Sinteza, karakterizacija i biološka aktivnost novih nitro-tiazolnih derivata

master's thesis

• Title (english): Synthesis, characterization and biological activity of novel nitro-thiazole derivatives
• Author: Marin Božičević
• Mentor: Irena Škorić (mentor)
• Committee member: Irena Škorić (predsjednik povjerenstva)
• Committee member: Zvonimir Katančić (član povjerenstva)
• Committee member: Dragana Vuk (član povjerenstva)
• Granter: University of Zagreb; Faculty of Chemical Engineering and Technology; Zagreb
• Defense date and country: 2020-09-23, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Chemistry

Abstract

Napredovanjem i širenjem farmaceutske industrije te novim razmišljanjima u istraživanju i razvoju novih lijekova, interesi znanstvenika sve su širi, a pristupi rješenjima se stalno mijenjaju. Razumijevanje vezanja i interakcije biološki aktivnih spojeva s njihovim biološkim metama dovelo je do preciznijih, bolje isplaniranih i više ciljanih sinteza novih spojeva. U tom pogledu heterociklički spojevi predstavljaju bitnu skupinu građevnih jedinica novih molekula. Tiazol kao jedan od predstavnika takvih spojeva zauzima bitno mjesto u sintezi novih biološki aktivnih spojeva te nalazi primjenu u liječenju mnogih bolesti. Jedna od često istraživanih funkcija tiazolnih spojeva jest inhibicija acetilkolinesteraze i butirilkolinesteraze. Uvidom u sve veće zanimanje za spojeve sa tiazolom kao podstrukturnom jedinicom kao mogućih inhibitora kolinesteraza, za cilj ovog rada postavljena je sinteza novih spojeva koji se mogu biološki testirati za navedenu primjenu. Plan rada bio je sintetizirati 26 novih derivata nitro-tiazola, no zbog vrlo male čistoće korištenog polaznog reagensa 2-amin-5-nitrotiazola te njegove nereaktivnosti, kao zamjena je korišten 2-aminotiazol. Od planiranih 26 derivata, sintetizirano je 25. 10 amida, koji su dio biblioteke, sintetizirano je reakcijom amidacije iz HATU aktivirane karboksilne kiseline te 2-aminotiazola. Sinteza amida je bila uspješna te je optimirana tijekom priprave biblioteke spojeva. Promjenom omjera reaktanata dobivene su veće količine željenih spojeva. Nadalje, 5 imina uspješno je sintetizirano reakcijom reduktivne aminacije. Iz polovice reakcijske smjese u kojoj su sintetizirani imini, daljnjom reakcijom redukcije sintetizirani su 4 odgovarajuća amina, dok je sinteza jednog amina bila neuspješna. Naposljetku su izabrana 3 analogna sekundarna amina i amida kojima je na prisutnu NH skupinu amidne odnosno aminske veze uvedena metilna skupina kako bi se procijenio doprinos vodikove veze na biološku aktivnost. Svi produkti okarakterizirani su nuklearnom magnetskom rezonancijom i čistoća im je utvrđena tekućinskom kromatografijom ultravisoke djelotvornosti s UV i masenim detektorima.

Abstract (english)

Along with the advancement and expansion of pharmaceutical industry, as well as new consideration in research and development of new medicines, scientists' interests are getting broader, and approaches to the solutions are constantly changing. Understanding of bonding and interaction between biologically active compounds and their biological targets has led to more precise, better planned and more targeted syntheses of new compounds. Thus, heterocyclic compounds represent a significant group of building blocks of new molecules. As one of the important heterocyclic compounds, thiazole takes an important part in the synthesis of new biologically active compounds and its derivatives are used in treating different diseases. One of the frequently researched functions of thiazole derivatives is inhibition of acetylcholinesterase and butyrylcholinesterase. Considering the growing interest in thiazole derivatives as possible cholinesterase inhibitors, the goal of this research is synthesis of new compounds that can be biologically tested. Although it was planned to synthesize 26 novel nitro-thiazole derivatives, low purity and low reactivity of 2-amino-5-nitrothiazole forced us to use 2-aminothiazole as starting material. 25 new compounds were successfully synthesized. As part of compound library, 10 amides were synthesized using 2-aminothiazole and carboxylic acid activated by HATU. All amide were successfully synthesized, and the reaction was optimized during library preparation. The yield of final products was increased by changing starting material ratio. Reductive amination reaction was successfully used in synthesis of 5 imines. Half of reaction mixture containing formed imines was used to synthesize new amines, with one of five reactions being unsuccessful. In order to inspect importance of hydrogen bond in biological activity of new derivatives, 3 amides and 3 amines with same substituents were additionally methylated. All new products were characterized using nuclear magnetic resonance and their purity was determined by ultra performance liquid chromatography with UV and mass detectors.

• Keywords: tiazol; acetilkolinesteraza; reduktivna aminacija; reakcije amidacije; imini; amini; amidi; nuklearna magnetska rezonancija
• Keywords (english): thiazole; acetylcholinesterase; reductive amination; amidation; imines; amines; amides; nuclear magnetic resonance
• Language: croatian
• URN:NBN: urn:nbn:hr:149:249111
• Study programme: Title: Materials Science and Engineering - Graduate study; Study programme type: university; Study level: graduate; Academic / professional title: magistar/magistra inženjer/inženjerka kemijskog inženjerstva (magistar/magistra inženjer/inženjerka kemijskog inženjerstva)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2022-02-28 17:17:57