2-5-6-trichloro-1-(ribofuranosyl)benzimidazole and Cytomegalovirus-Infections

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.

Topics: Antiviral Agents; Benzimidazoles; Cell Division; Cell Line; Cytomegalovirus; Cytomegalovirus Infections; Drug Design; Humans; Magnetic Resonance Spectroscopy; Molecular Structure; Ribonucleosides; Simplexvirus

2-Chloro-5,6-difluorobenzimidazole (8) was prepared from 4,5-difluoro-2-nitroaniline (5) via successive reduction, cyclization, and diazotization reactions. 2-Chloro-5,6-dibromobenzimidazole (10) was obtained by a direct bromination of 2-chlorobenzimidazole (9) with bromine-water. 2-Chloro-5,6-diiodobenzimidazole (15) was synthesized by a stepwise transformation of the nitro functions of 2-chloro-5,6-dinitrobenzimidazole (11) into iodo groups via diazotization reactions. Ribosylation of 8, 10, and 15 gave the respective beta nucleosides 16a-c as the major products along with a small amount of the alpha anomers 17a-c. Deprotection of 16a-c afforded the corresponding free beta nucleosides 2-chloro-5,6-difluoro-1-beta-D-ribofuranosylbenzimidazole (2), 2-chloro-5,6-dibromo-1-beta-D-ribofuranosylbenzimidazole (3), and 2-chloro-5,6-diiodo-1-beta-D-ribofuranosylbenzimidazole (4). Similar deprotection of the alpha anomers (17a-c) resulted in a removal of the acetyl protecting groups and a concomitant cyclization to give the 2,2'-O-cyclonucleosides (18a-c). Most of the benzimidazole heterocycles, but not the difluoro analog, were active against human cytomegalovirus (HCMV) (IC50's = 3-40 microM) and herpes simplex virus type 1 (HSV-1) (IC50's = 50-90 microM). This activity, however, was not well separated from cytotoxicity, IC50's = 10-100 microM. The corresponding unsubstituted, the 5,6-dimethyl, and the 5,6-difluoro ribonucleosides (19, 20, and 2, respectively), were inactive against both viruses. Similar to the previously reported 2,5,6-trichloro analog (TCRB), the 5,6-dibromo ribonucleoside 3 was active against HCMV (IC50 approximately 4 microM) but more cytotoxic than TCRB. The 5,6-diiodo analog 4 also was active (IC50 approximately 2 microM) but more cytotoxic (IC50 = 10-20 microM) than either 3 or TCRB. The cyclonucleosides were inactive against both viruses and not cytotoxic, or slightly active with corresponding cytotoxicity. The order of activity against HCMV of the dihalobenzimidazole ribonucleosides was I approximately equal to Br approximately equal to CI > > F > H = CH3. The order of cytotoxicity among the most active compounds, however, was I > Br > Cl, thereby establishing that TCRB had the best antiviral properties.

Topics: Antiviral Agents; Benzimidazoles; Cell Division; Cell Line; Cytomegalovirus; Cytomegalovirus Infections; Drug Design; Humans; KB Cells; Magnetic Resonance Spectroscopy; Molecular Structure; Ribonucleosides; Simplexvirus