Issue in Honor of Prof Nicolò Vivona ARKIVOC 2009 (viii) 112-124 Phosphoroamidate derivatives of N,O-nucleosides as inhibitors of reverse transcriptase Luisa Borrello, a Ugo Chiacchio, a Antonino Corsaro, a Venerando Pistarà, a, * and Daniela Iannazzo b a Dipartimento di Scienze Chimiche, Università di Catania Viale Andrea Doria 6, I-95125, Catania, Italy b Dipartimento Farmaco-Chimico, Università di Messina Viale SS. Annunziata, I-98168, Messina, Italy E-mail: vpistara@unict.it Dedicated to Prof Nicolò Vivona on his 70 th birthday Abstract Phosphoroamidate derivatives of adenine and 5-fluorouracil N,O-nucleoside analogues have been synthesized as potential antiviral prodrugs. In particular, dimethoxyphenyl phosphates, linked via nitrogen to L-leucine methyl ester were studied. The synthesized compounds were also subjected to in vitro evaluation for their RT inhibition. Results show that phosphoroamidate derivatives, in comparison with their corresponding N,O-nucleosides, present a promising antiviral activity, though of micro-molar order. Keywords: Phosphoroamidates, N,O-nucleosides, 1,3-dipolar cycloadditions, nitrones, RT inhibitors Introduction The nucleoside structure has proven to be an effective template for the development of therapeutically useful agents with antiviral and antitumor activity. In particular nucleoside analogues were approved for the treatment of pathologies induced by infections from HCMV, HSV, HIV, and HBV. 1 Dideoxynucleoside analogues exert their antiviral activity by the competitive reversible inhibition of Reverse Transcriptase (RT) and/or viral DNA chain termination. These antiviral agents, acting via a nucleoside analogue mode, need to be phosphorylated into their corresponding 5’-triphosphates by cellular and/or viral enzymes. 2 As a part of our continuing efforts to the search of new templates for the development of new antiviral agents, in the last years, our research group has been interested in the synthesis and ISSN 1551-7012 Page 112 © ARKAT USA, Inc.