Synthesis of novel heterocyclic oximes and their efficiency in reactivation of phosphorylated cholinesterases

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.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 %