•Compound ZBMA-1 was identified as an anti-HIV-1 replication agent (IC50=1.01μM) with low toxicity (CC50>25μM).•Compound ZBMA-1 efficiently protected APOBEC3G from degradation by HIV-1 Vif protein in 293T cells.•Compound ZBMA-1intterupted the binding of Elongin C with Vif protein in Vif–APOBEC3G complex. HIV-1 Vif protein is one of the most crucial accessory proteins for viral replication. It efficiently counteracts the important host restriction factor APOBEC3G (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G, A3G) which is lethal to HIV-1 by causing G to A mutation of viral genome. Vif protein mediates degradation of APOBEC3G via the complicated protein–protein interactions of Vif, APOBEC3G, Elongin C/B and Cullin 5. The importance of Vif–APOBEC3G complex makes it a good potential target to develop new therapeutics of HIV-1. We identified a potent HIV-1 replication inhibitor (ZBMA-1, IC50=1.01μM) that efficiently protected APOBEC3G protein by targeting Vif–APOBEC3G complex. The co-immunoprecipitation and docking studies indicated that compound ZBMA-1 affected the binding of Elongin C with Vif protein.