A Heterocyclic Molecule with Significant Activity Against Dengue Virus

Abstract

The etiological agents of dengue fever (DF) and dengue hemorrhagic fever (DHF) are four closely related dengue viruses, which are antigenically similar but immunologically distinct serotypes of the family called Flavivirus.1–3 The major vector for these viruses is the mosquito, Aedes aegypti. Estimates make the number of cases of dengue fever as high as 100 million annually, which makes this arthropod-borne viral infection a serious global health problem.4 Dengue virus genome is a single, positive-stranded RNA of about 11 kD with a 5′-cap but without a polyadenylated terminus. After fusion and entry, translation of genomic RNA occurs in infected cells.1,3 Processing of the viral polyprotein is apparently catalyzed by both viral and cellular enzymes. NS proteins are involved in the replication cycle. For example, the NS3 viral protease protein is essential for viral replication.5 The NS5 conserved protein has a methyltransferase motif in the N-terminal domain and an RNA-dependent RNA polymerase in the C-terminal domain. The transferase and polymerase are possible viral targets in antiviral strategies.5–7 However, there are no specific approved drugs or vaccines for the treatment or prevention of DF and DHF. This communication reports on the synthesis and antiviral activity of a novel, uracil-based multifunctional compound, 1, which is a potent inhibitor of the replication of dengue virus. In contrast, its deaza analog, 2, was inactive against this flavivirus (Figure 1). Figure 1 Structures of target compounds