Synthesis and evaluation of thionucleoside analogues against enteric RNA viruses

Thionucleosides are analogues of nucleosides in which one or more oxygen atoms are replaced by sulphur atoms. They are variants of nucleosides, compounds that form DNA and RNA. The substitution of oxygen with sulphur makes thionucleosides more resistant to chemical degradation and degradation by enzymes such as nucleases, glycosidases, and phosphorylases. In the literature, there are key examples of nucleoside analogues (NAs) with considerable potential for the treatment and prevention of a wide range of viral diseases. One notable example is 2'-deoxyuridine, the first nucleoside analogue approved for the treatment of herpes simplex virus (HSV), followed by Ribavirin, used against various RNA viruses such as hepatitis C, influenza A viruses, and respiratory syncytial virus. Additionally, acyclic nucleosides like aciclovir and ganciclovir are used for HSV and cytomegalovirus infections, respectively. Sulphur is similar to oxygen, as they are adjacent elements in the periodic table, but sulphur is larger and less electronegative. It also forms a range of bond types depending on the different oxidation states. The bond between carbon and sulphur is longer and less polar than the carbon-oxygen bond. Due to these characteristics, sulphur-containing molecules hold particular interest in organic and medicinal chemistry. Two classes of natural thiosugars, thioglycosides and 1,4-thioanhydrosugars, are found in nature. In addition, synthetic thionucleosides have been studied and developed in recent years. Among these, 4'-thioamymidine has shown activity against HSV and cytomegalovirus, while 5-substituted 4'-thioarauracil derivatives have demonstrated anti-HSV activity. Notably, 6-thio-2'-deoxyguanosine is currently in clinical trials for the treatment of small cell lung cancer. As part of a larger research project, the focus is on investigating antiviral activities resulting from structural modifications in the sugar unit, particularly against norovirus, a single-stranded positive RNA virus for which there is currently no specific treatment or vaccine. Currently, norovirus prevention relies on hygiene measures, highlighting the need for novel therapeutic approaches. The goal of this thesis is to identify modified nucleoside candidates with potential antiviral activity. The project begins with the synthesis of the modified sugar unit, followed by its combination with various modified nitrogenous bases. The synthesized analogues will be evaluated for their antiviral properties, contributing valuable knowledge for future applications in medicinal chemistry.