Sinteza i karakterizacija 1,2,3-triazolskih derivata Beta-karbolina i primakina

master's thesis

• Title (english): Synthesis and characterization of 1,2,3 - triazole Beta-carbolinr and primaquine derivatives
• Author: Lucija Fureš
• Mentor: Ivana Perković (mentor)
• Committee member: Ivana Perković (predsjednik povjerenstva)
• Committee member: Zrinka Rajić (član povjerenstva)
• Committee member: Biljana Blažeković (član povjerenstva)
• Granter: University of Zagreb; Faculty of Pharmacy and Biochemistry; (Department of medicinal chemistry); Zagreb
• Defense date and country: 2023-07-13, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Pharmacy; Pharmacy

Abstract

β-Karbolini su velika skupina prirodnih i sintetskih spojeva koju karakterizira heterociklički prsten
koji se sastoji od indola i piridina. Biološko djelovanje β-karbolinia je raznoliko; npr. pokazali su
antimalarijsko, antibakterijsko i antiproliferativno djelovanje in vivo i in vitro. Pretpostavljen
mehanizam antimalarijskog djelovanja harmina kao nabolje istraženog β-karbolina je inhibicija
PfHsp90 proteina. Primakin je 8-aminokinolinski antimalarik koji je u primjeni od 1952. godine.
U ovom radu prikazana je sinteza dva nova derivata β-karbolina i primakina (6 i 7) koji su povezani
1,2,3-triazolskim prstenom s ciljem dobivanja derivata poboljšane učinkovitosti. Kao početni spoj
u sintezi korišten je metilni ester triptofana koji je Pictet-Spenglerovom reakcijom u mikrovalnom
reaktoru preveden u tetrahidro-β-karbolin (1). Oksidacijom spoja 1 uz Pd/C i Li2CO3 dobiven je
spoj 2 (6-metoksiharman) koji se kiselom hidrolizom prevodi u odgovarajući alkohol 3 (6-
hidroksiharman). Dobiveni alkohol se uz propargil bromid prevodi u spoj 4. Konačni produkti (6 i
7) sintetizirani su iz propargilnog derivata β-karbolina 4 i azida primakina 5 u reakciji Huisgenove
1,3-dipolarne cikloadicije.
Strukture sintetiziranih spojeva 6 i 7 potvrđene su standardnim analitičkim i spektroskopskim
metodama (1H i 13C NMR, IR, MS) i određeno im je talište.
Pomoću programskih alata SwissADME, Lipinskijevih i Veberovih pravila utvrđeno je da spoj 6
zadovoljava gotovo sva Lipinskijeva i Veberova pravila pa ima potencijala za razvoj kao novi
antimalarijski lijek.
Sintetiziranim spojevima 6 i 7 će u daljnjim istraživanjima biti ispitano biološko djelovanje.

Abstract (english)

β-Carbolines are a large group of natural and synthetic compounds characterized by a heterocyclic
ring consisting of indole and pyridine. The biological effects of β-carbolines are diverse; for
example, they showed antimalarial, antibacterial, and antiproliferative activity in vivo and in vitro.
Assumed mechanism of antimalarial action of harmine, the best-studied β-carboline, is inhibition of
the PfHsp90 protein. Primaquine is an 8-aminoquinoline antimalarial that has been used since 1952.
This research describes synthesis of two new derivates of β-carboline and primaquine linked with
1,2,3-triazole bridge with the aim of obtaining derivatives with improved activity. The initial
compound for the synthesis was tryptophan methyl ester, which was converted to tetrahydro-βcarboline 1 by the Pictet-Spengler reaction in a microwave reactor. Oxidation of compound 1 with
Pd/C and Li2CO3 gave compound 2 (6-methoxyharman), which was converted to the corresponding
alcohol 3 (6-hydroxyharman) by acid hydrolysis. The β-carboline alcohol 3 was converted to
compound 4 with propargyl bromide. The target products (6 and 7) were synthesized from the
propargylated β-carboline derivative 4 and primaquine azide 5 in the Huisgen 1,3-dipolar
cycloaddition.
The structures of synthesized compounds 6 and 7 were confirmed by standard analytical and
spectroscopic methods (1H and 13C NMR, IR, MS), and their melting points were determined.
Using the SwissADME software and Lipinski and Weber rules, compound 6 was found to satisfy
almost all Lipinski and Weber rules and thus has the potential to be a new antimalarial drug.
The biological activity of synthesized compounds 6 and 7 will be tested in further studies.

• Keywords: malarija; primakin; β-karbolin; „click” reakcija; 1; 2; 3-triazol
• Keywords (english): malaria; primaquine; β-carboline; “click” reaction; 1; 2; 3-triazole
• Language: croatian
• URN:NBN: urn:nbn:hr:163:213653
• Study programme: Title: Pharmacy; Study programme type: university; Study level: integrated undergraduate and graduate; Academic / professional title: magistar/magistra farmacije (magistar/magistra farmacije)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Embargoed access; Embargo expiration date: 2025-07-13
• Created on: 2023-11-21 13:55:47