Dizajn, sinteza i evaluacija farmakokineticki relevantnih svojstava novih spirohidantoina izvedenih iz [beta]-tetralona/New spirohydantoins derived from [beta]-tetralone: design, synthesis and evaluation of their pharmacokinetically relevant propertie

• Published in: Hemijska industrija 2019-03, Vol.73 (2), p.79
• Main Authors: Lazic, Anita M, Mandic, Zeljko D, Valentic, Natasa V, Uscumlic, Gordana S, Trisovic, Nemanja P
• Format: Article
• Language: English
• Subjects: Anticonvulsants; Cytochrome P-450; Diagnostic imaging; Pets; Phenytoin; Ultraviolet-visible spectroscopy
• ISSN: 0367-598X
• DOI: 10.2298/HEMIND181203007L

U cilju kreiranja novih antikonvulzivnih lekova, sintetisana je serija spirohidantoina izvedenih iz [beta]-tetralona koji u polozaju 3 hidantoinskog prstena sadrze 4-supstituisanu benzil-grupu (1a-1g) ili 2-(4-supstituisanu fenil)-2-oksoetil-grupu (2a-2f). Hemijska struktura novosintetisanih molekula potvrdena je odredivanjem temperature topljenja, kao i primenom infracrvene spektroskopije sa Furijeovom transformacijom, protonske nuklearne magnetne rezonancije, nuklearne magnetne rezonancije ugljenika-13, UV-vidljive spektroskopije i elementarne analize. Efekat supstituenata na pomeranje apsorpcionih maksimuma jedinjenja 1a-1g i 2a-2f analiziran je Hametovom (Hammett) jednacinom. Uticaj hemijske strukture na farmakoloske osobine derivata hidantoina procenjen je primenom "pravila broja pet", Veberovog (Veber), Eganovog (Egan) i Gozovog (Ghose) empirijskog kriterijuma, kao i primenom razlicitih in silico metoda. U poredenju sa referentnim lekom fenitoinom, derivati koji u svojoj strukturi sadrze atome halogena ili elektron-donorske grupe, trebalo bi da ispoljavaju najbolju intestinalnu apsorpciju i prolazak kroz krvno-mozdanu barijeru. U zavisnosti od prirode supstituenta prisutnog u p-polozaju fenilnog jezgra, derivati 1a-1g i 2a-2f mogu da budu potencijalni aktivatori/inhibitori pojedinih izoenzima citohroma P450. Kljucne reci: spirohidantoini; solvatohromizam; farmakoloska aktivnost; ADMET svojstva; antikonvulzivi; antimigrenici. To create new anticonvulsant drugs, two series of spirohydantoins derived from [beta]-tetralone bearing a 4-substituted benzyl group (1a-1g) or a 2-(4-substituted phenyl)-2-oxoethyl group (2a-2f) in position 3 of the hydantoin ring were synthesized. The chemical structure of these compounds was confirmed by determination of the melting point, elemental analysis and FT-IR, [.sup.1]H NMR, [.sup.13]C NMR and UV-Vis spectroscopic methods. Effects of the substituents in the benzyl moiety on the shift of the absorption maxima of compounds 1a-1g and 2a-2f were analyzed using the Hammett's equation. Namely, a split in the Hammett plot at the parent compounds 1a and 2a revealed different electronic transitions within the molecules with the electron-donating substituents from those bearing the electron-accepting substituents, thus the electron-accepting effect on the shift of the absorption maxima being considerably stronger. The influence of the chemical structure on the pharmacokinetically relevant properties of the investigated hydantoi