Potent inhibition of NTPase/helicase of the West Nile Virus by ring-expanded (fat) nucleoside analogues

A series of ring-expanded (“fat”) nucleoside analogues (RENs) containing the 6-aminoimidazo[4,5-e][1,3]diazepine-4,8-dione ring system have been synthesized and screened for inhibition of NTPase/helicase of the West Nile Virus (WNV). To assess the selectivity of RENs against the viral enzymes, a truncated form of human enzyme Suv3(Δ1-159) was also included in the study. Ring-expanded nucleosides 16, 17, and 19, which possess the long C12, C14, and C18 side-chains, respectively, at position 6, as well as the ring-expanded heterocycle 39, which contains aralkyl substitution at position 1, were all found to have excellent profiles of activity and selectivity toward the viral versus human enzymes against the West Nile Virus (IC50 ranging 1−10 μM). Compound 30, while being an equally potent inhibitor of WNV, was found to be somewhat less selective, whereas compound 36, which is an α-anomeric counterpart of 30, exhibited potent and selective inhibition of WNV (IC50 1−3 μM). The same compounds that showed potent...