Ring Distortion of Vincamine Leads to the Identification of Re-Engineered Antiplasmodial Agents

[Image: see text] There is a significant need for new agents to combat malaria, which resulted in ∼409,000 deaths globally in 2019. We utilized a ring distortion strategy to create complex and diverse compounds from vincamine with the goal of discovering molecules with re-engineered biological activities. We found compound 8 (V3b) to target chloroquine-resistant Plasmodium falciparum Dd2 parasites (EC(50) = 1.81 ± 0.09 μM against Dd2 parasites; EC(50) > 40 μM against HepG2 cells) and established structure–activity relationships for 25 related analogues. New analogue 30 (V3ss, Dd2, EC(50) = 0.25 ± 0.004 μM; HepG2, EC(50) > 25 μM) was found to demonstrate the most potent activity, which prevents exit on the parasite from the schizont stage of intraerythrocytic development and requires >24 h to kill P. falciparum Dd2 cells. These findings demonstrate the potential that vincamine ring distortion has toward the discovery of novel antimalarial agents and other therapies significant to human health.