CORRELATION OF STRUCTURE AND POTENTIAL PHARMACOLOGICAL ACTIVITY OF SPIROHIDANTOINS DERIVED FROM α-TETRALONE

Abstract

Hydantoin is a nonaromatic five-membered heterocycle, which is considered a valuable, privileged scaffold in medicinal chemistry. The importance of the hydantoin scaffold in drug discovery has been reinforced by several medicines in clinical use, such as anticonvulsants (phenytoin), antibiotics(nitrofurantoin), anticancer drugs (enzalutamide) and keratolytics (allantoin). To design new potentially pharmacologically active compounds, six spirohydantoin derivatives were synthetized and fully characterized by determination of the melting points, elemental analysis, FT-IR, 1H and 13C NMR spectroscopic methods. Effects of the substituents on the shift of the absorption maxima of synthetized compounds were analyzed using the linear solvatation energy relationship, while the influence of the chemical structure on the pharmacokinetically relevant properties of the investigated spirohydantoin derivatives was evaluated using the Lipinski’s rule of five, Veber, Egan and Ghose’s empirical criteria, as well as different in silico methods. In order of detailed analysis of the potential pharmacological activity of the synthesized spirohydantoins, their potential pharmacological properties were correlated with the corresponding solvent effects.

Hidantoin je nearomatičan petočlani ciklični ureid koji predstavlja važan strukturni fragment velikog broja farmakološki aktivnih jedinjenja. Derivati ovog petočlanog cikličnog ureida primenjuju se kao antikonvulzivi (fenitoin), antibiotici (nitrofurantoin), antikancerogeni lekovi (enzalutamid) i keratolitici (alantoin). U cilju dizajniranja novih potencijalno farmakološki aktivnih jedinjenja, u ovom radu, sintetisano je šest derivata spirohidantoina koji su u potpunosti strukturno okarakterisani određivanjem temperature topljenja, elementarnom analizom, FT-IR, 1H i 13C NMR spektroskopskim metodama. Efekat supstituenata na pomeranje maksimuma apsorpcije analiziran je primenom linearne korelacije energije solvatacije, dok je uticaj hemijske strukture na farmakološka svojstva derivata spirohidantoina procenjen primenom “pravila broja pet”, Veberovog, Eganovog i Gozovog kriterijuma, kao i primenom različitih in silico metoda. U cilju opsežnije analize potencijalne farmakološke aktivnosti sintetisanih spirohidantoina, korelisana su njihova potencijalna farmakološka svojstva sa odgovarajućim efektima rastvarača.