Sinteza i biološka aktivnost makrolidnih konjugata s izoksazolom

master's thesis

• Title (english): Synthesis and biological activity of macrolide-isoxazole conjugates
• Author: Antonija Mamić
• Mentor: Tatjana Gazivoda Kraljević (mentor)
• Mentor: Linda Tomašković (komentor)
• Committee member: Tatjana Gazivoda Kraljević (predsjednik povjerenstva)
• Committee member: Linda Tomašković (član povjerenstva)
• Committee member: Dajana Kučić Grgić (član povjerenstva)
• Granter: University of Zagreb; Faculty of Chemical Engineering and Technology; Zagreb
• Defense date and country: 2023-09-27, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Chemistry

Abstract

Makrolidni antibiotici predstavljaju skupinu prirodnih ili polusintetskih spojeva koji se sastoje od makrocikličkog laktonskog prstena koji je povezan s jednim ili više deoksišećera. Često se koriste u liječenju i prevenciji raznih zaraznih bolesti. S druge strane, zbog širokog spektra biološkog djelovanja, izoksazol ima značajnu ulogu u dizajniranju lijekova. Kao rezultat višegodišnjih istraživanja spojeva koji sadrže izoksazolni prsten, brojni odgovarajući lijekovi našli su se na tržištu. U ovom radu opisana je sinteza novih makrolidnih konjugata s izoksazolom. Pripravljene su četiri klase makrolidnih konjugata s izoksazolom sintezom u četiri stupnja, a njihova ispitivanja antibakterijske aktivnosti su u tijeku. U prvom stupnju sinteze Michaelovom adicijom 9-deokso-9a-aza-9a-homoeritromicina A na akrilonitril pripravljen je 9a-N-(2-cijanoetil)-9-deokso-9a-aza-9a-homoeritromicin A (1). Njegovom katalitičkom redukcijom u drugom stupnju, u atmosferi vodika uz PtO2 pripravljen je 9a-N-(3-aminopropil)-9-deokso-9a-aza-9a-homoeritromicin A (2). U idućem stupnju, reakcijom amidiranja spoja 2 uz odgovarajuću izoksazol-5-karboksilnu kiselinu, HATU ili T3P kao aktivatore te DIPEA ili TEA kao baze pripravljeni su derivati makrolida s izoksazolom (3–5). U posljednjem stupnju sinteze, hidrolizom spojeva 3–5 pripravljeni su dekladinozilni derivati 6–8. Iz ranije pripravljenog 4''-O-(3-aminopropil)-9-deokso-9a-aza-9a-metil-9a-homoeritromicina A uz odgovarajuću izoksazol-5-karboksilnu kiselinu te HATU i DIPEA priređena je treća klasa spojeva (9–11). Četvrta klasa makrolidnih konjugata s izoksazolom (12–14) pripravljena je amidiranjem 9a-N-(3-aminopropil)-9-deokso-9a-aza-9a-3-O-dekladinozil-5-O-dedesozaminil-9a-homoeritromicina A uz odgovarajuću izoksazol-5-karboksilnu kiselinu te HATU i DIPEA. Strukture svih novopripravljenih spojeva potvrđene su 1H- i 13C-NMR spektroskopijom.

Abstract (english)

Macrolide antibiotics represent a group of natural or semi-synthetic compounds consisting of a macrocyclic lactone ring connected to one or more deoxysugars. They are ofen used in the treatment and prevention of various infectious diseases. On the other hand, due to their broad spectrum of biological activity, isoxazole plays a significant role in drug design. As a result of years of research on compounds containing the isoxazole ring, numerous corresponding drugs have found their way to the market. This paper describes the synthesis of new macrolide-isoxazole conjugates. Four classes of macrolide-isoxazole conjugates were prepared through a four-step synthesis and their antibacterial activity tests are underway. In the first step of synthesis, By Michael's addition of 9-deoxo-9a-aza-9a-homoerythromycin A to acrylonitrile, 9a-N-(2-cyanoethyl)-9-deoxo-9a-aza-9a-homoerythromycin A (1) was prepared. By its catalytic reduction in the second step, in a hydrogen atmosphere with PtO2, 9a-N-(3-aminopropyl)-9-deoxo-9a-aza-9a-homoerythromycin A (2) was prepared. In the next step, derivatives of macrolide with isoxazole (3–5) were prepared by amidation of 2 with the appropriate isoxazole-5-carboxylic acid, using HATU or T3P as acid activators and DIPEA or TEA as bases. In the final step of synthesis, decladinosyl derivatives (6–8) were prepared by hydrolysis of compounds 3–5. The third class of derivatives (9–11) was prepared from the previously prepared 4''-O-(3-aminopropyl)-9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A, using the appropriate isoxazole-5-carboxylic acid with HATU and DIPEA. The fourth class of macrolide-isoxazole conjugates (12–14) was prepared by amidation of 9a-N-(3-aminopropyl)-9-deoxo-9a-aza-9a-3-O-decladinosyl-5-O-dedesosaminyl-9a-homoerythromycin A with the appropriate isoxazole-5-carboxylic acid with HATU and DIPEA. The structures of all newly prepared compounds were confirmed by 1H- and 13C-NMR spectroscopy.

• Keywords: makrociklički spojevi; izoksazol; amidiranje; antibakterijsko djelovanje
• Keywords (english): macrocycles; isoxazole; amidation; antibacterial activity
• Language: croatian
• URN:NBN: urn:nbn:hr:149:514191
• Study programme: Title: Materials Science and Engineering - Graduate study; Study programme type: university; Study level: graduate; Academic / professional title: sveučilišni/a magistar/magistra inženjer/inženjerka kemijskog inženjerstva (sveučilišni/a magistar/magistra inženjer/inženjerka kemijskog inženjerstva)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Embargoed access; Embargo expiration date: 2025-10-01
• Created on: 2023-11-22 11:42:54