Synthesis and Antiviral Activity of Novel 5-(1-Cyanamido-2-haloethyl) and 5-(1-Hydroxy(or methoxy)-2-azidoethyl) Analogues of Uracil Nucleosides

A new class of 5-(1-cyanamido-2-haloethyl)-2‘-deoxyuridines (4−6) and arabinouridines (7, 8) were synthesized by the regiospecific addition of halogenocyanamides (X-NHCN) to the 5-vinyl substituent of the respective 5-vinyl-2‘-deoxyuridine (2) and 2‘-arabinouridine (3). Reaction of 2 with sodium azide, ceric ammonium nitrate, and acetonitrile−methanol or water afforded the 5-(1-hydroxy-2-azidoethyl)-(10) and 5-(1-methoxy-2-azidoethyl)-2‘-deoxyuridines (11). In vitro antiviral activities against HSV-1-TK+ (KOS and E-377), HSV-1-TK-, HSV-2, VZV, HCMV, and DHBV were determined. Of the newly synthesized compounds, 5-(1-cyanamido-2-iodoethyl)-2‘-deoxyuridine (6) exhibited the most potent anti-HSV-1 activity, which was equipotent to acyclovir and superior to 5-ethyl-2‘-deoxyuridine (EDU). In addition, it was significantly inhibitory for thymidine kinase deficient strain of HSV-1 (EC50 = 2.3−15.3 μM). The 5-(1-cyanamido-2-haloethyl)-2‘-deoxyuridines (4−6) all were approximately equipotent against HSV-2 and were ∼1.5- and 15-fold less inhibitory for HSV-2 than EDU and acyclovir, respectively. Compounds 4−6 were all inactive against HCMV but exhibited appreciable antiviral activity against VZV. Their anti-VZV activity was similar or higher to that of EDU and approximately 5−12-fold lower than that of acyclovir. The 5-(1-cyanamido-2-haloethyl)-(7,8) analogues of arabinouridine were moderately inhibitory for VZV and HSV-1 (strain KOS), whereas compounds 10 and 11 were inactive against herpes viruses. Compounds 5 and 6 also demonstrated modest anti-hepatitis B virus activity against DHBV (EC50 = 19.9−23.6 μM). Interestingly, the related 5-(1-azido-2-bromoethyl)-2‘-deoxyuridine (1n) analogue proved to be markedly inhibitory to DHBV replication (EC50 = 2.6−6.6 μM). All compounds investigated exhibited low host cell toxicity to several stationary and proliferating host cell lines as well as mitogen-stimulated proliferating human T lymphocytes.