SYNTHESIS AND ANTIVIRAL ACTIVITY OF CERTAIN 5'-MODIFIED ANALOGS OF ,6-TRICHLORO-1-(BETA-D-RIBOFURANOSYL)BENZIMIDAZOLE

A series of 5'-modified 2,5,6-trichlorobenzimidazole ribonucleosides h as been synthesized and tested for activity against two human herpesvi ruses and for cytotoxicity. The 5'-methoxy, 5'-ethoxy, and 5'-butoxy a nalogs of ,6-trichloro-1-(beta-D-ribofuranosyl)benzimidazole (TCRB) we re prepared by coupling the appropriate 5-O-alkyl-1,2,3-tri-O-acetyl-b eta-D-ribose derivatives with 2,5,6-trichlorobenzimidazole followed by removal of the protecting groups. The 5'-deoxy-5'-fluoro, -5'-chloro, -5'-bromo, -5'-iodo, -5'-azido, and -5'-thiomethyl derivatives were s ynthesized in a similar fashion. All of these 5'-modified derivatives had significant activity against HCMV in plaque and yield reduction as says (IC50's = 0.5-14.2 mu M) but had little activity (IC50's > 100 mu M) against HSV-1. This pattern is similar to the antiviral activity p rofile observed for TCRB. The 5'-halogenated derivatives were more act ive than the other 5'-modified derivatives with antiviral activity wel l separated from cytotoxicity. In general, cytotoxicity of all the 5'- modified derivatives was greater in human foreskin fibroblasts (HFF ce lls) than in L1210 or K-B tumor cells. These results indicate that the viral target tolerates significant modifications of TCRB at the 5'-po sition without adversely affecting activity against HCMV, whereas the 5'-modifications increased cytotoxicity in human diploid cells.