Synthesis and pharmacological properties of amiridine analogs

Zhidkova, A. M.; Berlyand, A. S.; Knizhnik, A. Z.; Lavretskaya, É. F.; Robakidze, T. N.; Sukhanova, S. A.; Mufazalova, T. P.

doi:10.1007/bf00764431

Cited by 6 publications

(5 citation statements)

References 5 publications

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“…Whereas “9-Cl-tacrine” is mainly used for the synthesis of tacrine derivatives, the analogous “Cl-amiridine” is not easy to obtain; moreover, the chlorine in “Cl-amiridine” proved to be difficult to displace. The reduced activity of amiridine in reactions that are common for tacrine can be associated with both the steric factor of two polymethylene rings and the close pK a values of the endo- and exocyclic nitrogen atoms [ 80 , 81 ].…”

Section: Resultsmentioning

confidence: 99%

“…As is known, similarly to 4-aminopyridine, the alkylation reactions of amiridine proceed at the endocyclic nitrogen atom, and the acylation reactions proceed at the exocyclic amino group nitrogen atom [ 80 ]. Due to this, we started the functionalization of the amiridine molecule at the external nitrogen by acylation with chloroacetic acid chloride.…”

Section: Resultsmentioning

confidence: 99%

“…However, the amiridine structure has a lower reactivity compared to tacrine. In this regard, there is practically no information on amiridine derivatives in the literature, and the functionalization of the amiridine molecule at the external nitrogen, while maintaining the unique amiridine scaffold, is a separate issue [ 80 , 81 ].…”

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: Resultsmentioning

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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“…However, this scaffold was practically not used for the development of new agents for the treatment of AD. 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.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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Synthesis and pharmacological properties of amiridine analogs

Cited by 6 publications

References 5 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

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

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

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