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Synthesis, characterization and analysis of physico-chemical properties of 1H-indol-5-yl(4-(2- phenoxyethyl)piperazine-1-yl)methanone

With the aim to prepare 1H-indol-5-yl(4-(2- phenoxyethyl)piperazine-1-yl)methanone three synthetic steps were performed. First step in synthesis included making a good leaving group from commercially available alcohol by nucleophilic substitution with mesyl-chloride. Obtained sulfonate ester was further substituted with piperazine using triethylamine as base. In final step of synthesis obtained intermediate reacted with indole-5-carboxylic acid accordingly to the Steglich mechanism of amidation using DMAP as the catalyst. During the isolation of compounds, based on the prediction of pKa values, yields of intermediate products as well as the final compound were optimized. In addition, alternative synthesis was proposed with the aim to increase overall yield due to possible application for the scale-up synthesis. Furthermore, analysis of the physicochemical and ADME (absorption, distribution, metabolism and excretion) properties of target molecule were performed using ACDLabs/Percepta software, with aim of profiling the compound as a potential drug according to Lipinski's Ro5 rules. Performed synthetic route was not described in the literature, nor is the final compound. Synthesis of analogs showing activity in in vitro assay on Kv1.5 potassium ion channel was described in the literature, which is validated biological target in the treatment of arrhythmia. With regards to this result, 1H-indol- 5-yl-(4-(2-phenoxyethyl)piperazine-1-yl)methanone is potentially interesting compound for further in vitro profiling of Kv1.5 inhibition.

piperazine, nucleophilic substitution, Steglich amidation, ADME prediction, Kv1.5 inhibition

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