ACYCLIC NUCLEOSIDE/NUCLEOTIDE ANALOGUES WITH AN IMIDAZOLE RING SKELETON

Abstract

Syntheses of a few acyclic nucleoside and acyclic nucleoside phosphonate analogues containing an imidazole ring have been reported. These analogues include methyl 1-(2-hydroxyethoxymethyl)imidazole-4,5-dicarbo-xylate (1), 4,5-dicarbamoyl-1-(2-hydroxyethoxymethyl)imidazole (2), 4,5-dicya-no-1-(2-hydroxyethoxymethyl)imidazole (4), Methyl 1-(2-bromoethoxymethyl)- imidazole-4,5-dicarboxylate (7), 4,5-dicyano-(2-bromoethoxymethyl)imidazole (8), and Methyl 1-(2-phosphonomethoxyethyl)imidazole (10). Also reported are a few potential prodrugs of the above compounds, including the acetyl derivatives 5 and 6 (of 1 and 4, respectively), and the diethyl phosphonate ester 9 (of 10). In addition, the corresponding benzyl-protected precursors 11 and 12 (of 1 and 4, respectively), along with their common hydrolysis product, 1-(2-benzyloxy-ethoxymethyl)-4,5-imidazoledicarboxylic acid (3), are reported. Another potential prodrug included in the list is 1-(2-acetoxyethyl)-4,5-dicyanoimidazole (15). The compounds were screened for in vitro antiviral activity against a wide variety of herpes and respiratory viruses. The most active compound was the phosphonate analogue 9 which exhibited an anti-measles virus activity with an EC₅₀ of <2.5 μg/mL and an SI value of > 176.

ACKNOWLEDGMENTS

This research was supported by a grant from the National Institutes of Health (# 1RO1CA71079). Mass spectral data were run at the Michigan State University Mass Spectrometry Facility which was supported, in part, by a grant (DRR-00480) from the Biotechnology Research Technology Program, National Center for Research Resources, National Institutes of Health. The authors gratefully acknowledge Dr. Chris Tseng of NIAID, Dr. Earl Kern of the University of Alabama, Birmingham, and Drs. Robert Sidwell, Dale Barnard, and D. Smee of the Utah State University, Logan. for all the antiviral screening results reported in this paper, and described in reference [44].