Zou R, Drach J C, Townsend L B
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor 48109-1065, USA.
J Med Chem. 1997 Feb 28;40(5):802-10. doi: 10.1021/jm960533b.
The syntheses of 2,4,6-trichlorobenzimidazole (4a) and 2-bromo-4,6-dichlorobenzimidazole (4b) were accomplished via the 2-amino intermediate (3) using a mild diazotization procedure. Ribosylation of 4a and 4b and subsequent deprotection afforded the corresponding 2,4,6-trichloro-1-beta-D-ribofuranosylbenzimidazole (7a) and 2-bromo-4,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (7b). The 2-azido (10), 2-amino (11), 2-thione (13), 2-methylthio (14a), and 2-benzylthio (14b) derivatives were prepared via displacement reactions at the 2-position of the 2,3,5-tri-O-acetyl derivative of 7a. 2,4,5-Trichlorobenzimidazole (17a) and 2-bromo-4,5-dichlorobenzimidazole (17b) were synthesized from the corresponding 1,2-phenylenediamines via successive cyclization with cyanogen bromide and diazotization in the presence of an appropriate cupric halide. Ribosylation of compounds 17a and 17b was followed by deprotection to afford 2,4,5-trichloro-1-beta-D-ribofuranosylbenzimidazole (20a), and 2-bromo-4,5-dichloro-1-beta-D-ribofuranosylbenzimidazole (20b). Heterocycles (3, 4a, 17a) and nucleosides (7a, b, 8, 10, 11, 13, 14a,b, 20a,b) were evaluated for activity against human cytomegalovirus (HCMV) and herpes simplex virus type 1 (HSV-1) and for cytotoxicity. The 2-chloro but not the 2-amino heterocycles were active against HCMV (IC50's = 5-8 microM) but not HSV-1; both also were somewhat cytotoxic to uninfected cells (IC50's = 32-100 microM). Among the nucleosides, the 2-chloro and 2-bromo analogs in both the 4,5- and 4,6-dichloro series (20a,b, 7a,b, respectively) were active against HCMV (IC50's = 1-10 microM) and noncytotoxic in their antiviral dose ranges. The 2-bromo compounds were more active than the 2-chloro analogs; the 2-azido and 2-thiobenzyl analogs (10, 14b) were weakly active against HCMV, but this activity was not well separated from cytotoxicity. None of the nucleosides were active against HSV-1. This pattern of activity and cytotoxicity is similar to that of the 2-chloro- and 2-bromo-5,6-dichloro analogs (TCRB, BDCRB) which we reported previously. Although these new 4,5- and 4,6-dichloro analogs are potent and selective inhibitors of HCMV, they are not as potent at TCRB and BDCRB.
通过温和的重氮化程序，利用2-氨基中间体（3）完成了2,4,6-三氯苯并咪唑（4a）和2-溴-4,6-二氯苯并咪唑（4b）的合成。4a和4b的核糖基化反应以及随后的脱保护反应得到了相应的2,4,6-三氯-1-β-D-呋喃核糖基苯并咪唑（7a）和2-溴-4,6-二氯-1-β-D-呋喃核糖基苯并咪唑（7b）。2-叠氮基（10）、2-氨基（11）、2-硫酮（13）、2-甲硫基（14a）和2-苄硫基（14b）衍生物是通过7a的2,3,5-三-O-乙酰基衍生物2位上的取代反应制备的。2,4,5-三氯苯并咪唑（17a）和2-溴-4,5-二氯苯并咪唑（17b）是由相应的1,2-苯二胺在适当的卤化铜存在下，通过与溴化氰连续环化和重氮化反应合成的。化合物17a和17b的核糖基化反应之后进行脱保护反应，得到2,4,5-三氯-1-β-D-呋喃核糖基苯并咪唑（20a）和2-溴-4,5-二氯-1-β-D-呋喃核糖基苯并咪唑（20b）。对杂环化合物（3、4a、17a）和核苷（7a、b、8、10、11、13、14a、b、20a、b）进行了抗人巨细胞病毒（HCMV）和1型单纯疱疹病毒（HSV-1）活性以及细胞毒性评估。2-氯代杂环化合物而非2-氨基杂环化合物对HCMV有活性（IC50 = 5 - 8 μM），但对HSV-1无活性；两者对未感染细胞也都有一定细胞毒性（IC50 = 32 - 100 μM）。在核苷中，4,5-二氯系列和4,6-二氯系列中的2-氯代和2-溴代类似物（分别为20a、b和7a、b）对HCMV有活性（IC50 = 1 - 10 μM），且在抗病毒剂量范围内无细胞毒性。2-溴代化合物比2-氯代类似物活性更强；2-叠氮基和2-硫代苄基类似物（10、14b）对HCMV活性较弱，但其活性与细胞毒性区分不明显。这些核苷均对HSV-1无活性。这种活性和细胞毒性模式与我们之前报道的2-氯代和2-溴代-5,6-二氯类似物（TCRB、BDCRB）相似。尽管这些新的4,5-和4,6-二氯类似物是HCMV的强效和选择性抑制剂，但它们的效力不如TCRB和BDCRB。
