DESIGN, SYNTHESIS, AND ANTIVIRAL EVALUATION OF RO-5,6-DIHALO-1-BETA-D-RIBOFURANOSYLBENZIMIDAZOLES AS POTENTIAL AGENTS FOR HUMAN CYTOMEGALOVIRUS INFECTIONS

2-Chloro-5,6-difluorobenzimidazole (8) was prepared from 4,5-difluoro- 2-nitroaniline (5) via successive reduction, cyclization, and diazotiz ation reactions. 2-Chloro-5,6-dibromobenzimidazole (10) was obtained b y 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-dinitrobenzimida zole (11) into iodo groups via diazotization reactions. Ribosylation o f 8, 10, and 15 gave the respective beta nucleosides 16a-c as the majo r products along with a small amount of the alpha anomers 17a-c. Depro tection of 16a-c afforded the corresponding free beta nucleo sides o-5 ,6-difluoro-1-beta-D-ribofuranosylbenzimidazole (2), ro-5,D-dibromo-1- beta-D-ribofuranosylbenzimidazole (3), and oro-5,6-diiodo-1-beta-D-rib ofuranosylbenzimidazole (4). Similar deprotection of the alpha anomers (17a-c) resulted in a removal of the acetyl protecting groups and a c oncomitant cyclization to give the 2,2'-O-cyclonucleosides (18a-c). Mo st of the benzimidazole heterocycles, but not the difluoro analog, wer e active against human cytomegalovirus (HCMV) (IC50's = 3-40 mu M) and herpes simplex virus type 1 (HSV-1) (IC50's = 50-90 mu M). This activ ity, however, was not well separated from cytotoxicity, IC50's = 10-10 0 mu M. 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-trichl oro analog (TCRB), the 5,6-dibromo ribonucleoside 3 was active against HCMV (IC50 approximate to 4 mu M) but more cytotoxic than TCRB. The 5 ,6-diiodo analog 4 also was active (IC50 approximate to 2 mu M) but mo re cytotoxic (IC50 = 10-20 mu M) than either 3 or TCRB. The cyclonucle osides were inactive against both viruses and not cytotoxic, or slight ly active with corresponding cytotoxicity. The order of activity again st HCMV of the dihalobenzimidazole ribonucleosides was I similar or eq ual to Br similar or equal to Cl much greater than F > H = CH3. The or der of cytotoxicity among the most active compounds, however, was I > Br > Cl, thereby establishing that TCRB had the best antiviral propert ies.