Townsend L B, Devivar R V, Turk S R, Nassiri M R, Drach J C
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor 48109-1065, USA.
J Med Chem. 1995 Sep 29;38(20):4098-105. doi: 10.1021/jm00020a025.
A new series of 2-substituted 5,6-dichlorobenzimidazole ribonucleosides has been synthesized and tested for activity against two human herpes viruses and for cytotoxicity. 2,5,6-Trichloro-1-(beta-D-ribofuranosyl)benzimidazole (TCRB) was prepared by ribosylation of the heterocycle 2,5,6-trichlorobenzimidazole followed by a removal of the protecting groups. The 2-bromo derivative (BDCRB) was made in a similar fashion from 2-bromo-5,6-dichlorobenzimidazole. In contrast, the 2-iodo derivative presented a more difficult problem since the appropriate heterocycle was unavailable. This prompted us to prepare the 2-amino derivative followed by nonaqueous diazotization and removal of the blocking groups. Biological evaluation revealed marked differences in the activities of these compounds and the closely related known compound 5,6-dichloro-1-(beta-D-ribofuranosyl)benzimidazole (DRB). DRB was weakly active against both human cytomegalovirus (HCMV) and herpes simplex virus type 1 (HSV-1), (IC50's = 42 and 30 microM, respectively) but was cytotoxic to uninfected human foreskin fibroblasts and KB cells in the same dose range. Similar results were obtained with the heterocycle 2,5,6-trichlorobenzimidazole. In marked contrast, the ribonucleoside of 2,5,6-trichlorobenzimidazole (TCRB) was active against HCMV (IC50 = 2.9 microM, plaque assay; IC90 = 1.4 microM, yield assay) but only weakly active against HSV-1 (IC50 = 102 microM, plaque assay). Little to no cytotoxicity was observed in HFF and KB cells at concentrations up to 100 microM. By changing the substituent at the 2-position from chlorine to bromine (BDCRB), a 4-fold increase in activity against HCMV was observed without any significant increase in cytotoxicity. In contrast, the 2-I and 2-NH2 derivatives were only weakly active against HCMV and HSV-1 with activity not well-separated from cytotoxicity. These data establish that for maximum activity against HCMV with separation from cytotoxicity, ribose is preferred at the 1-position and that Cl or Br is apparently preferred at the 2-position. The activity and selectivity of both TCRB and BDCRB were better than that observed with either ganciclovir or foscarnet.
已合成了一系列新的2-取代5,6-二氯苯并咪唑核糖核苷，并测试了它们对两种人类疱疹病毒的活性和细胞毒性。2,5,6-三氯-1-(β-D-呋喃核糖基)苯并咪唑(TCRB)是通过杂环2,5,6-三氯苯并咪唑的核糖基化反应，然后去除保护基团制备而成。2-溴衍生物(BDCRB)以类似方式由2-溴-5,6-二氯苯并咪唑制备。相比之下，2-碘衍生物存在更棘手的问题，因为合适的杂环无法获得。这促使我们制备2-氨基衍生物，随后进行非水重氮化并去除保护基团。生物学评估揭示了这些化合物与密切相关的已知化合物5,6-二氯-1-(β-D-呋喃核糖基)苯并咪唑(DRB)活性上的显著差异。DRB对人巨细胞病毒(HCMV)和单纯疱疹病毒1型(HSV-1)均表现出较弱活性(IC50分别为42和30 microM)，但在相同剂量范围内对未感染的人包皮成纤维细胞和KB细胞具有细胞毒性。用杂环2,5,6-三氯苯并咪唑也得到了类似结果。与之形成鲜明对比的是，2,5,6-三氯苯并咪唑的核糖核苷(TCRB)对HCMV有活性(IC50 = 2.9 microM，蚀斑试验；IC90 = 1.4 microM，产量试验)，但对HSV-1仅表现出较弱活性(IC50 = 102 microM，蚀斑试验)。在浓度高达100 microM时，在HFF和KB细胞中几乎未观察到细胞毒性。通过将2-位的取代基从氯变为溴(BDCRB)，观察到对HCMV的活性增加了4倍，且细胞毒性没有任何显著增加。相比之下，2-I和2-NH2衍生物对HCMV和HSV-1仅表现出较弱活性，其活性与细胞毒性没有很好地分离。这些数据表明，为了在与细胞毒性分离的情况下对HCMV具有最大活性，1-位优选核糖，2-位显然优选Cl或Br。TCRB和BDCRB的活性和选择性均优于更昔洛韦或膦甲酸钠。
