Design and synthesis of 2-substituted analogs of 2,5,6-trichloro-1-(beta-D-ribofuranosyl)benzimidazole and related imidazo(4,5-b)pyridine nucleosides as potential antiviral agents for the treatment of human cytomegalovirus infections.

Human cytomegalovirus (HCMV) is a leading opportunistic virus causing morbidity and mortality among immunosuppressed individuals. A new agent, 2,5,6-trichloro-l-($\beta$-D-ribofuranosyl)benzimidazole (TCRB), has demonstrated promising activity against HCMV in vitro. Our studies were directed at modifying the chemical structure of TCRB in an effort to understand the mode of action of this compound and to synthesize an analog that was more selective. It was apparent that the substituent at the 2-position was important in determining the compound's activity, selectivity, and cytotoxicity. We therefore synthesized TCRB analogs with different types of substituents at this position. The evaluation of various 2-alkylthio, 2-alkylamino, 2-alkoxy, 2-alkyl, and 2-halogeno TCRB analogs identified 2-bromo-5,6-dichloro-l-($\beta$-D-ribofuranosyl)benzimidazole (BDCRB) as a compound that was more selective than TCRB against HCMV. The leaving-group potential of the halogen at the 2-position and the reactive potential at the 2-position of the benzimidazole ring were thought to contribute to the antiviral activity of TCRB and BDCRB. This hypothesis was studied by synthesizing imidazo(4,5-$b\rbrack$pyridine analogs of BDCRB which were designed to be more reactive at the 2-position. These imidazo(4,5-$b\rbrack$pyridine analogs were found to be toxic in human cells, indicating that reactivity at the 2-position was associated with cytotoxicity. We investigated the possible activation of TCRB at the $5\prime$-hydroxyl moiety by preparing $5\prime$-deoxy TCRB, a compound that cannot be phosphorylated at the $5\prime$-position. $5\prime$-Deoxy TCRB was found to be approximately ten-fold more potent than TCRB against HCMV. These results strongly suggest that phosphorylation of TCRB is not necessary for antiviral activity. Based on our results, we have begun to develop important structure-activity relationships for TCRB and its analogs.PhDMedicinal ChemistryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/104896/1/9611035.pdfDescription of 9611035.pdf : Restricted to UM users only