Modified nucleosides represent the cornerstone of antiviral chemotherapy. Their progressive development over the last 50 years permitted to contain many epidemics and provided effective treatments against many viruses such as herpes, hepatitis or HIV. However, viral infections remain a major public health problem due to the emergence of resistant strains to existing treatments and the appearance of new viruses. As such, the development of new antivirals, most active and safer and/or acting through alternative mechanisms remains, more than ever, necessary. In this context, the work presented in this manuscript are part of the effort to design and synthesize new molecules with antiviral activities. This manuscript, divided in two parts, firstly focus on the metallo-catalyzed synthesis of new families of nucleoside derivatives (acyclic and osidic) and continue with the synthesis of heterocyclic structures targeting anti-HIV activity. Thus, the use of Ru-catalyzed metathesis reactions under ultrasonic activation and the lipases-catalyzed regioselective protection/deprotection reactions allowed us to develop two new families of alkenyl acyclic nucleosides. The synthesis and antiviral evaluation of C5-(1,3-diyne)-2'-deoxyuridine derivatives, prepared by Ni/Cu-mediated alkyne C-H heterocoupling reaction, are also described. In the second part, the multicomponent Biginelli reaction has been used to develop a series of dihydropyrimidine derivatives bearing a β-diketoacids unit targeting anti-HIV activity by inhibition of the viral integrase.
