Conjugates of anticholinesterase drugs ipidacrine and tacrine with thiouracils: synthesis and biological properties

Abstract

Chloroalkylene amide derivatives were obtained by acylation of known Cholinesterase inhibitors, ipidacrine and tacrine. The acylated derivatives were used in the alkylation of substituted 2-thiouracils (R = Me, CF₂H, CF₃, (CF₂)₂H)) for the synthesis of new hybrid compounds. Study of the esterase profile revealed a pronounced activity and selectivity of the obtained conjugates against butyrylcholinesterase (IC₅₀ up to 2.03 µmol L⁻¹), moderate displacement of propidium from the acetylcholinesterase peripheral anionic site, and moderate inhibition of the β-amyloid self-aggregation. It was found that conjugation of thiouracils with tacrine leads to a decrease in the hepatotoxicity of the hybrid compounds compared to that of tacrine, while in the case of ipidacrine derivatives, no hepatotoxicity was observed.