Naslov (srp)

Sinteza, karakterizacija, biološko i DFT ispitivanje hinoksalinona i benzoksazinona

Autor

Petronijević, Jelena, 1991-, 54981129

Doprinosi

Janković, Nenad, 1985-, 25111399
Bugarčić, Zorica, 1954-, 14093927
Ratković, Zoran, 1958-, 14095207
Vraneš, Milan, 1978-, 23196263

Opis (eng)

Compounds that contain quinoxaline and benzoxazine scaffolds present a group of very important heterocyclic pharmacophores. In the last few decades, this type of compounds occupied the attention of many scientists. Their ring moieties are part of biologically active molecules with anti-inflamatory, anticoagulant, antidiabetic, antituberculosis, antimicrobial, antiviral and anticancer activities. It is known that quinoxalines, benzoxazines and their derivatives have wide application and possess great potential for use in clinical practice. They have been used for the synthesis of therapeutically usable drugs, as organic semiconductors and DNA cleaving agents. Regarding to this, we developed a simple, green and efficient method for the synthesis of twenty one novel 3,4-dihydro-2(1H)-quinoxalinones and 3,4-dihydro-1,4-benzoxazin-2-ones from different ethyl 2-hydroxy-4-alkyl(aryl)-4-oxo-2-butenoate and o-phenylenediamine or oaminophenol. All compounds were characterized by spectroscopic techniques (IR and NMR) and mass spectrometry. One of synthesized compounds was suitable for X-ray analysis. Mentioned synthetic route considerate usage of lemon juice as a biocatalytic system. Also, reaction conditions in lemon juice provide a clean and simple procedure, achieving the criteria of green chemistry. The presented methodology has excellent values of green chemistry metrics, that are very important facts for method applicability in pharmaceutical industry. All synthesized compounds were tested on potential cytotoxic activity against human cervix adenocarcinoma (HeLa), human colon carcinoma (LS174), non-small cell lung carcinoma (A549), and normal human fetal lung fibroblast cell line (MRC-5). Four compounds showed a significant cytotoxic activity against all tested malignant cell lines. Results of DNA interactions indicate that these compounds bind strongly with DNA through intercalation that is in order with the constants obtained for potential metal-drugs. Protein binding experiments were also performed. The obtained results indicate that these compounds have appropriate affinity for binding to transport proteins. Beside this, the inhibition of the α-glucosidase of these compounds was also evaluated. The results suggest that two compounds could be further analyzed as new potential control postprandial hyperglycemia compounds. For better understanding of the electronic properties of these compounds, theoretical study (DFT calculations) have been done. Obtained results suggests that investigated molecules possess charge transfer abilities, meaning that the mentioned compounds have corrosion inhibition properties. The vibrations of the analyzed molecules are well identified in the collected Raman spectra within their characteristic regions and their calculated peak values match very well with the experimental values. The values of the calculated vibrations and chemical shifts are in excellent agreement with the experimental values, almost in all cases.

Opis (srp)

Jedinjenja koja sadrže hinoksalinske i benzoksazinske fragmente predstavljaju grupu veoma važnih heterocikličnih farmakofora. Ova vrsta jedinjenja okupirala je pažnju mnogih naučnika poslednjih nekoliko decenija. Njihovi heterociklični fragmenti su deo biološki aktivnih molekula sa anti-inflamatornim, antikoagulantnim, antidijabetskim, antituberkuloznim, antimikrobnim, antivirusnim i antitumorskim aktivnostima. Poznato je da hinoksalini, benzoksazini i njihovi derivati imaju široku primenu i veliki potencijal za upotrebu u kliničkoj praksi. Koriste se za sintezu lekova koji se već upotrebljavaju u terapiji, kao organski poluprovodnici i sredstava za denaturaciju DNK. Uzimajući u obzir pomenute činjenice, razvili smo jednostavnu, “zelenu” i efikasnu metodu za sintezu dvadeset i jednog novog 3,4-dihidro-2(1H)-hinoksalinona i 3,4-dihidro-1,4-benzoksazin-2-ona od različitih etil 2-hidroksi-4-alkil(aril)-4-okso-2- butenoata i o-fenilendiamina ili o-aminofenola. Sva jedinjenja su okarakterisana spektroskopskim metodama (IR i NMR) i masenom spektrometrijom. Jedno od sintetisanih jedinjenja bilo je pogodno za rendgensku strukturnu analizu. Pomenuta metoda sinteze podrazumeva upotrebu limunovog soka koji se ponaša i kao rastvarač i kao katalizator. Takođe, uslovi reakcije u limunovom soku omogućavaju čist i jednostavan postupak, pri čemu se ispunjavaju kriterijumi zelene hemije. Novorazvijena metodologija ima odlične vrednosti parametara zelene hemije, što predstavlja vrlo važnu činjenicu za primenu sintetičkih metoda u farmaceutskoj industriji. Sva sintetisana jedinjenja su testirana na potencijalnu citotoksičnu aktivnost na ćelijskim linijama adenokarcinoma grlića materice (HeLa), karcinoma debelog creva (LS174), karcinoma pluća (A549) i ćelijskoj liniji fibroblasta pluća (MRC-5). Četiri jedinjenja su pokazala značajnu citotoksičnu aktivnost prema svim testiranim malignim ćelijskim linijama. Rezultati DNK interakcije, odnosno vrednosti dobijenih konstanti, pokazuju da se ova jedinjenja snažno vezuju za DNK interkalacijom što je u skladu sa vrednostima konstanti dobijenih za potencijalne lekove koji sadrže metal. Ispitivana je i mogućnost vezivanja sintetisanih jedinjenja za transportne proteine. Dobijeni rezultati pokazuju da ova jedinjenja imaju odgovarajući afinitet prema transportnim proteinima. Pored citotoksične aktivnosti, ispitivana je i inhibicija α-glukozidaze ovih jedinjenja. Rezultati ukazuju na to da se dva jedinjenja mogu dalje analizirati kao potencijalna kontrolna jedinjenja postprandijalne hiperglikemije. Za bolje razumevanje elektronskih osobina ovih jedinjenja urađena je eksperimentalna i teorijska studija (DFT proračuni). Dobijeni rezultati ukazuju na to da ispitivani molekuli poseduju sposobnost prenosa naelektrisanja, što znači da pomenuta jedinjenja imaju sposobnost da inhibiraju koroziju.

Jezik

srpski

Datum

2020

Licenca

Ovo delo je licencirano pod uslovima licence
Creative Commons CC BY-NC-ND 2.0 AT - Creative Commons Autorstvo - Nekomercijalno - Bez prerada 2.0 Austria License.

CC BY-NC-ND 2.0 AT

http://creativecommons.org/licenses/by-nc-nd/2.0/at/