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

undergraduate thesis

• Title (croatian): Sinteza, karakterizacija i analiza fizikalno kemijskih svojstava 1H-indol-5-il-[4-(2-fenoksietil)piperazin-1-il]metanona
• Author: Ian Horvat
• Mentor: Irena Škorić (mentor)
• Committee member: Irena Škorić (predsjednik povjerenstva)
• Committee member: Domagoj Vrsaljko (član povjerenstva)
• Committee member: Krunoslav Žižek (član povjerenstva)
• Granter: University of Zagreb; Faculty of Chemical Engineering and Technology; Zagreb
• Defense date and country: 2022-09-22, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Chemistry

Abstract

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 the 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 physico-chemical 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 analogues 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.

Abstract (croatian)

U cilju priprave 1H-indol-5-il-[4-(2-fenoksietil) piperazin-1-il] metanona provedena je sinteza u tri stupnja. Prvi korak u sintezi je prevođenje komercijalno dostupnog alkohola u dobru izlaznu skupinu reakcijom nukleofilne supstitucije sa mesil-kloridom, potom slijedi supstitucija dobivenog sulfonatnog estera sa piperazinom uz prisustvo trietilamina kao baze. Dobiveni produkt u 3. sintetskom stupnju reagira sa indol-5-karboksilnom kiselinom prema Steglich mehanizmu amidacije uz DMAP kao katalizator. Prilikom izolacije spojeva, na osnovu predikcije pKa vrijednosti optimirana su iskorištenja međuprodukata kao i finalnog spoja, te predložena alternativna sinteza u svrhu većih ukupnih iskorištenja, te primjene u sintezi na uvećanoj skali. Nadalje, provedena je analiza fizikalno-kemijskih i ADME (apsorpcija, distribucija, metabolizam i izlučivanje) svojstava dobivene ciljne molekule primjenom ACDLabs/Percepta Software-a, a u smislu profiliranja spoja kao potencijalnog lijeka prema Ro5 pravilima Lipinskog. Provedeni sintetski put nije literaturno opisan kao niti finalni spoj, no literaturno je opisana sinteza analoga koji pokazuju aktivnost prilikom in vitro testiranja na Kv1.5 kalijev ionski kanal, koji je validirana biološka meta u tretmanu aritmije. U tom smislu 1H-indol-5-il-(4-(2-fenoksietil)piperazin-1-il)metanon je potencijalno zanimljiv spoj u daljnjem in vitro profiliranju inhibicije Kv1.5.

• Keywords: piperazine; nucleophilic substitution; Steglich amidation; ADME prediction; Kv1.5 inhibition
• Keywords (croatian): piperazin; nukleofilna supstitucija; Steglich amidacija; ADME predikcija; inhibicija Kv1.5
• Language: english
• URN:NBN: urn:nbn:hr:149:450715
• Study programme: Title: Environmental Engineering - Undergraduate study; Study programme type: university; Study level: undergraduate; Academic / professional title: sveučilišni/a prvostupnik/ prvostupnica (baccalaureus/baccalaurea) inženjer/inženjerka ekoinženjerstva (sveučilišni/a prvostupnik/ prvostupnica (baccalaureus/baccalaurea) inženjer/inženjerka ekoinženjerstva)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2023-02-24 09:13:19