Design, synthesis and biological evaluation of anti-HIV-1 Vif inhibitors based on prodrug strategy

In this work, we describe the design, synthesis, and biological evaluation of a series of novel dual-target prodrugs that simultaneously target HIV-1 viral infection factors (Vif) and reverse transcriptase (RT). Among them, the two most effective compounds, A1 and A7, were found to inhibit HIV-1IIIB at nanomolar concentrations (EC₅₀ = 8.1 nM, EC₅₀ = 9.4 nM) in C8166 cells, which were 95 and 81 times higher than the parent drug 6 m, respectively, and 2.7 and 2.3 times higher than that of stavudine (d4T). The stability of compound A1 in the medium suggests that it can effectively release the parent drugs 6 m and stavudine with a half-life of 6 h, suggesting that it is a potential dual-target prodrug targeting HIV Vif and reverse transcriptase.