o:1757 Razvoj novih tioureidnih derivata naproksena: sinteza, fizičko-hemijska i biološka karakterizacija Development of new thiourea derivatives of naproxen: synthetis, physico-chemical and biological characterization : doctoral dissertation sr Uvod: Funkcionalizacijom karboksilne grupe naproksena u tioureidnu grupuprimenom sterno voluminoznih i lipofilnih aromatičnih amina i estaraaromatičnih aminokiselina mogu se sintetisati novi molekuli koji potencijalnoimaju istu ili snažniju antiinflamacijsku i citotoksičnu aktivnost u odnosu napolazni naproksen.Materijal i metode: Reakcijom naproksena, kalijum-tiocijanata i jedinjenja sa aminogrupom sintetisani su odgovarajući tioureidni derivati naproksena. Strukturnaanaliza je izvršena određivanjem temperature topljenja i spektroskopskim metodama.Lipofilnost je ispitana primenom shake-flask metode, reverzno-fazne hromatografijena tankom sloju (RP-TLC) i reverzno-fazne visokoefikasne tečne hromatografije (RPHPLC). Procena gastrointestinalne apsorpcije je sprovedena primenom PAMPA testai bioparticione micelarne hromatografije (BMC). Veza između parametara apsorpcijei hemijske strukture ispitivanih jedinjenja utvrđena je analizom kvantitativnihodnosa strukture i permeabilnosti (QSPR) i kvantitativnih odnosa strukture iretencije (QSRR). Ispitivanim jedinjenjima je procenjena antiinflamacijska icitotoksična aktivnost, kao i potencijal inhibicije SOH-2 i 5-LOX enzima.Rezultati: Sintetisano je 14 tioureidnih derivata naproksena. Među ispitanimjedinjenjima najveće vrednosti RP-TLC i RP-HPLC hromatografskih parametaraposeduju derivati 6 i 7. Samo je derivat 7 pokazao veći stepen pasivnegastrointestinalne apsorpcije u odnosu na naproksen. Jedinjenja 2, 4 i 7 pokazala sunajsnažniji antiinflamacijski potencijal. Sva sintetisana jedinjenja posedujuslabiju SOH-2 inhibitornu aktivnost u odnosu na naproksen, dok je značajnainhibicija 5-LOX enzima zabeležena za jedinjenja 1-5. Najizraženiji citotoksičniefekat ostvarili su derivati 3 i 8 na HeLa tumorsku ćelijsku liniju. Introduction: By functionalizing the carboxyl group of naproxen into a thioureа group usingsterically voluminous and lipophilic aromatic amines and esters of aromatic amino acids, novelmolecules can be synthesized that potentially have the same or stronger anti-inflammatory andcytotoxic activity compared to the parent naproxen.Material and methods: Corresponding thioureа derivatives of naproxen were synthesized bythe reaction of naproxen, potassium thiocyanate and compounds with an amino group.Structural analysis was performed by determining the melting point and spectroscopic methods.Lipophilicity was tested using the shake-flask, RP-TLC and RP-HPLC methods. Assessmentof gastrointestinal absorption was carried out using the PAMPA and BMC tests. Therelationship between the absorption parameters and the chemical structure of the testedcompounds was determined by analyzing quantitative structure-permeability ratios (QSPR) andquantitative structure-retention ratios (QSRR). Anti-inflammatory and cytotoxic activity, aswell as the inhibition potential of COX-2 and 5-LOX enzymes, were evaluated with theinvestigated compounds.Results: Fourteen thiourea derivatives of naproxen were synthesized. Among the testedcompounds, derivatives 6 and 7 have the highest values of RP-TLC and RP-HPLCchromatographic parameters. Only derivative 7 showed a higher degree of passivegastrointestinal absorption compared to naproxen. Compounds 2, 4, and 7 showed the strongestanti-inflammatory potential. All synthesized compounds have weaker COX-2 inhibitoryactivity compared to naproxen, while significant inhibition of 5-LOX enzyme was observed forcompounds 1-5. Derivatives 3 and 8 had the most pronounced cytotoxic effect on the HeLatumor cell line. - 91552100 150916873 91552101 8790 2024-10-29T15:01:43.053Z 45 no 46 Nikola, 1995- Nedeljković 88531977 2024 63 komentor Miloš, 1987- Nikolić 20627559 2024 63 komentor Vladimir, 1984- Dobričić 15607143 2024 63 predsednik komisije Vladimir, 1971- Jakovljević 13564775 2024 63 član komisije Zorica, 1963- Vujić 12647783 2024 63 član komisije Jovana, 1991- Bradić 24560743 2024 127 listova 7372917 http://phaidrakg.kg.ac.rs/o:1757 no yes 15 2024-10-29T15:01:43.320Z 70 Tioureidni derivati naproksena, lipofilnost, pasivnagastrointestinalna apsorpcija, hemometrijska analiza, antiinflamacijska aktivnost,COX-2 i 5-LOX inhibicija, citotoksična aktivnost. Thiourea derivatives of naproxen, lipophilicity, passive gastrointestinal absorption,chemometric analysis, anti-inflammatory activity, COX-2 and 5-LOX inhibition, cytotoxicactivity. 615.33.015:54(043.3) Farmacija 1738 34A05 2024