BACKGROUND Although a number of agents can achieve high response in acquired immunodeficiency syndrome (AIDS) patients, safer and more active HIV inhibitors are still needed for the growing number of patients infected with resistant HIV virus strains. GW678248, is one of the most potent benzophenone derivatives, exhibiting high potency against a panel of HIV-1 virus (wild-type, K103N mutant, Y181C, etc.) at 1 nM/L concentrations. However, the safety issues associated with rash and liver metabolic enzymes ultimately led to discontinue its further development. As a continuation of our structural modifications on this template, in this manuscript, a new series of benzophenones are described as potential HIV inhibitors. METHODS All the title molecules were synthesized according to the routes in scheme 1 and scheme 2, and were tested for anti-HIV-1 activity using the MTT method. In the molecular simulation, the docking program of AutoDock 4.0.1 in parallel with the default parameters were used. RESULTS A series of novel benzophenone derivatives (BPs) with nanomolar anti-HIV-1 activity was identified. Of these inhibitors, analogue 10i (EC50 = 2.9 nmol/L), the most active inhibitor, was comparable to the lead compound in inhibiting the wild-type HIV-1 virus. Additionally, analogue 13b, which not only exhibited strong inhibitory activity against the HIV-1 virus (EC50 = 4.2 nmol/L), but also has very low cytotoxicity with a TI value of more than 219178.1 was also discovered. CONCLUSIONS This study led to the identification of a series of benzophenone derivatives with nanomolar level of anti-HIV-1 activity. Analogue 10i and analogue 13b, with low cytotoxicity along with high activity are worthy of further development.