Synthesis and antiherpesvirus activities of 5-alkyl-2-thiopyrimidine nucleoside analogues

Abstract

Twenty S-alkyl-2-thiopyrimidine nucleosides were newly synthesized and examined for antiviral activities against herpes simplex virus (HSV), varicella-zoster virus (VZV) and human cytomegalovirus (HCMV). In this study, 2′-deoxy-5-alkyl-2-thiocytidine analogues had lower 50% effective concentration (EC50) values against HSV-1, and 2′-deoxy-5-alkyl-2-thiouridine analogues showed lower EC50 against VZV than their congeners of arabinoside form. Among the compounds examined, 2′-deoxy-5-ethyl and 5-propyl-2-thiocytidine (TN-53 and TN-54) were most potent and selective anti-HSV compounds. Their EC50S were 0.04 and 0.15 μM, and selectivity indexes were more than 7215 and 1849, respectively. On the other hand, 2′-deoxy-5-propyl-2-thiouridine (TN-51), 5-bromovinyl-2-thiouracil arabinoside (TN-65) and 5-styryl-2-thiouracil arabinoside (TN-67) were most potent and selective anti-VZV compounds. Their EC50S were 3.1, 3.8 and 2.6 μM for CaQu strain of VZV, respectively, and 2.1 to 3.0 times lower than that of acyclovir. All 2-thiopyrimidine nucleoside analogues did not show antiviral activities against thymidine kinase (TK) negative strains of HSV-1 and VZV. Only three 2-thiocytosine arabinoside compounds showed marginal anti-CMV activities (EC50S were 57-159 μM). All of the five alkyl-2-thio-pyrimidine nucleoside analogues examined were not cytotoxic to human lymphoblastoid cells (RPMI8226) and human embryonic fibroblast cells (MRC-5) at 240 μM (100 μg/ml) or more. Regarding the structure-activity relationship of 5-alkyl-2-thiopyrimidine nucleoside analogues, the following remarks will be noted. Elongation of 5-alkyl chain (methyl to ethyl) of 2-thiocytosine in both deoxyribosyl and arabinosyl nucleosides increased anti-HSV-1 activity but not anti-VZV activity. Furthermore, elongation of the same chain (ethyl to propyl) of 2-thiodeoxyuridine increased anti-VZV activity whereas it did not in the case of 2-thiouracil arabinosides.