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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-resistan Plasmodium falciparum Dd2 parasites (EC 50 = 1.81 ± 0.09 μM against Dd2 parasites; EC 50 &gt; 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 &gt; 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 &gt;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.

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