Synthesis and study of the biological activity of thiourea-containing amiridine derivatives as potential multi-target drugs for the treatment of Alzheimer’s disease

Махаева, Галина Ф.; Прошин, А. Н.; Kovaleva, N. V.; Рудакова, Е. В.; Boltneva, Natalia P.; Lushchekina, Sofya V.; Astakhova, T. Yu.; Серков, И. В.; Kalashnikova, I. P.; Бачурин, С. О.

doi:10.1007/s11172-022-3668-y

Cited by 15 publications

(8 citation statements)

References 56 publications

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“…[ 103 ] 2‐Chloro‐ N ‐(2,3,5,6,7,8‐hexahydro‐1 H ‐cyclopenta[ b ]quinolin‐9‐yl)‐acetamide 3a was synthesized by referring to the previously published methods. [ 72 ]…”

Section: Methodsmentioning

confidence: 99%

“…[103] 2-Chloro-N-(2,3,5,6,7,8-hexahydro-1H-cyclo penta[b]quinolin-9-yl)-acetamide 3a was synthesized by referring to the previously published methods. [72] Methylthiouracil 5a, [104] 6-(difluoromethyl)-2,3-dihydro-2-thioxo-4(1H)-pyrimidinone 5b, 2,3-dihydro-2-thioxo-6-(trifluoromethyl)-4(1H)-pyrimidinone 5c, [105] 2,3-dihydro-6-(…”

Section: According To Thementioning

confidence: 99%

“…Thus, the synthesis of only a few derivatives of amiridine is described in the literature, [70] and its use as a basis for the development of multifunctional conjugates was studied in only three recent publications. [37,71,72] The pyrimidine scaffold is of interest as a second pharmacophore for conjugation due to its biological effects promising for the development of anti-AD agents with reduced side effects and improved therapeutic efficacy. [73] Thus, pyrimidine derivatives have shown themselves to be MTDLs, combining a high inhibitory ability against AChE and BChE (most often with selectivity for AChE), [74][75][76] inhibition of Aβ self-aggregation, metal-chelating, antioxidant capacity, and low cytotoxicity.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Conjugates of amiridine and thiouracil derivatives as effective inhibitors of butyrylcholinesterase with the potential to block β‐amyloid aggregation

Khudina,

Grishchenko,

Makhaeva

et al. 2023

Archiv der Pharmazie

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New amiridine‐thiouracil conjugates with different substituents in the pyrimidine fragment (R = CH3, CF2Н, CF3, (CF2)2H) and different spacer lengths (n = 1–3) were synthesized. The conjugates rather weakly inhibit acetylcholinesterase (AChE) and exhibit high inhibitory activity (IC50 up to 0.752 ± 0.021 µM) 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 β‐amyloid, thereby exerting a disease‐modifying effect. According to computer calculations, all synthesized conjugates have an ADME profile acceptable for drugs.

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“…[ 103 ] 2‐Chloro‐ N ‐(2,3,5,6,7,8‐hexahydro‐1 H ‐cyclopenta[ b ]quinolin‐9‐yl)‐acetamide 3a was synthesized by referring to the previously published methods. [ 72 ]…”

Section: Methodsmentioning

confidence: 99%

Section: According To Thementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Conjugates of amiridine and thiouracil derivatives as effective inhibitors of butyrylcholinesterase with the potential to block β‐amyloid aggregation

Khudina,

Grishchenko,

Makhaeva

et al. 2023

Archiv der Pharmazie

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“…2) [18], and thiourea-containing amiridine derivatives (exemplified by 4 ; Fig. 2) [19]. In all the cases, the amiridine core was functionalized at the endocyclic nitrogen with either N -acyl- or N -thiourea-based spacers.…”

Section: Designmentioning

confidence: 99%

Morphing Cholinesterase Inhibitor Amiridine into Multipotent Drugs for the Treatment of Alzheimer's Disease

Mezeiova,

Prchal,

Hrabinova

et al. 2024

Preprint

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The search for novel drugs to address the medical needs of Alzheimer's disease (AD) is an ongoing process relying on the discovery of disease-modifying agents. Given the complexity of the disease, such an aim can be pursued by developing so-called multi-target directed ligands (MTDLs) that will impact the disease pathophysiology more comprehensively. Herewith, we contemplated the therapeutic efficacy of an amiridine drug acting as a cholinesterase inhibitor by converting it into a novel class of novel MTDLs. Applying the linking approach, we have paired amiridine as a core building block with memantine/adamantylamine, trolox, and substituted benzothiazole moieties to generate novel MTDLs endowed with additional properties like N-methyl-D-aspartate (NMDA) receptor affinity, antioxidant capacity, and anti-amyloid properties, respectively. The top-ranked amiridine-based compound 5d was also inspected by in silico to reveal the butyrylcholinesterase binding differences with its close structural analogue 5b. Our study provides insight into the discovery of novel amiridine-based drugs by broadening their target-engaged profile from cholinesterase inhibitors towards MTDLs with potential implications in AD therapy.

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Conjugates of amiridine and salicylic derivatives as promising multifunctional CNS agents for potential treatment of Alzheimer's disease

Makhaeva,

Grishchenko,

Kovaleva

et al. 2024

Archiv der Pharmazie

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New conjugates of amiridine and salicylic derivatives (salicylamide, salicylimine, and salicylamine) with different lengths of alkylene spacers were designed, synthesized, and evaluated as potential multifunctional central nervous system therapeutic agents for Alzheimer's disease (AD). Conjugates demonstrated high acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition (IC50: AChE, 0.265−4.24 μM; BChE, 0.01−0.64 μM) but poor activity against off‐target carboxylesterase (CES). Specifically, conjugates with a (CH2)8 spacer showed the highest AChE and BChE inhibition: 3–16 times more effective than amiridine. Salicylamides 7b and 7c had the maximum BChE/AChE selectivity ratios: 193 and 138, respectively. Conjugates were mixed‐type reversible inhibitors of both cholinesterases and displaced propidium from the AChE peripheral anionic site (PAS) at the level of donepezil. All conjugates inhibited Aβ42 self‐aggregation in the thioflavin test; inhibition increased with spacer elongation, being greatest for (CH2)8. The results agreed with molecular docking to AChE, BChE, and Aβ42. Conjugates exhibited high 2,2′‐azino‐bis(3‐ethylbenzothiazoline‐6‐sulfonic acid) (ABTS)•+‐scavenging activity comparable to the standard antioxidant Trolox, and they showed the ability to bind Cu2+, Fe2+, and Zn2+. Conjugates had favorable predicted intestinal absorption and blood–brain barrier permeability. Altogether, the results indicate that the new conjugates possess potential for further development as multifunctional anti‐AD drug candidates.

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Synthesis and study of the biological activity of thiourea-containing amiridine derivatives as potential multi-target drugs for the treatment of Alzheimer’s disease

Cited by 15 publications

References 56 publications

Conjugates of amiridine and thiouracil derivatives as effective inhibitors of butyrylcholinesterase with the potential to block β‐amyloid aggregation

Conjugates of amiridine and thiouracil derivatives as effective inhibitors of butyrylcholinesterase with the potential to block β‐amyloid aggregation

Morphing Cholinesterase Inhibitor Amiridine into Multipotent Drugs for the Treatment of Alzheimer's Disease

Conjugates of amiridine and salicylic derivatives as promising multifunctional CNS agents for potential treatment of Alzheimer's disease

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