Dizajn, sinteza i evaluacija farmakokinetički relevantnih svojstava novih spirohidantoina izvedenih iz β-tetralona
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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 (1a−1g) ili 2-(4-supstituisanu fenil)-2-oksoetil-grupu (2a−2f). 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 1a−1g i 2a−2f 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 1a−1g i 2a−2f mogu da budu potencijalni aktivatori/inhibitori pojedinih izoenzima citohroma P450.
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