Antioksidativni potencijal novosintetisanih benzohidrazidskih derivata 4-hidroksikumarina
Antonijević, Marko, 1995-
Marković, Zoran, 1958-
Avdović, Edina, 1979-
Milenković, Dejan, 1982-
Živić, Miroslav, 1972-
Petrović, Vladimir, 1984-
Simijonović, Dušica, 1982-
Dimić, Dušan, 1990-
This doctoral dissertation describes the synthesis, extensive structuralcharacterization of new benzohydrazide derivatives of 4–hydroxycoumarin, as wellas the multi–step examination of their antioxidant activity by experimental andcomputational methods. The compounds were obtained by a procedure aligned withthe principles of green synthesis, and then subjected to extensive structuralcharacterization using structural instrumental methods, as well as computationalmethods based in the density functional theory. The high degree of correlationbetween experimental and simulated spectral data indicates a precise definition of thestructure of the newly synthesized benzohydrazide derivatives. By comparing theantioxidant capacity using in vitro tests, it was shown that the investigated derivativespossessing three OH groups attached to the phenolic ring show the highestantioxidant capacity. These results were also highly correlated with thermodynamiccalculations. It was shown that SPLET is the dominant mechanistic pathway ofinactivation of the largest number of radical species, both in polar and non–polarenvironments, except for the inactivation of chlorinated methyl–peroxyl radicalswhere SPLET and HAA are in competition. The most favourable position for reactionwith free radicals, in most cases, is the nitrogen on the hydrazide bridge, which is whythe 4–hydroxycoumarinbenzohydrazide (CBH1) was used for the kinetics test, inorder to exclude the influence of side reactions. A detailed examination of the kineticparameters, in synergy with the experimental results, established a new multi–stagemechanism of SPLET–RRC antiradical activity, and the compound formed in thereaction of the CBH1 and HO● was shown to have lower toxicity compared to thestarting substance. The values of the pharmacokinetic parameters characterize thenewly synthesized compounds as potential candidates for future studies aimed attheir application as pharmaceutical or dietary supplements
U okviru ove doktorske disertacije opisana je sinteza novih benzohidrazidskihderivata 4–hidroksikumarina, kao i višestepeno ispitivanje njihove antioksidativneaktivnosti. Jedinjenja su dobijena procedurom koja podleže principima zelene sinteze,a zatim podvrgnuta ekstenzivnoj strukturnoj karakterizaciji primenominstrumentalnih i računarskih metoda baziranih na teoriji funkcionala gustine. Visokstepen korelacije između eksperimentalnih i simuliranih spektralnih podatakaukazuje na precizno definisanje struktura novosintetisanih derivata. Rezultatiispitivanja antioksidativnog kapaciteta in vitro testovima pokazali su da ispitivaniderivati koji poseduju tri OH grupe vezane za fenolni prsten pokazuju najvećiantioksidativni potencijal. Ovi rezultati su takođe bili u dobroj korelaciji saizračunatim termodinamičkim parametrima. Pokazalo se da je SPLET dominantanmehanistički put inaktivacije najvećeg broja radikalskih vrsta, i u polarnoj i nepolarnojsredini, osim pri inaktivaciji hlorovanih metil–peroksi radikala gde se SPLET i HAAnalaze u kompeticiji. Najpovoljniji položaj za reakciju sa slobodnim radikalima, uvećini slučajeva je azot na hidrazidnom mostu, zbog čega je za ispitivanje kinetikekorišćen 4–hidroksikumarinbenzohidrazid (CBH1), kako bi se isključio uticajsporednih reakcija. Detaljnim ispitivanjem izračunatih kinetičkih parametara, usinergiji sa eksperimentalnim rezultatima, postavljen je novi mehanizamantiradikalske aktivnosti, SPLET–RRC, a jedinjenje koje nastaje u reakciji CBH1 i HO●je pokazalo nižu toksičnost u odnosu na polazne supstance. Vrednostifarmakokinetičkih parametara karakterišu novosintetisana jedinjenja potencijalnimkandidatima za buduća ispitivanja u cilju njihove primene kao farmaceutskih ilidijetetskih suplemenata.
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Serbian
2024
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