From Oxetane to Thietane: Extending the Antiviral Spectrum of 2′-Spirocyclic Uridines by Substituting Oxygen with Sulfur

Abstract

In continuation of our efforts of finding novel nucleoside inhibitors for the treatment of viral diseases, we initiated a discovery research program aimed at identifying novel nucleos­(t)­ide inhibitors for emerging diseases like Dengue and Chikungunya. Based on the previously reported 2′-spiro-oxetane uridine derivatives active against Hepatitis C Virus (HCV), we envisaged its sulfur analogue as an interesting congener both from a synthetic as well as biological point of view. Surprisingly, we found the 2′-spirothietane uridine derivatives not only to be active against HCV and Dengue virus (DENV), viruses belonging to the flavivirus family, but also to demonstrate activity against alphaviruses like Chikungunya virus (CHIKV) and Sindbis virus (SINV).

Oxetanes in Drug Discovery Campaigns

“… (a) Examples of bioactive four-membered heterocycles. 8 (b) Appearance of four-membered heterocycles in the literature. 9 (Left) Absolute number of publications.…”