There have been relatively few small molecules developed with direct activity against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Two existing antimalarial drugs, pyronaridine and quinacrine, display whole cell activity against SARS-CoV-2 in A549 + ACE2 cells (pretreatment, IC 50 = 0.23 and 0.19 μM, respectively) with moderate cytotoxicity (CC 50 = 11.53 and 9.24 μM, respectively). Moreover, pyronaridine displays in vitro activity against SARS-CoV-2 PL pro (IC 50 = 1.8 μM). Given their existing antiviral activity, these compounds are strong candidates for repurposing against COVID-19 and prompt us to study the structure-activity relationship of the 9-aminoacridine scaffold against SARS-CoV-2 using traditional medicinal chemistry to identify promising new analogs. Our studies identified several novel analogs possessing potent in vitro activity in U2-OS ACE2 GFP 1-10 and 1-11 (IC 50 < 1.0 μM) as well as moderate cytotoxicity (CC 50 > 4.0 μM). Compounds such as 7g, 9c, and 7e were more active, demonstrating selectivity indices SI > 10, and 9c displayed the strongest activity (IC 50 ≤ 0.42 μM, CC 50 ≥ 4.41 μM, SI > 10) among them, indicating that it has potential as a new lead molecule in this series against COVID-19.