20.500.12556/RUL-155926 Sinteza in vrednotenje karbamoil fluoridnih zaviralcev in oksimskih reaktivatorjev butirilholin esteraze Synthesis and evaluation of carbamoyl fluoride inhibitors and oxime reactivators of butyrylcholinesterase Organofosforjeve (OP) spojine predstavljajo veliko nevarnost tako v vojnih razmerah kot tudi za civilno prebivalstvo, saj povzročijo tudi do 3 milijone zastrupitev letno. Mednje na primer spadajo različni pesticidi ter živčni bojni strupi razreda G in V. Ti se kovalentno vežejo s katalitičnim Ser200 v človeški acetilholin esterazi in ireverzibilno zavrejo encimsko aktivnost, kar vodi v kopičenje acetilholina v sinapsah, holinergično krizo in na koncu smrt. Kmalu po izpostavljenosti OP je možno encim še reaktivirati z uporabo oksimskih reaktivatorjev – ti so močni nukleofili, ki so zmožni cepiti vezi P-O. V okviru magistrske naloge smo pripravili različne oksimske derivate, ki naj bi selektivno reaktivirali z OP-zavrto človeško butirilholin esterazo (hBChE). Spojini 3 in 5 sta izkazovali primerno afiniteto do hBChE, spojina 5 pa je bila sposobna reaktivirati hBChE, ki je bila zavrta s sarinom in VX. Dokaj visoko afiniteto do hBChE je pokazala spojina 18, neoksimski hidroksipiridinski derivat, ki bi lahko imel večjo sposobnost prehajanja krvno-možganske bariere ter reaktivacije holin esteraz v centralnem živčnem sistemu. Psevdo-ireverzibilni zaviralci holin esteraz karbamatnega tipa se med drugim uporabljajo za profilakso pred zastrupitvami z OP in za zdravljenje Alzheimerjeve bolezni. Pripravili smo fokusirano knjižnico karbamoil fluoridov, ki namesto običajnih fenolov kot izstopajočo skupino vsebujejo fluorid. Sintetizirali smo jih iz sekundarnih aminov z uporabo novega postopka preko N-karbamoilimidazolov. Te spojine so večinoma neselektivno zavirale obe holin esterazi. Organophosphorus compounds (OP) pose a major threat to both military and civilian populations, causing up to 3 million poisonings worldwide every year. Some examples of these compounds are various pesticides and chemical warfare nerve agents of G and V class that can covalently bind to the catalytic Ser200 of human acetylcholinesterase and irreversibly inhibit enzyme’s activity. This leads to increased synaptic acetylcholine levels, a cholinergic crisis, and, ultimately, death. Only shortly after exposure to OPs can the inhibited enzyme be reactivated using oxime reactivators – strong nucleophiles that are able to cleave P-O bonds. In this master thesis, we synthesised different oxime derivatives to selectively reactivate the OP-inhibited human butyrylcholinesterase (hBChE). Compounds 3 and 5 had moderate affinity for hBChE, and compound 5 was able to reactivate hBChE that had previously been inhibited by sarin and VX. Compound 18, a non-oxime hydroxypyridine derivative, also exhibited micromolar affinity for hBChE and is more likely to permeate the blood-brain barrier to reactivate cholinesterases in the central nervous system. Pseudo-irreversible cholinesterase inhibitors with a carbamate scaffold are, among other things, prophylactically used in case of OP-exposure and for the treatment of Alzheimer's disease. We have prepared a focused library of carbamoyl fluorides, which feature fluoride as the leaving group instead of the usual phenols. We have synthesized them using a novel procedure via N-carbamoylimidazoles. These carbamoyl fluorides were mostly non-selective inhibitors of both cholinesterases. organofosfati oksimi butirilholin esteraza psevdoireverzibilni karbamatni zaviralci karbamoil fluoridi ganophosphates oximes butyrylcholinesterase pseudo-irreversible carbamate inhibitors carbamoyl fluorides true false false Slovenski jezik Angleški jezik Magistrsko delo/naloga 2024-04-24 08:45:04 2024-04-24 08:45:16 2024-04-25 04:14:09 0000-00-00 00:00:00 2024 0 0 0000-00-00 NiDoloceno NiDoloceno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 1970-01-01 104869 20866.pdf 20866.pdf 1 B9A585903BBBE141A6A19B1AD15E27F2 85ff439bea63698a48aac5fbdb962c1477dd5a2b1ff3573cc45519911d4c0c12 37e36310-0206-11ef-a15b-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=183059 Fakulteta za farmacijo 0 0 0