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

Abstract

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 (EC50 = 1.81 ± 0.09 μM against Dd2 parasites; EC50 > 40 μM against HepG2 cells) and established structure–activity relationships for 25 related analogues. New analogue 30 (V3ss, Dd2, EC50 = 0.25 ± 0.004 μM; HepG2, EC50 > 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.

Biannual Account of Anti‐malarial Agents reported in 2021 and 2022: A Comprehensive Coverage

“…By re‐engineering and ring distortion of vincamine leads, Norwood and co‐workers identified indole derivative ( 83 ) as an anti‐plasmodial agent with EC 50 of 0.25±0.004 μM with the least cytotoxicity (EC 50 >25 μM) against hepg2 cell lines [100] . Further, compound 83 was revealed to act on trophozoite and schizont stage and can kill pf dd2 in less than a day as evident from the kill kinetics study.…”

Recent ring distortion reactions for diversifying complex natural products

“…10). [58][59][60] Tochtrop and coworkers presented an iterative allylic oxidation/oxidative cleavage to produce transannular polyketones, followed by the aldol addition reactions to form distinct molecular skeletons for remodeling a triterpenoid skeleton (Fig. 11).…”