Synthesis and anticholinesterase activity of 2-(dimethylamino)ethyl and choline esters of N-substituted α,β-dehydroamino acids

A new method for the synthesis of tertiary and quaternary aminoesters of N-substituted α,β-dehydroamino acids is described. Aseries of 16 dehydroamino acids esterified to choline or to its tertiary analog have been synthesized by the proposed method with a yield of 84-93%, and their interactions with human erythrocyte acetylcholinesterase (ACE) and human plasma butyrylcholinesterase (BCE) has been studied. The half-inhibiting concentrations IC₅₀ of the synthesized compounds (determined with respect to cholinesterase hydrolysis of a model substrate, 0.1 mM ATC) vary within a broad range (0.16-1840 μM). The values of traditional parameters of the wave functions of ligands estimated using the Hartree-Fock method do not explain the observed pattern of the anticholinesterase activity. The specific properties of the molecules, especially in their quaternary ammonium salt forms, are probably related to their structural features, in particular, to the ability of the inhibitors to form cyclic conformations (so-called crown structures). Such structures are probably stabilized as a result of the formation of intramolecuar hydrogen bonds between protons of the choline residue and oxygen of the terminal peptide group.