Mehanizam oksidacije diazepama hipokloritnom kiselinom. Kvantno-kemijska studija.

master's thesis

• Title (english): Mechanism of diazepam oxidation with hypochlorous acid. Quantum-chemical study.
• Author: Helena Sremec
• Mentor: Davor Šakić (mentor)
• Committee member: Davor Šakić (predsjednik povjerenstva)
• Committee member: Valerije Vrček (član povjerenstva)
• Committee member: Tin Weitner (član povjerenstva)
• Granter: University of Zagreb; Faculty of Pharmacy and Biochemistry; (Department of analytical chemistry); Zagreb
• Defense date and country: 2019-09-25, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Pharmacy; Pharmacy

Abstract

Diazepam je danas jedan od najkorištenijih farmaceutika, kako u Hrvatskoj, tako i u svijetu te se kao takav u velikoj mjeri nalazi u otpadnim vodama koje se potom tretiraju hipokloritnom kiselinom. Hipokloritna se kiselina također može naći kao medijator upalnih stanja u ljudskome organizmu stoga je promatrana njegova sudbina u prisutstvu toga oksidansa. Pažnja je usmjerena na reaktivna mjesta u diazepamu – N1C, C3 te N4 atome te je računato koji su produkti vjerojatniji s obzirom da energetske barijere procesa te stabilnost samih produkata i kojim putevima oni nastaju. Rezultati dobiveni u ovome radu pokazali su da se hipokloritna kiselina uspješno može koristiti za proučavanje oksidacije i demetilacije ksenobiotika te je razjašnjen mehanizam tih reakcija na primjeru diazepama. Demetilaciji prethodi sekundarna hidroksilacija N1C atoma, dok će se oksidacija vjerojatnije odvijati na C3 nego na N4 atomima.
Mehanizmi oksidacije i demetilacije 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. Za simulaciju utjecaja vode kao otapala korišten je SMD model na istom baznom skupu te funkcionalu (ε=78.4), dok je položaj eksplicitnih voda uključenih u reakciju određen modificiranom verzijom stohastičke metode.

Abstract (english)

Diazepam is one of the most used pharmaceuticals both in Croatia and in the world and can as such be found in waste waters which are treated with hypochlorous acid. Hypochlorous acid can also be found in the human body as a mediator of inflammation and was therefore observed as an oxidizing agent. This paper focused on reactive places in the diazepam molecule – N1C, C3 and N4 atoms, the product stablility and energy barriers of the processes were calculated. Results show that hypochlorous acid can succesfully be used as a xenobiotic oxidizing and demethylating agentand mechanisms of those paths were shown on the diazepam molecule. Secundary hydroxylation of the N1C atom preceds it's demethylation while oxydation is more likely to take place on C3 than N4 atom.
Oxidation and demethylation mechanisms were studied using quantum chemichal models to calculate energies of reactants, transition states and products while the structures were optimized using B3LYP funcional with 6-31/G(d) as standard basis. To simulate the effect of water as a solvent SMD model combined with the same standard basis and funcional was used (ε=78.4). The position of explicit water molecules included in the reaction was determined using a modified version of the stocastic method.

• Keywords: diazepam; oksidacija; demetilacija; hipokloritna kiselina; računalna studija; nordiazepam; oksazepam
• Keywords (english): diazepam; oxidation; demethylation; hypochlorous acid; computer study; nordiazepam; oxazepam
• Language: croatian
• URN:NBN: urn:nbn:hr:163:788232
• 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: 2021-04-23 07:52:00