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Synthesis, structure and properties of novel potentially biological active azo derivatives of 2(1H)-pyrimidinone

dc.contributor.advisorMijin, Dušan
dc.contributor.otherPetrović, Slobodan
dc.contributor.otherStanojković, Tatjana
dc.contributor.otherVitnik, Željko J.
dc.contributor.otherLađarević, Jelena
dc.creatorTadić, Julijana
dc.date.accessioned2022-09-06T14:03:08Z
dc.date.available2022-09-06T14:03:08Z
dc.date.issued2021-11-05
dc.identifier.urihttps://eteze.bg.ac.rs/application/showtheses?thesesId=8738
dc.identifier.urihttps://uvidok.rcub.bg.ac.rs/bitstream/handle/123456789/4516/Referat.pdf
dc.identifier.urihttps://fedorabg.bg.ac.rs/fedora/get/o:26321/bdef:Content/download
dc.identifier.urihttps://plus.cobiss.net/cobiss/sr/sr/bib/70954761
dc.identifier.urihttps://nardus.mpn.gov.rs/handle/123456789/20630
dc.description.abstractHeterociklični azo derivati predstavljaju značajnu klasu sintetskih boja. Ova jedinjenja dobijaju pažnju kako u akademskim istraživanjima, tako i u industrijskim krugovima, pre svega zahvaljujući izuzetnim svojstvima za bojenje, ali i zbog širokog spektra bioloških aktivnosti koje ispoljavaju. U ovoj doktorskoj disertaciji sintetisana su nova heterociklična azo jedinjenja i njihova struktura, svojstva i biološka aktivnost su temeljno proučavani. Prvo su sintetisani polazni heterociklični molekuli – 2-piridoni i 3,4-dihidropirimidin-2(1H)-oni (DHPM), koji su potom korišćeni za dobijanje ciljanih azo derivata. Sinteza različitih 2- -piridona ispitana je korišćenjem metode kontinualnog protoka, u kapilarnom mikroreaktoru, u cilju razvijanja efikasnijeg sintetskog postupka. U Biđinelijevoj (Biginelli) reakciji je sintetisan derivat DHPM-a sa nitro-grupom u fenilnom jezgru, a zatim je izvršena njegova redukcija do amino derivata, koristeći blage reakcione uslove. Nakon toga, DHPM derivat je diazotovan i kuplovan sa 2-piridonima, pri čemu se prvi put dobijaju azo jedinjenja koja u svojoj strukturi sadrže fragmente i 2-piridona i dihidropirimidinona. Hemijska struktura jedinjenja potvrđena je eksperimentalnim podacima (elementalnom analizom, termičkom analizom, ESI-MS, ATR-FTIR i NMR spektroskopijom) i kvantno-hemijskom (DFT) proračunima. Pomoću DFT metode dobijeni su parametri optimizovane geometrije, teorijski FT-IR, NMR, UV-Vis spektri, oblik i energije graničnih molekulskih orbitala (EHOMO, ELUMO, ΔE). Poređenjem izračunatih i eksperimentalnih rezultata ustanovljeno je dobro slaganje podataka. Kako bi se rasvetlila reaktivnost ispitivanih molekula izračunate su mape elektrostatičkih molekulskih potencijala, kao i kvantno-hemijski molekulski deskriptori. Fotofizička svojstva proučavanih azo derivata ispitana su korišćenjem UV-Vis i fluorescentne spektroskopije. Ova analiza je pružila detaljne informacije o azo-hidrazon tautomeriji, interakcijama rastvarača sa molekulima boja, kao i uticaju pH sredine na kiselo-bazna svojstva datih molekula. Proučavanjem sposbnosti sintetisanih boja da emituju zračenje, ustanovljena su njihova fluorescentna svojstva, što je naročito značajno sa stanovišta otkrivanja novih fluorescentnih azo boja. Dalje je ispitana potencijalna biološka aktivnost novih azo derivata određivanjem in vitro antioksidativnih, antimikrobnih i antikancerogenih svojstava. Antioksidativna aktivnost je procenjena ABTS metodom. Antimikrobna svojstva su određena metodom difuzije na agarnoj podlozi, a test je sproveden na na patogenim sojevima Staphylococcus aureus ATCC 25923 (Gram-pozitivna bakterija), Escherichia coli ATCC 25922 (Gram-negativna bakterija) i Candida albicans ATCC 24433 (oportunistička gljivica). Citotoksična svojstva su proučavana prema humanim malignim ćelijskim linijama: PC-3 (adenokarcinom prostate), A549 (karcinom pluća), K562 (hronična mijeloidna leukemija), koristeći MTT test. Takođe, citotoksičnost novih azo derivata određena je i prema humanim normalnim fibroblastima pluća MRC-5, kako bi se odredila selektivnost u citotoksičnom dejstvu. Dejstvo derivata, sa najboljim citotoksičnim svojstvima, na promenu u distribuciji ciljanih K562 ćelija u pojedinim fazama ćelijskog ciklusa, ispitano je analizom na protočnom citometru. Na ovaj način rasvetljen je mehanizam citotoksičnog delovanja izabranog azo jedinjenja. Na kraju, primenom in silico modela izračunati su fizičko-hemijski deskriptori i farmakokinetički parametri, na osnovu kojih je procenjena oralna aktivnost ispitivanih azo jedinjenja.sr
dc.description.abstractHeterocyclic azo derivatives represent a significant class of synthetic dyes. They have gained attention both in academia and industry, due to its exceptional coloration properties and a broad range of biological activities. In this doctoral dissertation, novel heterocyclic azo compounds have been synthesized and their structure, properties and biological activity have been thoroughly investigated. The starting heterocyclic molecules, 2-pyridones and 3,4- -dihydropyrimidin-2(1H)-ones (DHPM) were synthesized, and then were used in order to obtain the target azo derivatives. The synthesis of different 2-pyridones was studied using the continuous flow synthesis method, in a capillary microreactor, in order to develop a more efficient synthetic approach. In the Biginelli reaction, a DHPM derivative with a nitro group in the phenyl ring was synthesized, and then its reduction to the amino DHPM was performed, using mild reaction conditions. Thereafter, the amino DHPM was diazotized and coupled with different 2-pyridones, giving the series of novel azo compounds. The chemical structure of the azo compounds was confirmed by experimental data (elemental analysis, thermal analysis, ESI-MS, ATR-FTIR and NMR spectroscopy) and quantum chemical (DFT) calculations. Using the DFT method, the parameters of optimized geometry, calculated FT-IR, NMR, UV-Vis spectra and frontier molecular orbital energies (EHOMO, ELUMO, ΔE) were obtained. By comparing the calculated and experimental results, a good corelation of the data was established. In order to elucidate the reactivity of the investigated molecules, maps of electrostatic molecular potentials were calculated, as well as quantum chemical molecular descriptors. The photophysical properties of the studied azo dyes were examined using UV-Vis and fluorescence spectroscopy. This analysis provided detailed information on azo-hydrazone tautomerism, solvent interactions with dye molecules, and the influence of pH of the medium on the acid-base properties of the studied molecules. Moreover, fluorescent properties of the novel dyes were established, which is important discovery since the fluorescent azo dyes are infrequent. The potential biological activity of the novel azo derivatives was investigated by determining in vitro antioxidant, antimicrobial and anticancer properties. Antioxidant activity was assessed by the ABTS method. Antimicrobial properties were determined by agar well diffusion method, and the test was performed on pathogenic strains: Staphylococcus aureus ATCC 25923 (Gram-positive bacteria), Escherichia coli ATCC 25922 (Gram-negative bacteria) and Candida albicans ATCC 24433 (opportunistic yeast). Cytotoxic properties were studied against human cancer cell lines: PC-3 (prostate adenocarcinoma), A549 (lung cancer), K562 (chronic myelogenous leukemia), using the MTT assay. Also, the cytotoxicity of novel azo dyes was determined against human normal lung fibroblasts MRC-5, in order to determine selectivity in cytotoxic action. The cell cycle analysis of most prominent compound was examined in K562 cells, by flow cytometry, to study its mechanism of anticancer action. Finally, physicochemical parameters and ADME properties of novel compounds were calculated in silico in order to evaluate its oral activity.en
dc.formatapplication/pdf
dc.languagesr
dc.publisherУниверзитет у Београду, Технолошко-металуршки факултетsr
dc.rightsopenAccessen
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.sourceУниверзитет у Београдуsr
dc.subjectBiđinelijeva reakcija, sinteza metodom kontinualnog protoka, fluorescentna spektroskopija, antikancerogena svojstva, leukemija, ćelijski ciklus, ADMEsr
dc.subjectBiginelli reaction, continuous flow synthesis, fluorescence spectroscopy, anticancer properties, leukemia, cell cycle analysis, ADMEen
dc.titleSinteza, struktura i svojstva novih potencijalno biološki aktivnih azo derivata 2(1H)-pirimidinonasr
dc.title.alternativeSynthesis, structure and properties of novel potentially biological active azo derivatives of 2(1H)-pyrimidinoneen
dc.typedoctoralThesis
dc.rights.licenseBY-NC-ND
dc.identifier.fulltexthttp://nardus.mpn.gov.rs/bitstream/id/145477/Disertacija_12444.pdf
dc.identifier.fulltexthttp://nardus.mpn.gov.rs/bitstream/id/145478/Izvestaj_Komisije_12444.pdf
dc.identifier.rcubhttps://hdl.handle.net/21.15107/rcub_nardus_20630


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