Antiviral activity of triazine analogues of 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine (cidofovir) and related compounds

作者:Krecmerova Marcela*; Holy Antonin; Piskala Alois; Masojidkova Milena; Andrei Graciela; Naesens Lieve; Neyts Johan; Balzarini Jan; De Clercq Erik; Snoeck Robert
来源:Journal of Medicinal Chemistry, 2007, 50(5): 1069-1077.

摘要

Treatment of 5-azacytosine sodium salt with diisopropyl [(2-chloroethoxy)methyl]phosphonate followed by removal of ester groups with BrSi(CH3)(3) afforded 1-[2-(phosphonomethoxy)ethyl]-5-azacytosine (3). Reaction of 5-azacytosine with [(trityloxy)methyl]-(2S)-oxirane followed by etherification with diisopropyl (bromomethyl)phosphonate and removal of ester groups gave 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine (1). The synthesis of 6-azacytosine congener 2 was analogous using N-4-benzoylated intermediates. Compound 1 was shown to exert strong activity against a broad spectrum of DNA viruses including adenoviruses, poxviruses, and herpesviruses (i.e., herpes simplex viruses, varicella zoster virus, and human cytomegalovirus). Decomposition of 1 in alkaline solutions resulted in products 17 and 18. While the N-formylguanidine derivative 17 proved active, the carbamyolguanidine derivative 18 was devoid of antiviral activity.