A novel series of uracil derivatives with a 3,5-dimethylbenzyl group at the N3-position were synthesized and evaluated as non-nucleoside HIV-1 reverse transcriptase inhibitors. Some of these compounds showed good-to-moderate activity with EC50 values in the submicromolar range. Among them, compound 10c showed significant potency against HIV-1 activity with an EC50 value of 0.03 μM and a high selectivity index of 2863. Preliminary structure–activity relationships and molecular modeling analyses were used to explore the major interactions between HIV-1 reverse transcriptase and the potent inhibitor 10c, which may serve as an important lead for further optimization.

On the basis of our previous study on antiviral agents against the severe acute respiratory syndrome (SARS) coronavirus, a series of nucleoside analogues whose 5′-hydroxyl groups are masked by various protective groups such as carboxylate, sulfonate, and ether were synthesized and evaluated to develop novel anti-hepatitis C virus (HCV) agents. Among these, several 5′-O-masked analogues of 6-chloropurine-2′-deoxyriboside (e.g., 5′-O-benzoyl, 5′-O-p-methoxybenzoyl, and 5′-O-benzyl analogues) were found to exhibit effective anti-HCV activity. In particular, the 5′-O-benzoyl analogue exhibited the highest potency with an EC50 of 6.1 μM in a cell-based HCV replicon assay. Since the 5′-O-unmasked analogue (i.e., 6-chloropurine-2′-deoxyriboside) was not sufficiently potent (EC50 = 47.2 μM), masking of the 5′-hydroxyl group seems to be an effective method for the development of anti-HCV agents. Presently, we hypothesize two roles for the 5′-O-masked analogues: One is the role as an anti-HCV agent by itself, and the other is as a prodrug of its 5′-O-demasked (deprotected) derivative.

Nucleoside analogues that have 6-chloropurine as the nucleobase were synthesized and evaluated for anti-SARS-CoV activity by plaque reduction and yield reduction assays in order to develop novel anti-SARS-CoV agents. Among these analogues, two compounds, namely, 1 and 11, exhibited promising anti-SARS-CoV activity that was comparable to those of mizoribine and ribavirin, which are known anti-SARS-CoV agents. Moreover, we observed several SAR trends such as the antiviral effects of the 6-chloropurine moiety, unprotected 5′-hydroxyl group and benzoylated 5′-hydroxyl group.