Sinteza i karakterizacija harmicina; novih 1,2,3- triazolskih derivata harmina i cimetne kiseline

master's thesis

• Title (english): Synthesis and characterization of harmicines; novel 1,2,3- triazole derivatives of harmine and cinnamic acid
• Author: Vedrana Konjevod
• Mentor: Ivana Perković (mentor)
• Committee member: Ivana Perković (predsjednik povjerenstva)
• Committee member: Zrinka Rajić (član povjerenstva)
• Committee member: Mirela Matić (član povjerenstva)
• Granter: University of Zagreb; Faculty of Pharmacy and Biochemistry; (Department of medicinal chemistry); Zagreb
• Defense date and country: 2020-07-14, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Pharmacy; Pharmacy

Abstract

Cilj ovog rada bila je sinteza i karakterizacija četiriju novih harmicina, hibridnih spojeva koji preko triazolske poveznice vežu dva farmakofora s antimalarijskim učinkom u jednu molekulu; β-karboline harmin ili harmol te derivate cimetne kiseline (CAD). Za sintezu ciljanih spojeva odabran je prikazani reakcijski put koji je uključio prevođenje derivata cimetne kiseline u azide (5a,b), dok su harmin i harmol u reakcijama N- i O-propargiliranja iskorišteni za dobivanje redom N i O-alkina (1,2). Terminalni alkini 1 i 2 s azidima dobivenim iz derivata cimetne kiseline (5a,b) u reakciji Huisgenove cikloadicije katalizirane bakrom (I) dali su konačne produkte, 1,2,3-triazolske derivate harmina i cimetne kiseline (6a,b i 7a,b). Svim novosintetiziranim spojevima struktura je potvrđena uobičajenim analitičkim i spektroskopskim metodama (IR, 1H i 13C NMR, MS) te im je određena temperatura tališta. Za konačne produkte (6a,b i 7a,b) je temeljem izračuna molekulskih deskriptora napravljena računalna predikcija njihovih farmakokinetičkih svojstava., najvažnije od kojih je oralna bioraspoloživost. U daljnjim ispitivanjima, koja prelaze okvir ovog rada, sintetiziranim derivatima je ispitano antimalarijsko i citotoksično djelovanje.

Abstract (english)

The aim of this thesis was synthesis and characterization of four new harmicines, hybrides which through triazole spacer comprise two pharmacophores with antimalarial activity into single molecule; i.e. β-carboline harmine or harmol and cinnamic acid derivatives (CAD). The shown reaction pathway chosen for the synthesis of final compounds has included obtaining azides 5a,b from cinnamic acid derivatives in several steps, while harmine and harmol have generated N- and O-alkynes (1,2) in the reactions of N- and O-propargylations. Cu(I) catalyzed organic azide-terminal alkyne cycloaddition was employed for preparation of final 1,2,3-triazole N- (6a,b) and O- derivatives (7a,b) of harmine and cinnamic acid from above mentioned reactants. The structures of the newly synthesized compounds were confirmed using conventional analytical and spectroscopic methods (IR, 1H i 13C NMR, MS). Besides, the melting points of solid compounds were determined. Computer models have been fostered for the prediction of pharmacokinetical properties of the final compounds (6a,b i 7a,b), most important property being oral bioavailability. Subsequent studies, that have surpassed this thesis, had also investigated antimalarial and citotoxic activity of the final compounds.

• Keywords: harmin; derivati cimetne kiseline; organski azidi; click kemija; Huisgenova cikloadicija; antimalarici
• Keywords (english): harmine; cinnamic acid derivatives; organic azides; click chemistry; Huisgen 1; 3-dipolar cycloaddition; antimalarial drugs
• Language: croatian
• URN:NBN: urn:nbn:hr:163:638674
• 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: Open access
• Created on: 2021-04-29 09:10:56