Optimiranje strukture Beta-karbolinskog prstena: put prema novim hibridnim spojevima s potencijalnim antimalarijskim djelovanjem

master's thesis

• Title (english): Beta-carboline ring structure optimisation: the way towards new hybrid compounds with potential antimalary activity
• Author: Josip Rešetar
• Mentor: Zrinka Rajić (mentor)
• Mentor: Matija Gredičak (mentor)
• Committee member: Zrinka Rajić (predsjednik povjerenstva)
• Committee member: Matija Gredičak (član povjerenstva)
• Committee member: Kristina Pavić (član povjerenstva)
• Granter: University of Zagreb; Faculty of Pharmacy and Biochemistry; (Department of medicinal chemistry); Zagreb
• Defense date and country: 2024-08-26, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Pharmacy; Pharmacy

Abstract

Malarija je zarazna bolest koju uzrokuju različite vrste parazita roda Plasmodium, a od koje umire sve veći broj ljudi.
Harmala alkaloidi β-karbolinskog tipa identificirani su kao spojevi uzori za razvoj novih klasa antimalarika. Promjena
strukture postojećih antimalarika uvođenjem β-karbolinskog motiva pokazala se učinkovitom strategijom za pojačanje
antimalarijske aktivnosti, kao i potencijalno smanjenje rezistencije. S obzirom na poboljšanu antimalarijsku aktivnost
prethodno sintetiziranih hibrida β-karbolina i poznatih antimalarika, u okviru ovog rada odlučili smo modificirati β-
karbolinski prsten. U svrhu njegove priprave, bilo je potrebno sintetizirati N-tosil nitroindol te seriju aminokiselina
modificiranih izocijanidnom skupinom. Dearomatizacijom N-tosil nitroindola serijom aminokiselina modificiranih
izocijanidnom skupinom dobiven je novi triciklički prsten (heksahidropirolo[3,4-b]indol). Novosintetizirani, različito
supstituirani, triciklički prsteni su in situ alkilirani N-propargil indolom ili indolom čime su dobivene ciljne molekule
(16-18). Strukture svih novosintetiziranih molekula potvrđene su standardnim spektroskopskim metodama (1H i 13C
NMR). Dobivene molekule će se u nastavku istraživanja koristiti kao fragmenti za tvorbu hibridnih spojeva s poznatim
antimalaricima metodom Cu(I) katalizirane alkin-azid cikloadicije (klik-reakcijom).

Abstract (english)

Malaria is an infectious disease caused by various species of parasites of the Plasmodium genus, and from which an
increasing number of people are dying. Harmala alkaloids of the β-carboline type have been identified as lead
compounds for the development of new classes of antimalarials. Changing the structure of existing antimalarials by
introducing a β-carboline motif has proven to be an effective strategy for enhancing antimalarial activity, as well as
potentially reducing resistance. Given the improved antimalarial activity of previously synthesized β-carboline hybrids
and common antimalarials, we decided to modify the β-carboline ring in this work. For its preparation, it was necessary
to synthesize a N-tosyl nitroindole and a series of amino acids modified with an isocyano group. A new tricyclic ring
(hexahydropyrrolo[3,4-b indole]) was obtained by dearomatization of N-tosyl nitroindol with a series of amino acids
modified with an isocyano group. Newly synthesized, differently substituted, tricyclic rings were in situ alkylated with
N-propargyl indole or indole to obtain the target molecules (16-18). The structures of all newly synthesized molecules
were confirmed by standard spectroscopic methods (1H and 13C NMR). The obtained molecules will be used in the
continuation of the research as fragments for the formation of hybrid compounds with known antimalarials by the
method of Cu(I) catalyzed alkyne-azide cycloaddition (click-reaction).

• Keywords: antimalarici; β-karbolin; malarija; Plasmodium; sinteza
• Keywords (english): antimalarial drugs; β-carbolin; malaria; Plasmodium; synthesis
• Language: croatian
• URN:NBN: urn:nbn:hr:163:740077
• Study programme: Title: Pharmacy - integrated undergraduate and graduate - university study; Study programme type: university; Study level: integrated undergraduate and graduate; Academic / professional title: sveučilišni magistar farmacije (sveučilišni magistar farmacije)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Embargoed access; Embargo expiration date: 2026-08-26
• Created on: 2024-10-11 08:44:52