Synthesis of novel coumarin and L-ascorbic acid derivatives using click 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).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)