Mehanizam oksidacije atoma dušika hipokloritnom kiselinom u strukturama odabranih psihofarmaka. Kvantno-kemijska studija

master's thesis

• Title (english): Oxidation mechanism of nitrogen atoms by hypochlorous acid in structures of chosen psychofarmaceuticals
• Author: Marija Vrsaljko
• Mentor: Davor Šakić (mentor)
• Committee member: Davor Šakić (predsjednik povjerenstva)
• Committee member: Marijan Marijan (član povjerenstva); MBZ: 335524
• Committee member: Hrvoje Rimac (član povjerenstva)
• Granter: University of Zagreb; Faculty of Pharmacy and Biochemistry; (Department of analytical chemistry); Zagreb
• Defense date and country: 2021-09-29, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Chemistry; Analytic Chemistry

Abstract

Psihofarmaci su široko korišteni lijekovi zbog velike prevalencije mentalnih bolesti među stanovništvom. Upotreba ovih lijekova najčešće je kronična, a simptomi bolesti se javljaju relativno rano, što znači da je većina pacijenata na terapiji od mlađe odrasle dobi Zbog relativno široke upotrebe, ovi lijekovi mogu se naći otpadnim vodama gdje dolaze u doticaj s hipokloritnom kiselinom, glavnim agensom za pročišćavanje otpadnih voda metodom kloriranja. Također, hipokloritna kiselina stvara se i u organizmu utjecajem enzima iz porodice hemperoksidaza, poglavito mijeloperoksidaze, najčešće pri određenim patološkim stanjima. U organizmu sudjeluje u tvorbi slobodnih radikala reakcijama s različitim endomolekulama te posljedično uzrokovanju oksidativnog stresa.
Pažnja je usmjerena na supstituirani i nesupstituirani piperazinski i piperidinski prsten kao dijelove strukture odabranih psihofarmaka: aripiprazola i haloperidola. Računato je koji su produkti vjerojatniji s obzirom da energetske barijere procesa.
Rezultati dobiveni u ovome radu pokazali su da se hipokloritna kiselina u reakcijama s navedenim strukturama u okolišu bez otapala ponaša kao donor kloridne, ali i hidroksilne skupine, stvarajući N-okside, N-kloride, N-hidrokside, C-kloride i C-hidrokside.
Mehanizmi ovih reakcija proučavani su kvantno-kemijskim modelima kojima su se računale energije produkata, prijelaznih stanja te reaktanata, dok su se strukture optimizirale na B3LYP funkcionalu u kombinaciji s 6-31/G(d) baznim skupom.

Abstract (english)

Due to the high prevalence of mental illness among the population, psychopharmaceutical drugs are widely used. These drugs are most often used to treat chronic illnesses, with the symptoms appearing relatively early. This results in most patients starting treatment as young adults. As a result of the wide usage, these drugs can be found in wastewater where they could potentially react with hypochlorous acid, a commonly used agent for disinfecting wastewater by chlorination. Hypochlorous acid is also formed in the body by enzymes from the hemperoxidase family, especially myeloperoxidase, most often in certain pathological conditions. It participates in the formation of free radicals by reactions with various endomolecules and consequently causes oxidative stress.
This paper focused on the substituted and unsubstituted piperazine and piperidine ring as parts of the structure of selected psychopharmaceuticals: aripiprazole and haloperidol. It was calculated which products are more likely given the kinetic and thermodynamic properties of the reactions. The results obtained in this work showed that hypochlorous acid in reactions with these structures in a solvent-free environment acts as a donor of chloride and hydroxyl groups, forming N-oxides, N-chlorides, N-hydroxides, C-chlorides, and C-hydroxides.
The mechanisms of these reactions were studied by quantum chemical models that calculated the energies of the reactants, transition states, and products. Structures were optimized with the B3LYP functional in combination with the 6-31/G(d) basis set.

• Keywords: psihofarmaci; aripiprazol; haloperidol; hipokloritna kiselina; piperidin; piperazin; N-hidroksilacija; C-hidroksilacija; N-kloriranje
• Keywords (english): psychopharmaceuticals; aripiprazole; haloperidol; hypochlorous acid; piperidine; piperazine; N-hydroxylation; C-hydroxylation; N-chlorination
• Language: croatian
• URN:NBN: urn:nbn:hr:163:930999
• Study programme: Title: Pharmacy; Study programme type: university; Study level: integrated undergraduate and graduate; Academic / professional title: magistar/magistra farmacije (magistar/magistra farmacije)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2022-03-28 12:44:27