Synthesis and Evaluation of 9-Aminoacridines with SARS-CoV-2 Antiviral Activity
Thane Jones, Natalia Monakhova, Florence Guivel‐Benhassine, Alexander Lepioshkin, Timothée Bruel, Thomas R. Lane, Olivier Schwartz, Ana C. Puhl, Vadim Makarov, Sean Ekins
Abstract
High Resolution Image Download MS PowerPoint Slide 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.