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.
- MeSH
- acetylcholinesterasa chemie MeSH
- butyrylcholinesterasa chemie MeSH
- cholinesterasové inhibitory chemická syntéza chemie MeSH
- Electrophorus MeSH
- enzymatické testy MeSH
- estery chemická syntéza chemie MeSH
- indoly chemická syntéza chemie MeSH
- koně MeSH
- piperaziny chemická syntéza chemie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Tertiary amines 3-(dialkylamino)-2-hydroxypropyl 4-[(alkoxycarbonyl)amino]benzoates and their quaternary ammonium salts were synthesized. The final step of synthesis of quaternary ammonium salts was carried out by microwave-assisted synthesis. Software-calculated data provided the background needed to compare fifteen new resulting compounds by their physicochemical properties. The acid dissociation constant (pKa) and lipophilicity index (log P) of tertiary amines were determined; while quaternary ammonium salts were characterized by software-calculated lipophilicity index and surface tension. Biological evaluation aimed at testing acetylcholinesterase and butyrylcholinesterase-inhibiting activity of synthesized compounds. A possible mechanism of action of these compounds was determined by molecular modelling study using combined techniques of docking; molecular dynamics simulations and quantum mechanics calculations.
- MeSH
- acetylcholinesterasa MeSH
- aktivace enzymů účinky léků MeSH
- benzoáty chemická syntéza chemie farmakologie MeSH
- butyrylcholinesterasa MeSH
- chemické modely MeSH
- cholinesterasové inhibitory chemická syntéza chemie farmakologie MeSH
- kvartérní amoniové sloučeniny chemická syntéza chemie farmakologie MeSH
- molekulární modely * MeSH
- soli chemie MeSH
- techniky syntetické chemie * MeSH
- vazba proteinů MeSH
- Publikační typ
- časopisecké články MeSH
Quaternary ammonium salts (QUATs) are compounds with wide use in organic synthesis, pharmacy or other fields of industry. Thanks to their specific physical and chemical properties resulting from their amphiphilic character they are already used as phase-transfer catalysts, ionic liquids, dyes, antimicrobial agents and disinfectants, antiarrhythmics, bronchodilators etc. There is still an effort to prepare new active compounds. Several organosynthetic methods are used to prepare QUATs: probably the best way is the Menshutkin reaction. Recently, also a microwave synthesis was introduced to prepare QUATs bringing better yields, shorter reaction times and a possibility of solvent-free reactions.
