Background:
The indole derivatives and the N-phenylpiperazine fragment represent interesting
molecular moieties suitable for the research of new potentially biologically active compounds. This study was
undertaken to identify if indol-2-carboxylic acid esters containing N-phenylpiperazine moiety possess
acetylcholinesterase and butyrylcholinesterase inhibitory activity.
Materials and Methods:
The study dealt with the synthesis of a novel series of analogs of 1H-indole-2-
carboxylic acid and 3-methyl-1H-indole-2-carboxylic acid. The structure of the derivatives was represented by
the indolylcarbonyloxyaminopropanol skeleton with the attached N-phenylpiperazine or diethylamine moiety,
which formed a basic part of the molecule. The final products were synthesized as dihydrochloride salts, fumaric
acid salts, and quaternary ammonium salts. The first step of the synthetic pathway led to the preparation of esters
of 1H-indole-2-carboxylic acid from the commercially available 1H-indole-2-carboxylic acid. The Fischer indole
synthesis was used to synthesize derivatives of 3-methyl-1H-indole-2-carboxylic acid.
Results and Discussion:
Final 18 indolylcarbonyloxyaminopropanols in the form of dihydrochlorides, fumarates,
and quaternary ammonium salts were prepared using various optimization ways. The very efficient way for the
formation of 3-methyl-1H-indole-2-carboxylate (Fischer indole cyclization product) was the one-pot synthesis of
phenylhydrazine with methyl 2-oxobutanoate with acetic acid and sulphuric acid as catalysts.
Conclusion:
Most of the derivatives comprised of an attached N-phenylpiperazine group, which formed a basic
part of the molecule and in which the phenyl ring was substituted in position C-2 or C-4. The synthesized
compounds were subjected to cholinesterase-inhibiting activity evaluation, by modified Ellman method.
Quaternary ammonium salt of 1H-indole-2-carboxylic acid which contain N-phenylpiperazine fragment with
nitro group in position C-4 (7c) demonstrated the most potent activity against acetylcholinesterase.
Synthesis of New Quaternary Ammonium Salts Based on Monochloroacetic Acid Esters