Dizajn i sinteza kvazienantiomernih derivata cinchona alkaloida

doctoral thesis

• Title (english): Design and synthesis of quasi-enantiomeric derivatives of cinchona alkaloids
• Author: Alma Ramić
• Mentor: Ines Primožič (mentor)
• Committee member: Snežana Miljanić (predsjednik povjerenstva)
• Committee member: Dijana Pešić (član povjerenstva)
• Committee member: Maja Majerić-Elenkov (član povjerenstva)
• Granter: University of Zagreb; Faculty of Science; (Department of Chemistry); Zagreb
• Defense date and country: 2021-07-16, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Chemistry
• Universal decimal classification (UDC): 54 - Chemistry. Crystallography. Mineralogy

Abstract

Pripravljena je knjižnica od 72 derivata kvazienantiomera cinhonidina i cinhonina. Redukcijom vinilne skupine pripravljeni su 10,11-dihidrocinhonidin i 10,11-dihidrocinhonin koji su iskorišteni zajedno s cinhonidinom i cinhoninom za sintezu N-kvaternih derivata (ukupno 58 spojeva). Nadalje, pripravljeni su monosupstituirani (N-etil, N-cikloheksil i N-fenil) i disupstituirani (N,N-dimetil, N,N-dietil i N,N-difenil) C9 karbamati (serija od 10 spojeva). Oksidacijom C9 hidroksilne skupine pripravljen je keton koji je preveden u ketoksim i kvaterniziran u N-metilni i N-benzilni derivat. Svim pripravljenim spojevima od kojih 22 do sada nisu opisani u literaturi, struktura je dokazana standardnim analitičkim metodama, a primijenjena je spektroskopija nuklearne magnetske rezonancije za studij konformera spojeva u otopini. Testirani derivati pokazali su umjeren do snažan antibiotski potencijal na reprezentativnom panelu Gram-pozitivnih i Gram-negativnih bakterija te su identificirani derivati s inhibicijskim potencijalom prema kolinesterazama. Spojevi odabrani za testiranje nisu pokazali toksičan utjecaj na proliferaciju HEK 293T i HeLa staničnih linija.

Abstract (english)

A library of 72 derivatives of quasienantiomers cinchonidine and cinchonine was prepared. Reduction of vinyl group resulted in 10, 11-dihydrocinchonidine and 10, 11-dihydrocinchonine which were used together with cinchonidine and cinchonine as starting material for the preparation of N-quaternary derivatives (total of 58 compounds). Furthermore, monosubstituted (N-ethyl, N-phenyl and N-cyclohexyl) and disubstituted (N,N-dimethyl, N,N-diethyl and N,N-diphenyl) C9-carbamates were prepared (total of 10 compounds). Oxidation of C9-hydroxyl group yielded a ketone which was further converted to ketoxime and quaternized into N-methyl and N-benzyl derivatives. For all prepared compounds, 22 of which have not been described in the literature so far, the structure was determined by standard analytical methods. Nuclear magnetic resonance spectroscopy was applied to study the conformers of the compounds in solution. The tested derivatives showed moderate to strong antibiotic potential on a representative panel of Gram-positive and Gram-negative bacteria, and derivatives with cholinesterase inhibitory potential were identified. Selected compounds showed no toxic effect on the proliferation of HEK 293T and HeLa cell lines.

• Keywords: cinhonidin; cinhonin; N-kvaterni derivati; karbamati; oksim; biološka aktivnost
• Keywords (english): cinchonidine; cinchonine; N-quaternary derivatives; oxime; carbamates; bioactivity
• Language: croatian
• URN:NBN: urn:nbn:hr:217:990304
• Promotion: 2021
• Project: Number: IP-2016-06-3775; Title: Aktivnošću i in silico usmjeren dizajn malih bioaktivnih molekula; Title: Activity and in silico guided design of bioactive small molecules; Acronym: ADESIRE; Leader: Tomica Hrenar; Jurisdiction: Croatia; Funder: HRZZ; Funding stream: IP
• 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: 113 str. ; 30 cm
• File origin: Born digital
• Access conditions: Open access; Embargo expiration date: 2023-07-16
• Created on: 2021-09-07 12:25:58