Synthesis and antiviral activity of novel 5-(1-azido-2-haloethyl) and 5- (1-azido-, amino-, or methoxyethyl) analogs of 2'-deoxyuridine

Article abstract of DOI:10.1021/jm00069a004

A new class of 5-(1-azido-2-haloethyl)-2'-deoxyuridines 3a-c was synthesized by the regiospecific addition of XN₃ (X = I, Br, Cl) to the vinyl substituent of 5-vinyl-2'-deoxyuridine. Treatment of the 5-(1-azido-2- iodoethyl) compound (3a) with H₂ and 10% Pd/C yielded the 5-(1-azidoethyl) (4) and 5-(1-aminoethyl) (5) derivatives of 2'-deoxyuridine. A similar hydrogenation of 5-(1-methoxy-2-iodoethyl)-2'-deoxyuridine (1f) afforded the 5-(1-methoxyethyl) analog 6. The 5-(1-azido-2-haloethyl)-2'-deoxyuridines 3a- c exhibited in vitro antiviral activity against HSV-1, HSV-2, VZV, and EBV, but they were inactive against HCMV. In this group of compounds, the activity order was Cl ≥ I > Br against HSV-1 and Br ≥ Cl > I against HSV-2. A halogen atom in the 5-(1-azido-2-haloethyl) moiety 3a-c is an essential requirement since the 5-(1-azidoethyl) analog 4 was inactive, except for weak antiviral activity against VZV. Although the 5-(1-aminoethyl)-2'- deoxyuridine·HI (5) was inactive against HSV-1 and HSV-2, the 5-(1- methoxyethyl) compound 6 was equiactive to 5-ethyl-2'-deoxyuridine (EDU) against both HSV-1 and HSV-2 and 7-fold and 12-fold less active against HCMV relative to EDU and ganciclovir, respectively. All compounds investigated (3- 6) exhibited low host cell cytotoxicity (IC₅₀ > 118 μM) and inhibited cell proliferation only at high concentrations (IC₅₀ > 76 μM).