Periodic outbreaks of dengue viral fever is a significant burden on global health, and the absence of broadly effective vaccines underscores the need for small‐molecule antivirals that target host pathways essential for virus replication. One such opportunity lies in inhibiting endoplasmic reticulum α‐glucosidases I and II, key enzymes required for the proper folding of viral glycoproteins. Guided by this concept, we report a concise and stereodivergent synthesis of iminosugar architectures, inspired by glycosidase inhibitors and their antiviral reports. d ‐glucose‐derived HWE product was strategically transformed via β‐azidation, double reductive amination, and intramolecular cyclization, enabling access to both 2( R )‐ and 2( S )‐azido indolizidines as advanced intermediates for diversification. The structural diversification yielded amino‐, amido‐, and triazolyl‐functionalized polyhydroxy indolizidine scaffolds related to castanospermine and swainsonine, along with two new iminononulols. These densely functionalized iminosugars were screened for anti‐dengue virus activity. Cytotoxicity screening showed that most castanospermine derivatives were well tolerated in BHK‐21 cells. Though most iminosugar derivatives did not exhibit significantly more antiviral efficacy than castanospermine in plaque reduction assays, compounds 16 and 22 displayed comparable activity. Our study describes a tunable approach for generating novel scaffolds for antiviral development against the dengue virus.
Ingaladal et al. (Sun,) studied this question.