Background: We have previously reported that a quinolizidine natural product, aloperine, and its analogs can inhibit influenza virus and/or HIV-1 at low μM concentrations. Objective: The main goal of this study was to further optimize aloperine for improved anti-influenza virus activity. Methods: Structural modifications have been focused on the N12 position of aloperine scaffold. Conventional chemical synthesis was used to obtain derivatives with improved antiviral activities. The anti-HIV and anti-influenza virus activities of the synthesized compounds were determined using an MT4 cell-based HIV-1 replication assay and an anti- influenza virus infection of MDCK cell assay, respectively. Results: Aloperine derivatives can be classified into three activity groups: those that exhibit anti-HIV activity only, anti–influenza virus only, or activity against both viruses. Aloperine optimized for potent anti-influenza activity often lost anti-HIV-1 activity, and vice versa. Compound 19 inhibited influenza virus PR8 replication with an IC50 of 0.091 μM, which is approximately 160- and 60-fold more potent than aloperine and the previously reported aloperine derivative compound 3, respectively. Conclusion: The data suggest that aloperine is a privileged scaffold that can be modified to become a selective antiviral compound with markedly improved potency against influenza virus or HIV-1.