Novel Uracil-Based Inhibitors of Acetylcholinesterase with Potency for Treating Memory Impairment in an Animal Model of Alzheimer’s Disease

Abstract

Novel derivatives based on 6-methyluracil and condensed uracil, 2,4-quinazoline-2,4-dione, were synthesized with terminal meta- and para-benzoate moieties in polymethylene chains at the N atoms of the pyrimidine ring. In the synthesized compounds, the polymethylene chains were varied from having tris- to hexamethylene chains and quaternary ammonium groups; varying substituents (ester, salt, acid) at benzene ring were introduced into the chains and benzoate moieties. In vivo biological experiments demonstrated the potency of these compounds in decreasing the number of β-amyloid plaques and their suitability for the treatment of memory impairment in a transgenic model of Alzheimer’s disease.

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

“…Previously, we have studied the alkylation of trifluoromethylsubstituted 2-thiouracil 5c with 2-bromoacetophenone. [86] Based on the data of 2D NMR ( 1 H-1 H COSY, 1 H- 13 C HSQC, and HMBC), it was found that alkylation proceeds at the O and S atoms. In the 13 T A B L E 1 Substituents and yields for compounds 6, 7, 8a,b, 9, 10a,c, 11a-c, 12a-c, and 13a-c.…”

“…[10] Initially, cholinergic therapy for AD was aimed at inhibiting acetylcholinesterase (AChE) as the main enzyme hydrolyzing the neurotransmitter acetylcholine. [11][12][13][14] The therapeutic effect of AChE inhibitors is due to an increase in the concentration and duration of action of acetylcholine in cholinergic synapses. [15] Butyrylcholinesterase (BChE) also takes part in the process of acetylcholine hydrolysis and is able to compensate for some of the functions of AChE, thereby improving cholinergic neurotransmission and, as a consequence, cognitive functions.…”

“…[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.…”

“…[74,77] For example, methyluracil derivatives linked through N-spacers with various aromatic fragments showed a high inhibitory ability against AChE along with inhibition of AChE-induced Aβ aggregation. [12][13][14] Much less is known about the use of thiouracil scaffold in anti-AD drugs development. [78] However, given the rich biological potential of this scaffold and its widespread use as a synthon for various biologically active compounds with anticancer, antimicrobial, molluscicidal, anti-leishmanial, antiviral, anti-thyroid, antioxidant activities, [79][80][81][82][83][84][85] it was of interest to combine it with an anticholineserase fragment to create potential multitarget anti-AD drugs.…”

“…[ 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 ]…”