Priprava novih heterocikličkih oksima i njihova učinkovitost pri reaktivaciji fosforiliranih kolinesteraza

doctoral thesis

• Title (english): Synthesis of novel heterocyclic oximes and their efficiency in reactivation of phosphorylated cholinesterases
• Author: Krešimir Baumann
• Mentor: Srđanka Tomić-Pisarović (mentor)
• Mentor: Ines Primožič (komentor)
• Committee member: Snežana Miljanić (predsjednik povjerenstva)
• Committee member: Srđanka Tomić-Pisarović (član povjerenstva)
• Committee member: Ruža Frkanec (član povjerenstva)
• Granter: University of Zagreb; Faculty of Science; (Department of Chemistry); Zagreb
• Defense date and country: 2014-06-10, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Chemistry
• Universal decimal classification (UDC): 54 - Chemistry. Crystallography. Mineralogy

Abstract

U okviru ove disertacije opisana je priprava devet N-alkilnih derivata te po jedanaest 2-
karbaldehida i 2-aldoksima imidazola i benzimidazola od kojih devet do sada nisu opisani u literaturi.
Ispitana je i mogućnost mehanokemijske sinteze oksima karbaldehida imidazola, benzimidazola i
piridina bez dodatka ili uz katalitičku količinu otapala s hidroksilaminom bez dodatka baze. Nadalje,
pripravljena su 34 različito supstituirana, kvaterna imidazolijeva i benzimidazolijeva 2-aldoksima (32
nova spoja) da bi se ispitala njihova učinkovitost u reaktivaciji butirilkolinesteraze iz ljudskog seruma
inhibirane O,O-dietil-O-(4-nitrofenil)fosfatom (paraoksonom). Kvaternizacija je provedena s metil-,
etil- i alil-jodidom i različito para i meta supstituiranim benzil-bromidima. Svi pripravljeni spojevi
dobiveni su u zadovoljavajućem iskorištenju te im je struktura dokazana standardnim analitičkim
spektroskopskim metodama (1D i 2D NMR, IR, MS). Oksimskim skupinama četiriju kvaternih derivata
određene su pKa vrijednosti. Stupanj disociranosti oksimske skupine derivata imidazola (pKa = 8,0–8,4)
je približno jednak ili manji od onoga PAM-2 (8,1), dok je pri fiziološkom pH prisutno najviše
disociranog derivata benzimidazola (pKa = 7,8). Svi kvaterni spojevi testirani su kao reverzibilni
inhibitori (IC50 0,12–390 μmol dm–3) te reaktivatori (8–88 %) paraoksonom inhibirane
butirilkolinesteraze.

Abstract (english)

In this thesis syntheses of nine novel N-alkyl derivatives as well as eleven 2-carbaldehydes and 2-
aldoximes of imidazole and benzimidazole are described. The possibility of mechanochemical synthesis
of imidazole, benzimidazole and pyridine oximes from appropriate carbonyl compounds and
hydroxylamine hydrochloride, without any base and with or without catalytic amount of solvent was
also tested. Further more, 34 differently substituted, quaternary imidazole and benzimidazole 2-
aldoxime derivatives were prepared (32 new compounds) in order to evaluate their efficiency in
reactivation of O,O-diethyl-O-(4-nitrophenyl)phosphate (Paraoxon) inhibited human serum
butyrylcholinesterase. Quaternization was carried out with methyl, ethyl, allyl iodide and differently
substituted meta and para benzyl bromides. All compounds were prepared in good yields and were
characterized by standard analytical spectroscopy methods (1D and 2D NMR, IR, MS). pKa values were
measured and compared to that of the antidote PAM-2 (8.1). Values for the oxime group of three
quaternary imidazoles were in the range of 8.0–8.4 and benzimidazole derivative 7.8. All tested
quaternary derivatives were shown to be reversible inhibitors of butyrylcholinesterase (IC50 0.12–390
μmol dm–3) and reactivators of Paraoxon inhibited enzyme in the range of 8–88 %.

• Keywords: imidazol; benzimidazol; butirilkolinesteraza; oksimi; reaktivacija
• Keywords (english): imidazole; benzimidazole; butyrylcholinesterases; oximes; reactivation
• Language: croatian
• URN:NBN: urn:nbn:hr:217:131355
• Study programme: Title: Doctoral study in chemistry; Study programme type: university; Study level: postgraduate; Academic / professional title: doktor/doktorica znanosti, područje prirodnih znanosti, polje kemija (doktor/doktorica znanosti, područje prirodnih znanosti, polje kemija)
• Type of resource: Text
• Extent: 141 str. ; 30 cm
• File origin: Born digital
• Access conditions: Closed access
• Created on: 2019-03-21 13:46:35