Sinteza i karakterizacija novih hibridnih urea harmina i meflokina

master's thesis

• Title (english): Synthesis and characterization of novel harmine and mefloquine hybrid ureas
• Author: Sara Tušek
• Mentor: Kristina Pavić (mentor)
• Committee member: Kristina Pavić (predsjednik povjerenstva)
• Committee member: Hrvoje Rimac (član povjerenstva)
• Committee member: Marijan Marijan (član povjerenstva); MBZ: 335524
• Granter: University of Zagreb; Faculty of Pharmacy and Biochemistry; (Department of medicinal chemistry); Zagreb
• Defense date and country: 2022-07-15, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Pharmacy; Pharmacy

Abstract

Ovaj rad dio je istraživanja provedenog na Zavodu za farmaceutsku kemiju Farmaceutsko-biokemijskog fakulteta Sveučilišta u Zagrebu. Istraživanje obuhvaća dizajn, sintezu i biološku evaluaciju derivata harmina s potencijalnim antimalarijskim djelovanjem. Cilj ovog rada bila je sinteza i karakterizacija novih hibridnih urea harmina i meflokina. Sinteza je započeta prevođenjem derivata meflokina do odgovarajućeg amina 1. Harmol 2 je dobiven iz harmina, dok je fenol 7 dobiven iz 5-metoksitriptamina. Harmin, harmol i fenol 7 su pomoću 2-(Boc-amino)etil bromida i klorovodične kiseline prevedeni u odgovarajuće amine 3, 5 i 10. Nukleofilnom supstitucijom uz CDI iz amina 3, 5 i 10 te amina 1 sintetizirani su konačni produkti – uree 12a-c.
Strukture svih novosintetiziranih spojeva potvrđene su uobičajenim analitičkim i spektroskopskim metodama (IR, 1H i 13C NMR, MS) te im je određena temperatura tališta. Sva tri konačna spoja djelomično zadovoljavaju Lipinskijeva i Veberova pravila koja se koriste za predviđanje oralne bioraspoloživosti lijekova. Također, web alat SwissADME predviđa slabu oralnu bioraspoloživost urea 12a-c. Antimalarijsko i citostatsko djelovanje novosintetiziranih derivata bit će ispitano u daljnjim istraživanjima koja prelaze okvire ovog rada.

Abstract (english)

This paper is part of ongoing research at the Department of Medicinal Chemistry, Faculty of Pharmacy and Biochemistry, University of Zagreb. The research includes the design, synthesis and biological evaluation of novel harmine derivatives as potential antimalarial drugs. The aim of this diploma thesis was the synthesis and characterization of novel harmine urea derivatives comprising mefloquine moiety in their structure. The synthesis began with the transformation of the mefloquine derivative to amine 1. Harmol 2 was generated from harmine, while phenol 7 was generated from 5-methoxytryptamine. Then, harmine, harmol and phenol 7 were converted into amines 3, 5 and 10 using 2-(Boc-amino)ethyl bromide and subsequently, hydrochloric acid. The final products, ureas 12a-c, were synthesized by nucleophilic substitution from amines 3, 5, 10 and amine 1. CDI was used as a coupling reagent.
The structures of newly synthesized compounds were confirmed using analytical and spectroscopic methods (IR, 1H and 13C NMR, MS). In addition, melting points were determined for solid compounds. Novel derivatives fulfil some of Lipinski’s and Veber’s criteria for good oral bioavailability of potential drugs. SwissADME web tool predicts poor oral bioavailability as well. The antimalarial and cytostatic activity of the newly synthesized compounds will be examined in further studies.

• Keywords: harmin; meflokin; urea; CDI
• Keywords (english): harmine; mefloquine; urea; CDI
• Language: croatian
• URN:NBN: urn:nbn:hr:163:421963
• 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; Embargo expiration date: 2023-07-15
• Created on: 2022-07-21 13:37:32