3+ 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.

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Section: Resultssupporting

confidence: 65%

New Multifunctional Agents for Potential Alzheimer’s Disease Treatment Based on Tacrine Conjugates with 2-Arylhydrazinylidene-1,3-Diketones

et al. 2022

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“…The mode of binding of salicylamides 5 was reported earlier [59]: the protonated tacrine fragment was bound in the active site, and the salicylamide group was bound in the PAS, advancing into it with increasing linker length. For the newly synthesized groups of compounds 6, 7, 8, and 10, this mode of binding was preserved (Figure 3a).…”

Section: Molecular Modeling Studiesmentioning

confidence: 59%

“…One of the most popular approaches to the synthesis of tacrine conjugates is the synthesis of aminopolymethylene-containing derivatives of tacrine 3 by the substitution of the chlorine atom in 9-chloro-1,2,3,4-tetrahydroacridine 1 with diaminoalkanes [55,70]. Earlier [59], we found that the reaction of tacrine derivatives 3a-c containing 4, 6, and 8 methylene units with salicylic acid 4a in dry methylene chloride at room temperature in the presence of HATU and DIPEA leads to hybrid compounds of tacrine with salicylamide 5a-c (Scheme 1). Using this protocol, we synthesized a series of conjugates 6a-c, 7a-c, and 8a-c via reaction of tacrine derivatives 3a-c with 2-methoxybenzoic 4b, 4,5-difluorosalicylic 4c, and 4,5-difluoro-2-methoxybenzoic 4d acids.…”

Section: Chemistrymentioning

confidence: 99%

“…These moieties possess a wide spectrum of biological activity, including AO and metal-chelating properties, as well as the ability to inhibit β-amyloid aggregation [56][57][58]. Recently, we showed that conjugates of tacrine and salicylamide (5a-c) have dual anticholinesterase activity with selectivity toward BChE [59]. Moreover, the hybrid compounds inhibited AChE and BChE two to three times more effectively than tacrine, had the potential to block AChE-induced βamyloid aggregation (propidium iodide displacement test), exhibited high ABTS •+ -scavenging activity, and displayed metal-chelating ability.…”

Section: Introductionmentioning

confidence: 99%

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Conjugates of Tacrine and Salicylic Acid Derivatives as New Promising Multitarget Agents for Alzheimer’s Disease

Makhaeva

Kovaleva

Рудакова

et al. 2023

IJMS

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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: IC50 values of the lead compound 10c were 0.0826 µM (AChE) and 0.0156 µM (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 β-amyloid aggregation. All conjugates inhibited Aβ42 self-aggregation in the thioflavin test, and inhibition increased with spacer elongation. Salicylimine 10c and salicylamide 5c with (CH2)8 spacers were the lead compounds for inhibiting Aβ42 self-aggregation, which was corroborated by molecular docking to Aβ42. 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 Cu2+, Fe2+, and Zn2+, with molar compound/metal (Cu2+) 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.

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“…CEH activity (nmol/(min X mg protein)) was calculated as To distinguish ChE and CES activity, specific inhibitors of either ChE or CES activity were pre-incubated with the planarian homogenate for 10 minutes (instead of methyl paraoxon mentioned above), followed by an Ellman or CEH assay as described above. The CES-specific inhibitor benzil (Wang et al 2018) was used to identify ChE activity, whereas tacrine, a ChE-specific inhibitor (Grishchenko et al 2022), was used to measure CES-specific activity. 16 mM benzil (10X stock) was dissolved in 100% ethanol.…”

Section: Carboxylesterase (Ces) Activity Assaysmentioning

confidence: 99%

Bioactivation and detoxification of organophosphorus pesticides in freshwater planarians shares similarities with humans

et al. 2022

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Organophosphorus pesticides (OPs) are a chemically diverse class of insecticides that inhibit acetylcholinesterase (AChE). Many OPs require bioactivation to their active oxon form via cytochrome P450 to effectively inhibit AChE. OP toxicity can be mitigated by detoxification reactions performed by carboxylesterase and paraoxonase. The relative extent of bioactivation to detoxification varies among individuals and between species, leading to differential susceptibility to OP toxicity. Because of these species differences, it is imperative to characterize OP metabolism in model systems used to assess OP toxicity to adequately evaluate potential human hazard. We have shown that the asexual freshwater planarian Dugesia japonica is a suitable model to assess OP neurotoxicity and developmental neurotoxicity via rapid, automated testing of adult and developing organisms in parallel using morphological and behavioral endpoints. D. japonica has two cholinesterase enzymes with intermediate properties between AChE and butyrylcholinesterase that are sensitive to OP inhibition. Here, we demonstrate that this planarian contains the major OP metabolic machinery to be a relevant model for OP neurotoxicity studies. Adult and regenerating D. japonica can bioactivate chlorpyrifos and diazinon into their respective oxons. Significant AChE inhibition was only observed after in vivo metabolic activation but not when the parent OPs were directly added to planarian homogenate. Additionally, we found that D. japonica has both carboxylesterase and paraoxonase activity. Using specific chemical inhibitors, we show that carboxylesterase activity is distinct from cholinesterase activity. Taken together, these results further support the use of D. japonica for OP toxicity studies.

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Conjugates of Tacrine with Salicylamide as Promising Multitarget Agents for Alzheimer's Disease

Cited by 16 publications

References 42 publications

New Multifunctional Agents for Potential Alzheimer’s Disease Treatment Based on Tacrine Conjugates with 2-Arylhydrazinylidene-1,3-Diketones

New Multifunctional Agents for Potential Alzheimer’s Disease Treatment Based on Tacrine Conjugates with 2-Arylhydrazinylidene-1,3-Diketones

Conjugates of Tacrine and Salicylic Acid Derivatives as New Promising Multitarget Agents for Alzheimer’s Disease

Bioactivation and detoxification of organophosphorus pesticides in freshwater planarians shares similarities with humans

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