Antioxidative potential of newly-synthesized benzohydrazide derivatives of 4-hydroxycoumarin

[M. R. Antonijević]

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U okviru ove doktorske disertacije opisana je sinteza novih benzohidrazidskih derivata 4–hidroksikumarina, kao i višestepeno ispitivanje njihove antioksidativne aktivnosti. Jedinjenja su dobijena procedurom koja podleže principima zelene sinteze, a zatim podvrgnuta ekstenzivnoj strukturnoj karakterizaciji primenom instrumentalnih i računarskih metoda baziranih na teoriji funkcionala gustine. Visok stepen korelacije između eksperimentalnih i simuliranih spektralnih podataka ukazuje na precizno definisanje struktura novosintetisanih derivata. Rezultati ispitivanja antioksidativnog kapaciteta in vitro testovima pokazali su da ispitivani derivati koji poseduju tri OH grupe vezane za fenolni prsten pokazuju najveći antioksidativni potencijal. Ovi rezultati su takođe bili u dobroj korelaciji sa izračunatim termodinamičkim parametrima. Pokazalo se da je SPLET dominantan mehanistički put inaktivacije najvećeg broja radikalskih vrsta, i u polarnoj i nepolarnoj sredini, osim pri inaktivaciji hlorovanih metil–peroksi radikala gde se SPLET i HAA nalaze u kompeticiji. Najpovoljniji položaj za reakciju sa slobodnim radikalima, u većini slučajeva je azot na hidrazidnom mostu, zbog čega je za ispitivanje kinetike korišćen 4–hidroksikumarinbenzohidrazid (CBH1), kako bi se isključio uticaj sporednih reakcija. Detaljnim ispitivanjem izračunatih kinetičkih parametara, u sinergiji sa eksperimentalnim rezultatima, postavljen je novi mehanizam antiradikalske aktivnosti, SPLET–RRC, a jedinjenje koje nastaje u reakciji CBH1 i HO● je pokazalo nižu toksičnost u odnosu na polazne supstance. Vrednosti farmakokinetičkih parametara karakterišu novosintetisana jedinjenja potencijalnim kandidatima za buduća ispitivanja u cilju njihove primene kao farmaceutskih ili dijetetskih suplemenata.

This doctoral dissertation describes the synthesis, extensive structural characterization of new benzohydrazide derivatives of 4–hydroxycoumarin, as well as the multi–step examination of their antioxidant activity by experimental and computational methods. The compounds were obtained by a procedure aligned with the principles of green synthesis, and then subjected to extensive structural characterization using structural instrumental methods, as well as computational methods based in the density functional theory. The high degree of correlation between experimental and simulated spectral data indicates a precise definition of the structure of the newly synthesized benzohydrazide derivatives. By comparing the antioxidant capacity using in vitro tests, it was shown that the investigated derivatives possessing three OH groups attached to the phenolic ring show the highest antioxidant capacity. These results were also highly correlated with thermodynamic calculations. It was shown that SPLET is the dominant mechanistic pathway of inactivation of the largest number of radical species, both in polar and non–polar environments, except for the inactivation of chlorinated methyl–peroxyl radicals where SPLET and HAA are in competition. The most favourable position for reaction with free radicals, in most cases, is the nitrogen on the hydrazide bridge, which is why the 4–hydroxycoumarinbenzohydrazide (CBH1) was used for the kinetics test, in order to exclude the influence of side reactions. A detailed examination of the kinetic parameters, in synergy with the experimental results, established a new multi–stage mechanism of SPLET–RRC antiradical activity, and the compound formed in the reaction of the CBH1 and HO● was shown to have lower toxicity compared to the starting substance. The values of the pharmacokinetic parameters characterize the newly synthesized compounds as potential candidates for future studies aimed at their application as pharmaceutical or dietary supplements

Kumarini, DFT, antioksidativna aktivnost, redoks status, ADMET analiza.

Coumarins, DFT, antioxidant activity, Redox status, ADMET analysis

547.587.51(043.3)

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