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

Abstract

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.

Machine Learning Prediction of Mycobacterial Cell Wall Permeability of Drugs and Drug-like Compounds

“…Providing efficient tools for various QSPR and QSAR problems [ 64 , 65 , 66 ], this approach has been successfully employed to model the structure influence on various pharmacokinetic, toxicity, and physico-chemical endpoints such as human intestinal absorption [ 67 ], blood–brain barrier permeability [ 68 , 69 ], hERG-mediated cardiac toxicity [ 70 ], lipophilicity [ 71 ], etc. Some of these models are available online at our ADMET Prediction Service page ( accessed on 1 December 2022) and have been successfully used to evaluate the key absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of diverse potential drug compounds in virtual screening and molecular design studies [ 72 , 73 , 74 , 75 , 76 ].…”

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

“…The estimated pK a value of the amiridine fragment [37,71] suggests that both protonated and noncharged forms could coexist in a solution at the experimental pH. Thus, molecular docking was performed for both forms of the ligands.…”

“…[27,31,32] This has led to an intensive search for compounds exhibiting dual activity: as AChE inhibitors and as inhibitors of Aβ aggregation, that is, these types of compounds can simultaneously improve cognitive function and have a diseasemodifying effect. [13,14,31,[33][34][35][36][37] BChE is also involved in the formation and/or maturation of Aβ plaques. [38][39][40] It was shown that BChE is associated with various stages and aspects of amyloidogenesis, including a production [19,[41][42][43] and toxicity of aggregates.…”

“…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.…”

“…[ 27,31,32 ] This has led to an intensive search for compounds exhibiting dual activity: as AChE inhibitors and as inhibitors of Aβ aggregation, that is, these types of compounds can simultaneously improve cognitive function and have a disease‐modifying effect. [ 13,14,31,33–37 ]…”