Amiridine-piperazine hybrids as cholinesterase inhibitors and potential multitarget agents for Alzheimer's disease treatment

Махаева, Галина Ф.; Lushchekina, Sofya V.; Kovaleva, N. V.; Astakhova, T. Yu.; Boltneva, Natalia P.; Рудакова, Е. В.; Serebryakova, Olga G.; Прошин, А. Н.; Серков, И. В.; Трофимова, Т. П.; Тафеенко, В. А.; Radchenko, Eugene V.; Palyulin, Vladimir A.; Фисенко, Владимир Петрович; Korábečný, Jan; Soukup, Ondřej; Richardson, Rudy J.

doi:10.1016/j.bioorg.2021.104974

Cited by 34 publications

(39 citation statements)

References 106 publications

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“…Due to this, we started the functionalization of the amiridine molecule at the external nitrogen by acylation with chloroacetic acid chloride. The obtained amiridine chloroacetamide was reacted with piperazines, providing amiridine-piperazine conjugates [ 78 ]. In this work, we used the reaction of amiridine chloroacetamide 2 with 1,ω-diaminoalkanes to prepare bis-amiridines 3 with bis- N -acyl-alkylene spacers ( Scheme 1 ).…”

Section: Resultsmentioning

confidence: 99%

“…Amiridine is an anticholinesterase drug that has found use in Russia and some other countries in Eastern Europe as a therapeutic agent for AD and certain other neurological disorders [ 70 , 71 , 72 , 73 , 74 , 75 ]. Known to inhibit AChE and BChE, with more potency against the latter enzyme, amiridine also exhibits numerous other biological activities [ 76 , 77 ] that have been reviewed in our previous publication [ 78 ].…”

Section: Introductionmentioning

confidence: 99%

“…Recently, our team performed the functionalization of the amiridine molecule by acylation with chloroacetic acid chloride. The resulting amiridine chloroacetamide was reacted with piperazines, resulting in the production of a number of amiridine-piperazine hybrids as prospective multifunctional agents for AD treatment [ 78 ]. In our current work, to obtain new amiridine-based MTDLs, we used the reaction of amiridine chloroacetamide with diaminoalkanes to synthesize amiridine–amiridine homodimers with bis- N -acyl-alkylene spacers.…”

Section: Introductionmentioning

confidence: 99%

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Bis-Amiridines as Acetylcholinesterase and Butyrylcholinesterase Inhibitors: N-Functionalization Determines the Multitarget Anti-Alzheimer’s Activity Profile

et al. 2022

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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 IC50(AChE) = 2.9–1.4 µM, IC50(BChE) = 0.13–0.067 µM, and 14–18% propidium displacement at 20 mM. 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 Aβ42 aggregation. Conjugates 3 had no effect on Aβ42 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.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Bis-Amiridines as Acetylcholinesterase and Butyrylcholinesterase Inhibitors: N-Functionalization Determines the Multitarget Anti-Alzheimer’s Activity Profile

et al. 2022

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“…To evaluate the esterase profiles of aminoadamantane-γ-carboline conjugates, their inhibitory activity against three structurally similar serine esterases, AChE, BChE and CES was determined. We used human erythrocyte AChE, equine serum BChE and porcine liver CES, which were shown to be suitable for this purpose in our previous studies [11,12,47,62,63]. The results showed (Table 2) that all of the conjugates were more potent inhibitors of BChE compared to AChE and that they had very weak inhibitory activity against CES.…”

Section: Evaluation Of the Esterase Profile Of Aminoadamantane-γ-carboline Conjugatesmentioning

confidence: 99%

“…The compounds were evaluated as potential inhibitors of proaggregation activity of AChE by measuring the displacement of propidium iodide from the PAS of the enzyme [53] using a fluorescence method [28]. AChE from Electrophorus electricus (EeAChE, type VI-S, lyophilized powder, Sigma-Aldrich, St. Louis, MO, USA) was used for consistency with our previous studies [8,13,63,74]. The fluorescence intensity of propidium iodide bound to AChE increases several-fold.…”

Section: Displacement Of Propidium Iodide From Ache Pasmentioning

confidence: 99%

Conjugation of Aminoadamantane and γ-Carboline Pharmacophores Gives Rise to Unexpected Properties of Multifunctional Ligands

et al. 2021

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A new series of conjugates of aminoadamantane and γ-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 β-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.

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Synthesis and biological evaluation of peripherally tetra‐({6‐[3‐(dimethylamino)phenoxy]hexyl}oxy) substituted water‐soluble phthalocyanines as cholinesterases inhibitors

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Akkaya

et al. 2022

Applied Organom Chemis

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In this paper, we synthesized peripherally tetra‐({6‐[3‐(dimethylamino)phenoxy]hexyl}oxy) substituted water‐soluble metallophthalocyanines (DM‐C6‐CoQ, DM‐C6‐CuQ, DM‐C6‐MnQ) and investigated their in vitro cholinesterases inhibitory properties by using the spectrophotometric method. The results revealed that the compounds inhibited cholinesterases and had remarkable inhibitory effects when compared with galantamine (p < 0.0001). The IC50 values of the compounds ranged from 2.11 ± 0.20 to 16.40 ± 1.25 μM for AChE and BuChE. Also, the inhibitory type and inhibition constant (Ki) of the compounds were evaluated using Lineweaver–Burk and Dixon plots. These plots showed that DM‐C6‐CoQ, DM‐C6‐CuQ, and DM‐C6‐MnQ were mixed inhibitors against AChE and DM‐C6‐MnQ is the strongest binding inhibitor to the enzyme. Also, DM‐C6‐CoQ inhibited BuChE via competitive manner with 10.05 ± 0.55 μM of Ki value. These results demonstrated that the compounds might be effective agents against Alzheimer's disease.

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Amiridine-piperazine hybrids as cholinesterase inhibitors and potential multitarget agents for Alzheimer's disease treatment

Cited by 34 publications

References 106 publications

Bis-Amiridines as Acetylcholinesterase and Butyrylcholinesterase Inhibitors: N-Functionalization Determines the Multitarget Anti-Alzheimer’s Activity Profile

Bis-Amiridines as Acetylcholinesterase and Butyrylcholinesterase Inhibitors: N-Functionalization Determines the Multitarget Anti-Alzheimer’s Activity Profile

Conjugation of Aminoadamantane and γ-Carboline Pharmacophores Gives Rise to Unexpected Properties of Multifunctional Ligands

Synthesis and biological evaluation of peripherally tetra‐({6‐[3‐(dimethylamino)phenoxy]hexyl}oxy) substituted water‐soluble phthalocyanines as cholinesterases inhibitors

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