Acyclovir (ACV) is an acyclic guanine nucleoside analogue used in the treatment of herpes simplex virus (HSV) and varicella zoster virus (VZV) infections. The human herpes virus-encoded thymidine kinase (HHV-TK) phosphorylates ACV generating ACV monophosphate, which is then converted to the active form ACV triphosphate by cellular kinases. The ProTide approach, causing the direct release of the monophosphate form into the cell, allows bypass of the first phosphorylation step of nucleoside analogues. In previous studies acyclovir ProTides were found to be active in vitro against human immunodeficiency virus (HIV), demonstrating a successful release of ACV monophosphate into the cell. In this work, an extensive study of structure-activity relationship was carried out varying the masking groups of the ACV ProTide. Subsequently, several substituents were considered on specific position of the guanine base and side chain of ACV resulting in the synthesis of the aryl phosphoramidate derivatives of ganciclovir, penciclovir, 6-O-alkyl acyclovir, 8-bromoacyclovir, and 8- methylacyclovir. These derivatives were evaluated in vitro for their antiviral activity against HSV, VZV, human cytomegalovirus (HCMV), and HIV. Enzymatic and molecular modeling studies were carried out in order to investigate the bioactivaton of the phosphoramidate derivatives synthesised in this work and correlate these results with their biological activity. Finally, the ProTide approach was also applied to cidofovir resulting in the formation of the phosphonoamidate derivative of cyclic cidofovir. The in vitro antiviral activity of this compound against herpes viruses and poxviruses is reported, as well as investigation of the mechanism of activation, using enzymatic and molecular modeling studies.EThOS - Electronic Theses Online ServiceGBUnited Kingdo