Dizajn, sinteza i evaluacija farmakokinetički relevantnih svojstava novih spirohidantoina izvedenih iz β-tetralona

Anita M. Lazić, Željko D. Mandić, Nataša V. Valentić, Gordana S. Ušćumlić, Nemanja P. Trišović

Abstract


U cilju kreiranja novih antikonvulzivnih lekova, sintetisana je serija spirohidantoina izvedenih iz β-tetralona koji u položaju 3 hidantoinskog prstena sadrže 4-supstituisanu benzil-grupu (1a1g) ili 2-(4-supstituisanu fenil)-2-oksoetil-grupu (2a2f). Hemijska struktura novo­sintetisanih molekula potvrđena je određivanjem 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 1a1g i 2a2f analiziran je Hametovom (Hammett) jednačinom. Uticaj hemijske strukture na farmakološke osobine derivata hidantoina procenjen je primenom „pravila broja pet“, Veberovog (Veber), Eganovog (Egan) i Gozovog (Ghose) empirijskog kriterijuma, kao i primenom različitih in silico metoda. U poređenju sa referentnim lekom fenitoinom, derivati koji u svojoj strukturi sadrže atome halogena ili elektron-donorske grupe, trebalo bi da ispoljavaju najbolju intestinalnu apsorpciju i prolazak kroz krvno-moždanu barijeru. U zavisnosti od prirode supstituenta prisutnog u p-položaju fenilnog jezgra, derivati 1a1g i 2a2f mogu da budu potencijalni aktivatori/inhibitori pojedinih izoenzima citohroma P450.


Keywords


spirohidantoini; solvatohromizam; farmakološka aktivnost; ADMET svojstva; antikonvulzivi; antimigrenici

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DOI: https://doi.org/10.2298/HEMIND181203007L

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