SYNTHESIS AND ANTIVIRAL ACTIVITY OF NOVEL 5-(1-AZIDO-2-HALOETHYL) AND5-(1-AZIDOETHYL, AMINOETHYL, OR METHOXYETHYL) ANALOGS OF 2'-DEOXYURIDINE

A new class of 5-(1-azido-2-haloethyl)-2'-deoxyuridines 3a-c was synth esized by the regiospecific addition of XN3 (X = I, Br, Cl) to the vin yl substituent of 5-vinyl-2'-deoxyuridine. Treatment of the 5-(1-azido -2-iodoethyl) compound (3a) with H-2 and 10% Pd/C yielded the 5-(1-azi doethyl) (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-haloeth yl)-2'-deoxyuridines 3a-c exhibited in vitro antiviral activity agains t HSV-1, HSV-2, VZV, and EBV, but they were inactive against HCMV. In this group of compounds, the activity order was Cl greater-than-or-equ al-to I > Br against HSV-1 and Br greater-than-or-equal-to Cl > I agai nst HSV-2. A halogen atom in the 5-(1-azido-2-haloethyl) moiety 3a-c i s an essential requirement since the 5-(1-azidoethyl) analog 4 was ina ctive, except for weak antiviral activity against VZV. Although the 5- (1-aminoethyl)-2'-deoxyuridine.HI (5) was inactive against HSV-1 and H SV-2, the 5-(1-methoxyethyl) compound 6 was equiactive to 5-ethyl-2'-d eoxyuridine (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 cytotoxicit y (IC50 > 118 muM) and inhibited cell proliferation only at high conce ntrations (IC50 > 76 muM).