Sinteza novih derivata kumarina i L-askorbinske kiseline primjenom klik kemije

master's thesis

• Title (english): Synthesis of novel coumarin and L-ascorbic acid derivatives using click chemistry
• Author: Ivana Kovačić
• Mentor: Silvana Raić-Malić (mentor)
• Committee member: Silvana Raić-Malić (predsjednik povjerenstva)
• Committee member: Sandra Babić (član povjerenstva)
• Committee member: Andrijana Meščić (član povjerenstva)
• Granter: University of Zagreb; Faculty of Chemical Engineering and Technology; Zagreb
• Defense date and country: 2015-07-13, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Chemistry; Organic Chemistry

Abstract

Cilj ovog rada bila je sinteza novih potencijalno biološki aktivnih derivata kumarina i derivata L-askorbinske kiseline regioselektivnom 1,3-dipolarnom cikloadicijom odgovarajućih terminalnih alkina i organskih azida. U tu svrhu je Pechmannovom ciklizacijom sintetiziran 7-hidroksi-4-(klormetil)kumarin 1, koji je potom preveden u odgovarajući kumarinski azid 2, te derivati L-askorbinske kiseline 3, 4 i 5 koji su bili potrebni za sintezu azida L-askorbinske kiseline 6. Također, sintetizirani su različiti terminalni alkini (7 – 13) koji su poslužili kao dipolarofili u 1,3-dipolarnoj cikloadiciji sa spojevima 2 i 6. Provedene su reakcije Huisgenove 1,3-dipolarne cikloadicije katalizirane bakrom 4-(azidometil)-7-hidroksikumarina i 6-azido-2,3-O,O-dibenzil-L-askorbinske kiseline s odgovarajućim terminalnim alkinima. U tim su reakcijama sintetizirani derivati s 1,2,3-triazolnim supstituentom vezanim u položaju C-4 7-hidroksikumarina i C-6 2,3-O,O-dibenzil-L-askorbinske kiseline (14 – 23). Ovakve reakcije udovoljile su većini uvjeta „klik“ reakcije.
Strukture svih priređenih spojeva potvrđene su spektroskopijom 1H- i 13C-NMR.
Provedena su ispitivanja antibakterijskog djelovanja spojeva 14 – 19 i 21 na osam bakterijskih vrsta (četiri Gram-pozitivne i četiri Gram-negativne beakterijske vrste). Spojevi 15, 16 i 18 pokazuju učinkovita djelovanja na Gram-pozitivne bakterijske vrste: Enterococcus faecali i Enterococcus faecium (VRE) te pokazuju bolju učinkovitost od antibiotika ceftazidim (CAZ) na Gram-pozitivnu bakterijsku vrstu Enterococcus faecali, te su učinkovitiji od oba ispitana atibiotika na Gram-pozitivnu bakterijsku vrstu Enterococcus faecium (VRE).

Abstract (english)

The aim of this work was the synthesis of novel coumarin and L-ascorbic acid derivatives with potential biological activity, using regioselective 1,3-dipolar cycloaddition of terminal alkynes and corresponding organic azides. For this purpose, 4-(Chloromethyl)-7-hydroxycoumarin 1 was synthesized and then converted to the corresponding azide 2. Furthermore, L-ascorbic acid derivatives 3, 4 and 5, required for the synthesis of L-ascorbic acid azide 6, were prepared. Different terminal alkynes (7 – 13), which are used as the dipolarophile in the 1,3-dipolar cycloaddition with compounds 2 and 6, were synthesized. A series of copper catalyzed Huisgen 1,3-dipolar cycloaddition reactions of 4-(azidomethyl)-7-hydroxycoumarin and 6-azido-2,3-O,O-dibenzyl-L-ascorbic acid with various terminal alkynes were performed. In these reactions derivatives with 1,2,3-triazole substituent attached at C-4 position of the C-7- hydroxycoumarin and C-6position of 2,3-O,O-dibenzyl-L-ascorbic acid were synthesized (14 – 23). This type of reaction fulfills majority of requirements for „click“ chemistry reaction.
The structures of all synthesized compounds were confirmed by 1H- and 13C-NMR spectroscopy.
The anti-bacterial activity of the synthesized compounds 14 – 19 and 21 were performed in vitro against four Gram-positive bacterial species and four Gram-negative bacterial species. The MIC determination of the tested compounds was investigated in comparison with Ceftazidime and Ciprofloxacin. Compounds 15, 16 and 18 showed anti-bacterial activity which was higher than Ceftazidime against Gram-negative bacterial specie: Enterococcus faecali and these compounds also showed anti-bacterial activity which was higher than Ceftazidime and Ciprofloxacin against Gram-negative bacterial species: Enterococcus faecium (VRE).

• Keywords: molekulski hibridi; kumarini; L-askorbinska kiselina; 1 2 3-triazoli; "klik“ kemija; Huisgenova cikloadicija
• Keywords (english): molecular hybrids; coumarin; L-ascorbic acid; 1 2 3-triazoles; "click“ chemistry; Huisgen cycloaddition
• Language: croatian
• URN:NBN: urn:nbn:hr:149:842777
• Study programme: Title: Applied Chemistry - Graduate study; specializations in: Environmental chemistry and green technologies, Advanced materials and technologies, Applied organic chemistry; Course: Applied organic chemistry; Study programme type: university; Study level: graduate; Academic / professional title: magistar/magistra primijenjene kemije (magistar/magistra primijenjene kemije)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2016-12-19 10:22:37