Publication details

Indol-2-Carboxylic Acid Esters Containing N-Phenylpiperazine Moiety - Preparation and Cholinesterase-inhibiting Activity

Authors

PADRTOVÁ Tereza MARVANOVÁ Pavlína KUBÍNOVÁ Renata CSÖLLEI Jozef FARSA Oldřich GONĚC Tomáš ODEHNALOVÁ Klára OPATŘILOVÁ Radka PAZOUREK Jiří SYCHROVÁ Alice ŠMEJKAL Karel MOKRÝ Petr

Year of publication 2020
Type Article in Periodical
Magazine / Source Current organic synthesis
MU Faculty or unit

Faculty of Pharmacy

Citation
Web https://europepmc.org/article/med/32560608
Doi http://dx.doi.org/10.2174/1570179417666200619132218
Keywords Acetylcholinesterase; butyrylcholinesterase; Fischer indole synthesis; indoles; N-phenylpiperazine; T3P (R)
Description 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 acetyleholinesterase 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 cyctization 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.

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