Novi pristup analizi oksima dizajniranih za zaštitu središnjeg živčanog sustava pri trovanju organofosfornim spojevima

doctoral thesis

• Title (english): New approach to the analysis of oximes designed to protect central nervous system in organophosphorus poisoning
• Author: Tamara Zorbaz
• Mentor: Zrinka Kovarik (mentor)
• Committee member: Ines Primožič (predsjednik povjerenstva)
• Committee member: Maja Katalinić (član povjerenstva)
• Committee member: Jasmina Rokov Plavec (član povjerenstva)
• Granter: University of Zagreb; Faculty of Science; (Department of Chemistry); Zagreb
• Defense date and country: 2018-11-09, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Chemistry
• Universal decimal classification (UDC): 54 - Chemistry. Crystallography. Mineralogy

Abstract

Toksični organofosforni spojevi inhibiraju acetilkolinesterazu (AChE; EC 3.1.1.7) u sinapsama perifernog i središnjeg živčanog sustava (SŽS) te uzrokuju smrt ili dugotrajne neurološke poremećaje. Današnja terapija jesu oksimski reaktivatori inhibirane AChE, ali oni ne postižu dovoljne koncentracije u SŽS-u. Učinkovitost novosintetiziranih hidroksipiridinskih i klorpiridinijevih oksima dizajniranih s ciljem prolaska u SŽS ispitana je detaljnim kinetičkim istraživanjima reaktivacije AChE i butirilkolinestereraze (EC 3.1.1.8) inhibirane sarinom, ciklosarinom, VX-om, tabunom i paraoksonom. Analize njihovih fizikalno-kemijskih svojstava bitnih za prolazak u SŽS, in vitro toksičnosti, metaboličke stabilnosti i farmakokinetičkog profila na modelu miša, poslužile su za racionalan odabir vodećeg oksima za daljnja istraživanja, oksima 2-[(hidroksiimino)metil]-6-[4-(morfolin-4-il)butil]piridin-3-ola, koji ima potencijal reaktivirati AChE u perifernim tkivima i mozgu. Ovaj pristup analizi omogućio je bolji probir vodećih reaktivatora od uobičajene analize bazirane na reaktivacijskoj učinkovitosti oksima. Stoga se preporuča da ovakva evaluacija reaktivatora prethodi in vivo antidotskim testiranjima u smislu uvažavanja općeprihvaćenih pravila za zaštitu životinja.

Abstract (english)

Toxic organophosphorus compounds inhibit acetylcholinesterase (AChE; EC 3.1.1.7) in the synapses of the peripheral and central nervous system (CNS) and cause death or long-term neurological impairments. Therapy includes oxime reactivators of the inhibited AChE, but they do not achieve sufficient concentrations in the CNS. The efficiency of newly-synthesized hydroxyl-pyridine and chloro-pyridinium oximes, designed with an aim to cross into the CNS, was evaluated here with a detailed kinetic investigation of the reactivation of AChE and butyrylcholinesterase (EC 3.1.1.8) inhibited by sarin, cyclosarin, VX, tabun and paraoxon. Analyses of physicochemical properties important for crossing into the CNS, in vitro toxicity, metabolic stability and pharmacokinetic profile in mouse model, were used for the rational determination of the lead oxime for further tests, 2-((hydroxyimino)methyl)-6-(4-(morpholin-4-yl)butyl)pyridin-3-ol oxime, that has potency to reactivate AChE in peripheral tissues and the brain. This approach enabled better screening for lead compounds in comparison to the standard analysis based on the reactivation efficiency of the oximes.
Therefore, this kind of reactivatior evaluation is recommended before in vivo antidotal testing, as it would singificantly improve adherence to rules for animal welfare.

• Keywords: antidot; farmakokinetika; kolinesteraze; krvno-moždana barijera; pesticidi; reaktivacija; bojni otrovi
• Keywords (english): antidote; blood-brain barrier; cholinesterases; pesticides; pharmacokinetics; reactivation; nerve agents
• Language: croatian
• URN:NBN: urn:nbn:hr:217:451370
• 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: 162 str. ; 30 cm
• File origin: Born digital
• Access conditions: Open access
• Created on: 2019-01-09 10:40:24