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 arabi nouridines (7, 8) were synthesized by the regiospecific addition of halogen ocyanamides (X-NHCN) to the 5-vinyl substituent of the respective 5-vinyl-2 '-deoxyuridine (2) and 2'-arabinouridine (3). Reaction of 2 with sodium azi de, ceric ammonium nitrate, and acetonitrile-methanol or water afforded the 5-(1-hydroxy-2-azidoethyl)-(10) and 5-(1-methoxy-2-azidoethyl)-2'-deoxyuri dines (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 synth esized 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 significant ly inhibitory for thymidine kinase deficient strain of HSV-1 (EC50 = 2.3-15 .3 muM). The 5-(1cyanamido-2-haloethyl)-2'-deoxyuridines (4-6) all were app roximately equipotent against HSV-2 and were similar to1.5- and 15-fold les s 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-cyanamid o-2-haloethyl)(7,8) analogues of arabinouridine were moderately inhibitory for VZV and HSV-1 (strain KOS), whereas compounds 10 and 11 were inactive a gainst herpes viruses. Compounds 5 and 6 also demonstrated modest anti-hepa titis B virus activity against DHBV (EC50 = 19.9-23.6 muM). Interestingly, the related 5-(1-azido-2-bromoethyl)-2'-deoxyuridine (1n) analogue proved t o be markedly inhibitory to DHBV replication (EC50 = 2.6-6.6 muM). All comp ounds investigated exhibited low host cell toxicity to several stationary a nd proliferating host cell lines as well as mitogen-stimulated proliferatin g human T lymphocytes.